AIM: To investigate the effects of Annexin A2 (ANXA2) silencing on invasion, migration, and tumorigenic potential of hepatoma cells. METHODS: Human hepatoma cell lines [HepG2, SMMC-7721, SMMC-7402, and MHCC97-H, a nov...AIM: To investigate the effects of Annexin A2 (ANXA2) silencing on invasion, migration, and tumorigenic potential of hepatoma cells. METHODS: Human hepatoma cell lines [HepG2, SMMC-7721, SMMC-7402, and MHCC97-H, a novel human hepatocellular carcinoma (HCC) cell line with high metastasis potential] and a normal hepatocyte cell line(LO2) were used in this study. The protein and mRNA expression levels of ANXA2 were analysed by western blotting and real-time polymerase chain reaction, re-spectively. The intracellular distribution profile of ANXA2 expression was determined by immunofluorescence and immunohistochemistry. Short hairpin RNA target-ing ANXA2 was designed and stably transfected into MHCC97-H cells. Cells were cultured for in vitro analy-ses or subcutaneously injected as xenografts in mice for in vivo analyses. Effects of ANXA2 silencing on cell growth were assessed by cell counting kit-8 (CCK-8) as-say (in vitro ) and tumour-growth assay (in vivo ), on cell cycling was assessed by flow cytometry and propidium iodide staining (in vitro ), and on invasion and migration potential were assessed by transwell assay and wound-healing assay, respectively (both in vitro ). RESULTS: The MHCC97-H cells, which are known to have high metastasis potential, showed the highest lev-el of ANXA2 expression among the four HCC cell types examined; compared to the LO2 cells, the MHCC97-H expression level was 8-times higher. The ANXA2 expres-sion was effectively inhibited (about 80%) by ANXA2-specific small hairpin RNA (shRNA). ANXA2 expression in the MHCC97-H cells was mainly localized to the cel-lular membrane and cytoplasm, and some localization was detected in the nucleus. Moreover, the proliferation of MHCC97-H cells was obviously suppressed by shR-NA-mediated ANXA2 silencing in vitro , and the tumour growth inhibition rate was 38.24% in vivo . The per-centage of MHCC97-H cells in S phase dramatically de-creased (to 27.76%) under ANXA2-silenced conditions. Furthermore, ANXA2-silenced MHCC97-H cells showed lower invasiveness (percentage of invading cells de-creased to 52.16%) and suppressed migratory capacity (migration distance decreased to 63.49%). It is also worth noting that shRNA-mediated silencing of ANXA2 in the MHCC97-H cells led to abnormal apoptosis. CONCLUSION: shRNA-mediated silencing of ANXA2suppresses the invasion, migration, and tumorigenic potential of hepatoma cells, and may represent a useful target of future molecular therapies.展开更多
AIM:To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma(HCC).METHODS:We used reverse transcription-polymer...AIM:To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma(HCC).METHODS:We used reverse transcription-polymerase chain reaction(RT-PCR),quantitative real-time RT-PCR and western blotting to detect p42.3 mRNA and protein expression in hepatic cell lines.We examined primary HCC samples and matched adjacent normal tissue by immunohistochemistry to investigate the correlation between p42.3 expression and clinicopathological features.HepG2 cells were transfected with a pIRES2EGFP-p42.3 expression vector to examine the function of the p42.3 gene.Transfected cells were analyzed for their viability and malignant transformation abilities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,colony formation assay,and tumorigenicity assay in nude mice.RESULTS:p42.3 is differentially expressed in primary HCC tumors and cell lines.Approximately 69.6%(96/138) of cells were p42.3-positive in hepatic tumor tissues,while 30.7%(35/114) were p42.3-positive in tumor-adjacent normal tissues.Clinicopathological characteristics of the HCC specimens revealed a significant correlation between p42.3 expression and tumor differentiation(P = 0.031).However,p42.3 positivity was not related to tumor tumor-node-metastasis classification,hepatitis B virus status,or hepatoma type.Regarding p42.3 overexpression in stably transfected HepG2 cells,we discovered significant enhancement of cancer cell growth and colony formation in vitro,and significantly enhanced tumorigenicity in nude mice.Western blot analysis of cell cycle proteins revealed that enhanced p42.3 levels promote upregulation of proliferating cell nuclear antigen,cyclin B1 and mitotic arrest deficient 2.CONCLUSION:p42.3 promotes tumorigenicity and tumor growth in HCC and may be a potential target for future clinical cancer therapeutics.展开更多
Colorectal cancer(CRC)is the third most common and the second most fatal cancer.In recent years,more attention has been directed toward the role of gut microbiota in the initiation and development of CRC.Some bacteria...Colorectal cancer(CRC)is the third most common and the second most fatal cancer.In recent years,more attention has been directed toward the role of gut microbiota in the initiation and development of CRC.Some bacterial species,such as Fusobacterium nucleatum,Escherichia coli,Bacteroides fragilis,Enterococcus faecalis,and Salmonella sp.have been associated with CRC,based upon sequencing studies in CRC patients and functional studies in cell culture and animal models.These bacteria can cause host DNA damage by genotoxic substances,including colibactin secreted by pks+Escherichia coli,B.fragilis toxin(BFT)produced by Bacteroides fragilis,and typhoid toxin(TT)from Salmonella.These bacteria can also indirectly promote CRC by influencing host-signaling pathways,such as E-cadherin/β-catenin,TLR4/MYD88/NF-κB,and SMO/RAS/p38 MAPK.Moreover,some of these bacteria can contribute to CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function,creating a proinflammatory environment,or influencing the autophagy process.Treatments with the classical antibacterial drugs,metronidazole or erythromycin,the antibacterial active ingredients,M13@Ag(electrostatically assembled from inorganic silver nanoparticles and the protein capsid of bacteriophage M13),berberine,and zerumbone,were found to inhibit tumorigenic bacteria to different degrees.In this review,we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria,as well as progress in developing effective antibacterial therapies.Specific bacteria have been shown to be active in the oncogenesis and progression of CRC,and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC.These bacteria may be useful as biomarkers or therapeutic targets for CRC.展开更多
BACKGROUND Acute pancreatitis(AP)is an inflammatory disease in which the regulatory pathway is complex and not well understood.Soluble suppression of tumorigenicity 2(sST2)protein receptor functions as a decoy recepto...BACKGROUND Acute pancreatitis(AP)is an inflammatory disease in which the regulatory pathway is complex and not well understood.Soluble suppression of tumorigenicity 2(sST2)protein receptor functions as a decoy receptor for interleukin(IL)-33 to prevent IL-33/suppression of tumorigenicity 2L(ST2L)-pathwaymediated T helper(Th)2 immune responses.AIM To investigate the role of sST2 in AP.METHODS We assessed the association between sST2 and severity of AP in 123 patients enrolled in this study.The serum levels of sST2,C-reactive protein(CRP)and Th1-and Th2-related cytokines,including interferon(IFN)-γ,tumor necrosis factor(TNF)-α,IL-2,IL-4,IL-5 and IL-13,were measured by highly sensitive ELISA,and the severity of AP in patients was evaluated by the 2012 Atlanta Classification Criteria.RESULTS Serum sST2 levels were significantly increased in AP patients,and further,these levels were significantly elevated in severe AP(SAP)patients compared to moderately severe AP(MSAP)and mild AP(MAP)patients.Logistic regression showed sST2 was a predictor of SAP[odds ratio(OR):1.003(1.001–1.006),P=0.000].sST2 cutoff point was 1190 pg/mL,and sST2 above this cutoff was associated with SAP.sST2 was also a predictor of any organ failure and mortality during AP[OR:1.006(1.003–1.009),P=0.000,OR:1.002(1.001–1.004),P=0.012,respectively].Additionally,the Th1-related cytokines IFN-γand TNF-αin the SAP group were higher and the Th2-related cytokine IL-4 in the SAP group was significantly lower than those in MSAP and MAP groups.CONCLUSION sST2 may be used as a novel inflammatory marker in predicting AP severity and may regulate the function and differentiation of IL-33/ST2-mediated Th1 and Th2 Lymphocytes in AP homeostasis.展开更多
BACKGROUND: Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of tissues and exhibit low immunogenicity. OBJECTIVE: To investigate isolation and in vitro cultivation methods of human cord...BACKGROUND: Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of tissues and exhibit low immunogenicity. OBJECTIVE: To investigate isolation and in vitro cultivation methods of human cord blood MSCs, to observe expression of neural stem cell (NSC) marker mRNA under induction, and to detect tumorigenicity in animals. DESIGN, TIME AND SETTING: A cell biological, in vitro trial and a randomized, controlled, in vivo experiment were performed at the Department of Neurology, Daping Hospital at the Third Military Medical University of Chinese PLA from August 2006 to May 2008. MATERIALS: Umbilical cord blood was collected from full-term-delivery fetus at the Department of Gynecology and Obstetrics of Daping Hospital, China. Eighteen BALB/C nu/nu nude mice were randomly assigned to three groups: back subcutaneous, cervical subcutaneous, and control, with 6 mice in each group. METHODS: Monocytes were isolated from heparinized human cord blood samples by density gradient centrifugation and then adherent cultivated in vitro to obtain MSC clones. After the cord blood MSCs were cultured for 7 days with nerve growth factor and retinoic acid to induce differentiation into NSCs, the cells (adjusted density of 1 × 10^7/mL) were prepared into cell suspension. In the back subcutaneous and cervical subcutaneous groups, nude mice were hypodermically injected with a 0.5-mL cell suspension into the back and cervical regions, respectively. In the control group, nude mice received a subcutaneous injection of 0.5 mL physiological saline into the back or cervical regions, respectively. MAIN OUTCOME MEASURES: Cellular morphology was observed by inverted microscopy, cultured cord blood MSCs were examined by flow cytometry, expression of nestin and musashi-1 mRNA was detected by reverse-transcriptase polymerase chain reaction prior to and after induction, and tumorigenicity following cord blood MSC transplantation was assayed by hematoxylin-eosin staining. RESULTS: Following adherent cultivation, the majority of cord blood monocytes became rhombic and strongly expressed CD29, but not CD34, CD1 la, or CD11 b. These results supported previously known characteristics of cord blood MSCs. Following differentiation induction, nestin and musashi-1 were expressed on the surface of NSCs, exhibiting strongest expression at 48 hours, and subsequently reducing expression. Cultured cord blood MSCs were not tumorigenic in the nude mice. Cellular morphology displayed no malignant changes between the control and subcutaneous groups. CONCLUSION: MSCs can be isolated from human cord blood, efficiently expanded under culture conditions, differentiated into NSCs following induction, and display no tumorigenicity in nude mice.展开更多
Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorig...Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways, particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.展开更多
OBJECTIVE Cervical cancer is the third most malignant tumor in the world.Farnesoid X receptor(FXR) is a member of nuclear receptor superfamily.It is highly expressed in liver,kidney and small intestine,while it showed...OBJECTIVE Cervical cancer is the third most malignant tumor in the world.Farnesoid X receptor(FXR) is a member of nuclear receptor superfamily.It is highly expressed in liver,kidney and small intestine,while it showed low expression level in other tissues.It not only plays an important role in the metabolism of bile acids and sugars,but also in the production of chronic inflammation in the early stage of cancer,the proliferation and migration of tumor.Compared with the normal tissue,the expression of FXR in most tumor tissues decreased.But there is no correlation between cervical cancer and FXR.So we aimed to find out the relationship between FXR and cervical cancer.METHODS A clinical study using q PCR,western blot and immunohistochemistry detected the expression of FXR in tumor tissues and normal tissues of clinical patients.FXR was activated by agonists or over-expressed by lentivirus.MTT,clone formation and flow cytometry were used to detect the relationship between FXR and proliferation of cervical cell lines.Tumor growth ability of FXR was detected by nude mice tumorigenicity.The interaction between FXR and CDKN2A-p14^(ARF)-MDM2-p53 pathway was detected by q PCR,Western blot and immunohistochemistry.RESULTS FXR was decreased in cancer tissues compared to normal control.Activation of FXR by agonist or constitutively-over-expression of FXR inhibited cervical cell proliferation.Over-expressed FXR attenuated Caski,Hela and Siha xenograft tumor growth in nude mice compared with control.Over-expression of FXR caused G1 cell-cycle arresting and up-regulated CDKN2A-p14^(ARF)-MDM2-p53 pathway.CONCLUSION FXR inhibits cervical cancer cell proliferation and cervical tumorigenicity which is related to CDKN2A-p14^(ARF)-MDM2-p53 pathway.Activation or overexpression of FXR may be a potential target for the treatment of cervical cancer.展开更多
Using Hela cell cultures as positive control and primary canine kidney cell (CKC) or feline kidney cell (FKC) cultures purified in vitro on passage 3 as negative control, the tumorigenicity of Madin-Darby canine kidne...Using Hela cell cultures as positive control and primary canine kidney cell (CKC) or feline kidney cell (FKC) cultures purified in vitro on passage 3 as negative control, the tumorigenicity of Madin-Darby canine kidney (MDCK) cells was tested in >273 nude mice, and colony formation in soft agarose and haemag-glutination under different concentration of plant lectins of these cells were carried out at the same time. Subsequently, very low tumorigenicity strains of MDCK line were successfully selected; these were evaluated for the production of canine or feline combination viral vaccines, free of infectious agents, and of known cytoge-netic and tumorigenic. It is thus evident that MDCK cell of M, JB, JC, WB or H strain can be approved as substrate for the preparation of attenuated viral vaccines, but MDCK cell of YA, YB and KA strains can not be approved as substrate for the preparation of attenuated viral vaccines. The heritable character of these cell sub-lines is comparatively stable, and shows little significant difference between passages.展开更多
Mesenchymal stem cells(MSCs)capable of tumour topotaxis have been served as cellular vehicles to deliver anti-tumour agents.As cellular components of the tumour microenvironment,MSCs also affect tumour progression.How...Mesenchymal stem cells(MSCs)capable of tumour topotaxis have been served as cellular vehicles to deliver anti-tumour agents.As cellular components of the tumour microenvironment,MSCs also affect tumour progression.However,the tumour transformation-related genes of MSCs remain unclear since either tumorigenic or tumour suppressor effects within these cells have been researched.Hence,we aimed to identify potential biomarkers indicative of tumorigenic risk by RNA-seq analysis of human placenta tissue-derived MSCs(hPTMSCs)exposed to the carcinogenic agent,3-methylcholanthrene(3-MC).Twenty-nine tumour transformation-related genes and three pluripotency-related genes were appraised as differentially expressed genes(DEGs)in hPTMSCs.Overexpression of sfrp1 led to reduced cell viability,migration,and colony formation in A549.In contrast,the overexpression of ptgs2 exerted the opposite effect.These results indicate that A549 cells with high ptgs2 expression but low sfrp1 expression may have a more potential tumorigenic capacity.Taken together,this study suggests that ptgs2 and sfrp1 may be tumorigenic risk genes.展开更多
<Abstract>In vitro proliferation and in vivo tumorigenicity of IL-2 and/or IL-3 gene transfected FBL-3erythroleukemia cells were observed to investigate the anti-tumor effect of tumor vaccine. Methods: Leukemiac...<Abstract>In vitro proliferation and in vivo tumorigenicity of IL-2 and/or IL-3 gene transfected FBL-3erythroleukemia cells were observed to investigate the anti-tumor effect of tumor vaccine. Methods: Leukemiacells were trans fected with IL-2 and/or IL-3 adenovlrus vector. The cytokine expressions were assayed, and the growth characteristics of the transfected FBL-3 cells were studied. Results: High levels of secreted IL-2 and IL-3remained for one week after transfection, and the trans fected leukemia cells became unchanged in growth in vitro and showed weak tumorigenicity in vlvo. The tumorigenicity of FBL-3 cells decreased more significantly when FBL-3 cells were transfected with both IL-2 gene and IL-3 gene than when FBL-3 cells were tran fected with IL-2or IL-3 gene only. The tumor growth was significantly delayed and survival time of the trans fected FBL-3 inoculat ed mice was significantly prolonged. Conclusion: The inhibition of tumor growth is most likely dependent on immune response induced by展开更多
Colorectal cancer(CRC)is presently the second most prevalent global mortalityinducing cancer.CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment.In addition...Colorectal cancer(CRC)is presently the second most prevalent global mortalityinducing cancer.CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment.In addition,non-neoplastic cell activities within tumor microenvironments for CRC development have been established.However,interleukin(IL)-33,secreted by such cell types,plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment.IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity(ST)2 receptor.Therefore,how to coordinate tumor microenvironment,design and optimize treatment strategies suitable for CRC,based on IL-33/ST2 signal is a challenge.Even though it has established influences upon immunitylinked conditions,IL-33 effects on CRC progression and prevention and related mechanisms are still controversial.Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention.Moreover,IL-33/ST2 signaling is a potential therapeutic target for CRC.展开更多
Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clin...Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clinical intervention for disorders such as injuries,diabetes,liver diseases, neurodegeneration and heart failure (Lee et al., 2013; Forbes and Rosenthal, 2014; Tabar and Studer, 2014).展开更多
Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined....Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations.Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.展开更多
Immortality and tumorigenicity are two distinct characteristics of cancers. Immortalization has been suggested to precede tumorigenesis. To understand the molecular mechanisms of tumorigenicity and cancer progression ...Immortality and tumorigenicity are two distinct characteristics of cancers. Immortalization has been suggested to precede tumorigenesis. To understand the molecular mechanisms of tumorigenicity and cancer progression in mammary epithelium, we established a tumori- genic cell model by means of heavy-ion radiation of an immortal cell model, which was created by overexpressing the human telomerase reverse transcriptase (hTERT) in normal human mammary epithelial cells. We examined the expression profile of this tumorigenic cell line (T hMEC) using the hTERT-overexpressing immortal cell line (IhMEC) as a control. In-depth RNA-seq data was generated by using the next-generation sequencing (NGS) platform (Life Technologies SOLID3). We found that house-keeping (HK) and tissue-spe- cific (TS) genes were differentially regulated during the tumorigenic process. HK genes tended to be activated while TS genes tended to be repressed. In addition, the HK genes and TS genes tended to contribute differentially to the variation of gene expression at different RPKM (gene expression in reads per exon kilobase per million mapped sequence reads) levels. Based on transcriptome analysis of the two cell lines, we defined 7053 differentially-expressed genes (DEGs) between immortality and tumorigenicity. Differential expression of 20 manually-selected genes was further validated using qRT-PCR. Our observations may help to further our understanding of cellular mechanism(s) in the transition from immortalization to tumorigenesis.展开更多
Background Cyclin B1 (CLB1) is necessary for mitotic initiation in mammalian cells and plays important roles in cancer development. Therefore, a potential strategy in cancer therapy is to suppress the activity of CL...Background Cyclin B1 (CLB1) is necessary for mitotic initiation in mammalian cells and plays important roles in cancer development. Therefore, a potential strategy in cancer therapy is to suppress the activity of CLB1 by delivering antisense constructs of CLB1 into tumor cells. In previous CLB1 studies, antisense constructs with a short half life were often used and these constructs might not persistently inhibit CLB1. Methods We successfully created a recombinant plasmid encoding the full-length antisense cDNA of mouse cyclin B1 (AS-mCLB1) and transfected this construct to the murine Lewis lung carcinoma (LL/2) and CT-26 colon carcinoma (CT-26) cells. We isolated clones of LL/2 and CT-26 transfectants with stable expression of AS-mCLB1. Reverse transcriptional polymerase chain reaction (RT-PCR) and Western blot were applied to detect the expression of the mRNA and protein levels of CLB1. To further test the efficacy of this strategy in vivo, AS-mCLBl-expressing LL/2 and CT-26 transfectants were implanted into mice. Results We found the expression of the mRNA and protein levels of CLB1 decrease in these transfectants. The inhibition of CLB1 caused prominent G1 arrest, abnormal morphology, retarded cell growth and an increase in apoptosis. In AS-mCLBl-expressing LL/2 and CT-26 transfectants implanted mice, tumorigenicity was effectively suppressed compared with the controls. In addition, the expression of AS-mCLB1 also significantly increases the survival duration of implanted animals. Conclusion AS-mCLB1 is likely to be useful in future cancer therapy, which may be associated with its ability to down-regulate the expression of CLB1 and then induce G1 arrest and apoptosis in tumor cells.展开更多
In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the...In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine.Of note,considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research.However,tumorigenicity,immunogenicity,and heterogeneity may hamper attempts to deploy this technology therapeutically.This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and howto assess the safety of induced pluripotent stem cells cell therapy products.展开更多
The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma(NPC), which is prevalent in southern China and closely related to Epstein-Barr virus(EBV) infection.How t...The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma(NPC), which is prevalent in southern China and closely related to Epstein-Barr virus(EBV) infection.How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1(LMP1) promoted cyclophilin A(CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis.CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection.展开更多
Objective To analyze the relationship between malignant transformation and abnormal expression of eukaryotic initiation factor 3 (eIF3 p36) in human bronchial epithelial (16HBE) cells induced by cadmium chloride ...Objective To analyze the relationship between malignant transformation and abnormal expression of eukaryotic initiation factor 3 (eIF3 p36) in human bronchial epithelial (16HBE) cells induced by cadmium chloride (CdCl2). Methods 16HBE cells were treated several times with different concentrations of CdCl2. Tumorigenic potential of transformed cells was identified by assays for anchorage-independent growth in soft agar and for tumorigenicity in nude mice after the 35th passage. Total RNA was isolated from 16HBE cells induced by CdC12, including non-transformed, Cd-transformed, and Cd-tumorigenic cell lines. Special primers for eIF3 p36 were designed and the expression of eIF3 mRNA in different cell lines was detected with fluorescent quantitative-polymerase chain reaction technique (FQ-PCR). Results The 35th passage of 16HBE cells transformed by CdCl2 exhibited overlapping growth. Compared with the non-transformed cells, colonies of transformed cell lines in soft agar showed statistically significant increases and dose-dependent effects (P〈0.01). All Cd-induced transformed cell lines formed rumors in nude mice within 2 weeks of inoculation, but none of the mice injected with non-transformed cells showed tumors even after 3 weeks. All tumors were pathologically identified as poorly differentiated squamous cell carcinoma. The eIF3 p36 genes in different stages of 16HBE cells transformed by CdCl2 were elevated as compared with the non-transformed control (P〈0.01), and the eIF3 expression increased with the degree of cell malignancy. Conclusion CdCl2 is capable of inducing morphological transformation in 16HBE cells and transformed cells are potentially tumorigenic. Over-expression of eIF3 p36 is positively correlated with malignant transformation of 16HBE cells induced by CdCl2 and may be one of the molecular mechanisms potentially responsible for carcinogenesis due to Cd.展开更多
This article is to summarize the molecular and functional analysis of the gene “suppression of tumorigenicity 13” (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone)...This article is to summarize the molecular and functional analysis of the gene “suppression of tumorigenicity 13” (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone) of the 70-kDa heat shock proteins (Hsc/Hsp70). By collaborating with other positive co-factors such as Hsp40 and the Hsp70-Hsp90 organizing protein (Hop), or competing with negative co-factors such as Bcl2-associated athanogen 1 (Bag1), Hip facilitates may facilitate the chaperone function of Hsc/Hsp70 in protein folding and repair, and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. Although the nomenclature of ST13 implies a role in the suppression of tumorigenicity (ST), to date available experimental data are not sufficient to support its role in cancer development, except for the possible down-regulation of ST13 in gastric and colorectal cancers. Further investigation of this gene at the physiological level would benefit our understanding of diseases such as endocrinological disorders, cancer, and neurodegeneration commonly associated with protein misfolding.展开更多
After more than a decade of controversy on the role of stromal cells in the tumor microenvironment,the emerging data shed light on pro-tumorigenic and potential anti-cancer factors,as well as on the roots of the discr...After more than a decade of controversy on the role of stromal cells in the tumor microenvironment,the emerging data shed light on pro-tumorigenic and potential anti-cancer factors,as well as on the roots of the discrepancies.We discuss the pro-tumorigenic effects of stromal cells,considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells,as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment,and cancer initiating cells'cellular senescence and adaptive metabolism.We summarize the emerging data supporting stromal cell therapeutic potential in cancer,discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects,and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature.展开更多
基金Supported by The Society Development of Nantong,No.HS2012034the Jiangsu Health Projects,No.BL2012053 and No.K201102+1 种基金the Priority Academic Program Development of Jiangsuthe International S and T Cooperation Program of China,No.2013DFA32150
文摘AIM: To investigate the effects of Annexin A2 (ANXA2) silencing on invasion, migration, and tumorigenic potential of hepatoma cells. METHODS: Human hepatoma cell lines [HepG2, SMMC-7721, SMMC-7402, and MHCC97-H, a novel human hepatocellular carcinoma (HCC) cell line with high metastasis potential] and a normal hepatocyte cell line(LO2) were used in this study. The protein and mRNA expression levels of ANXA2 were analysed by western blotting and real-time polymerase chain reaction, re-spectively. The intracellular distribution profile of ANXA2 expression was determined by immunofluorescence and immunohistochemistry. Short hairpin RNA target-ing ANXA2 was designed and stably transfected into MHCC97-H cells. Cells were cultured for in vitro analy-ses or subcutaneously injected as xenografts in mice for in vivo analyses. Effects of ANXA2 silencing on cell growth were assessed by cell counting kit-8 (CCK-8) as-say (in vitro ) and tumour-growth assay (in vivo ), on cell cycling was assessed by flow cytometry and propidium iodide staining (in vitro ), and on invasion and migration potential were assessed by transwell assay and wound-healing assay, respectively (both in vitro ). RESULTS: The MHCC97-H cells, which are known to have high metastasis potential, showed the highest lev-el of ANXA2 expression among the four HCC cell types examined; compared to the LO2 cells, the MHCC97-H expression level was 8-times higher. The ANXA2 expres-sion was effectively inhibited (about 80%) by ANXA2-specific small hairpin RNA (shRNA). ANXA2 expression in the MHCC97-H cells was mainly localized to the cel-lular membrane and cytoplasm, and some localization was detected in the nucleus. Moreover, the proliferation of MHCC97-H cells was obviously suppressed by shR-NA-mediated ANXA2 silencing in vitro , and the tumour growth inhibition rate was 38.24% in vivo . The per-centage of MHCC97-H cells in S phase dramatically de-creased (to 27.76%) under ANXA2-silenced conditions. Furthermore, ANXA2-silenced MHCC97-H cells showed lower invasiveness (percentage of invading cells de-creased to 52.16%) and suppressed migratory capacity (migration distance decreased to 63.49%). It is also worth noting that shRNA-mediated silencing of ANXA2 in the MHCC97-H cells led to abnormal apoptosis. CONCLUSION: shRNA-mediated silencing of ANXA2suppresses the invasion, migration, and tumorigenic potential of hepatoma cells, and may represent a useful target of future molecular therapies.
基金Supported by The Beijing Natural Science foundation,No.5102018National Bio-Tech 86-3,No. 2006AA02A402 and No.2012AA02A504
文摘AIM:To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma(HCC).METHODS:We used reverse transcription-polymerase chain reaction(RT-PCR),quantitative real-time RT-PCR and western blotting to detect p42.3 mRNA and protein expression in hepatic cell lines.We examined primary HCC samples and matched adjacent normal tissue by immunohistochemistry to investigate the correlation between p42.3 expression and clinicopathological features.HepG2 cells were transfected with a pIRES2EGFP-p42.3 expression vector to examine the function of the p42.3 gene.Transfected cells were analyzed for their viability and malignant transformation abilities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,colony formation assay,and tumorigenicity assay in nude mice.RESULTS:p42.3 is differentially expressed in primary HCC tumors and cell lines.Approximately 69.6%(96/138) of cells were p42.3-positive in hepatic tumor tissues,while 30.7%(35/114) were p42.3-positive in tumor-adjacent normal tissues.Clinicopathological characteristics of the HCC specimens revealed a significant correlation between p42.3 expression and tumor differentiation(P = 0.031).However,p42.3 positivity was not related to tumor tumor-node-metastasis classification,hepatitis B virus status,or hepatoma type.Regarding p42.3 overexpression in stably transfected HepG2 cells,we discovered significant enhancement of cancer cell growth and colony formation in vitro,and significantly enhanced tumorigenicity in nude mice.Western blot analysis of cell cycle proteins revealed that enhanced p42.3 levels promote upregulation of proliferating cell nuclear antigen,cyclin B1 and mitotic arrest deficient 2.CONCLUSION:p42.3 promotes tumorigenicity and tumor growth in HCC and may be a potential target for future clinical cancer therapeutics.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-007)the National Natural Science Foundation of China(Grant No.81803584)+1 种基金the Technology Major Projects for“Major New Drugs Innovation and Development”(Grant Nos.2018ZX09711001-005-025 and 2018ZX09711001-012)the Inner Mongolian Natural Science Foundation(Grant No.2018LH08032)。
文摘Colorectal cancer(CRC)is the third most common and the second most fatal cancer.In recent years,more attention has been directed toward the role of gut microbiota in the initiation and development of CRC.Some bacterial species,such as Fusobacterium nucleatum,Escherichia coli,Bacteroides fragilis,Enterococcus faecalis,and Salmonella sp.have been associated with CRC,based upon sequencing studies in CRC patients and functional studies in cell culture and animal models.These bacteria can cause host DNA damage by genotoxic substances,including colibactin secreted by pks+Escherichia coli,B.fragilis toxin(BFT)produced by Bacteroides fragilis,and typhoid toxin(TT)from Salmonella.These bacteria can also indirectly promote CRC by influencing host-signaling pathways,such as E-cadherin/β-catenin,TLR4/MYD88/NF-κB,and SMO/RAS/p38 MAPK.Moreover,some of these bacteria can contribute to CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function,creating a proinflammatory environment,or influencing the autophagy process.Treatments with the classical antibacterial drugs,metronidazole or erythromycin,the antibacterial active ingredients,M13@Ag(electrostatically assembled from inorganic silver nanoparticles and the protein capsid of bacteriophage M13),berberine,and zerumbone,were found to inhibit tumorigenic bacteria to different degrees.In this review,we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria,as well as progress in developing effective antibacterial therapies.Specific bacteria have been shown to be active in the oncogenesis and progression of CRC,and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC.These bacteria may be useful as biomarkers or therapeutic targets for CRC.
基金Supported by Henan Province Education Department for Henan Province University Key Scientific Research Project,No.20A320018 and No.20A320064。
文摘BACKGROUND Acute pancreatitis(AP)is an inflammatory disease in which the regulatory pathway is complex and not well understood.Soluble suppression of tumorigenicity 2(sST2)protein receptor functions as a decoy receptor for interleukin(IL)-33 to prevent IL-33/suppression of tumorigenicity 2L(ST2L)-pathwaymediated T helper(Th)2 immune responses.AIM To investigate the role of sST2 in AP.METHODS We assessed the association between sST2 and severity of AP in 123 patients enrolled in this study.The serum levels of sST2,C-reactive protein(CRP)and Th1-and Th2-related cytokines,including interferon(IFN)-γ,tumor necrosis factor(TNF)-α,IL-2,IL-4,IL-5 and IL-13,were measured by highly sensitive ELISA,and the severity of AP in patients was evaluated by the 2012 Atlanta Classification Criteria.RESULTS Serum sST2 levels were significantly increased in AP patients,and further,these levels were significantly elevated in severe AP(SAP)patients compared to moderately severe AP(MSAP)and mild AP(MAP)patients.Logistic regression showed sST2 was a predictor of SAP[odds ratio(OR):1.003(1.001–1.006),P=0.000].sST2 cutoff point was 1190 pg/mL,and sST2 above this cutoff was associated with SAP.sST2 was also a predictor of any organ failure and mortality during AP[OR:1.006(1.003–1.009),P=0.000,OR:1.002(1.001–1.004),P=0.012,respectively].Additionally,the Th1-related cytokines IFN-γand TNF-αin the SAP group were higher and the Th2-related cytokine IL-4 in the SAP group was significantly lower than those in MSAP and MAP groups.CONCLUSION sST2 may be used as a novel inflammatory marker in predicting AP severity and may regulate the function and differentiation of IL-33/ST2-mediated Th1 and Th2 Lymphocytes in AP homeostasis.
基金Supported by:Tackle Key Project of Chongqing Municipal Science and Technology Ministry,No. 7830
文摘BACKGROUND: Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of tissues and exhibit low immunogenicity. OBJECTIVE: To investigate isolation and in vitro cultivation methods of human cord blood MSCs, to observe expression of neural stem cell (NSC) marker mRNA under induction, and to detect tumorigenicity in animals. DESIGN, TIME AND SETTING: A cell biological, in vitro trial and a randomized, controlled, in vivo experiment were performed at the Department of Neurology, Daping Hospital at the Third Military Medical University of Chinese PLA from August 2006 to May 2008. MATERIALS: Umbilical cord blood was collected from full-term-delivery fetus at the Department of Gynecology and Obstetrics of Daping Hospital, China. Eighteen BALB/C nu/nu nude mice were randomly assigned to three groups: back subcutaneous, cervical subcutaneous, and control, with 6 mice in each group. METHODS: Monocytes were isolated from heparinized human cord blood samples by density gradient centrifugation and then adherent cultivated in vitro to obtain MSC clones. After the cord blood MSCs were cultured for 7 days with nerve growth factor and retinoic acid to induce differentiation into NSCs, the cells (adjusted density of 1 × 10^7/mL) were prepared into cell suspension. In the back subcutaneous and cervical subcutaneous groups, nude mice were hypodermically injected with a 0.5-mL cell suspension into the back and cervical regions, respectively. In the control group, nude mice received a subcutaneous injection of 0.5 mL physiological saline into the back or cervical regions, respectively. MAIN OUTCOME MEASURES: Cellular morphology was observed by inverted microscopy, cultured cord blood MSCs were examined by flow cytometry, expression of nestin and musashi-1 mRNA was detected by reverse-transcriptase polymerase chain reaction prior to and after induction, and tumorigenicity following cord blood MSC transplantation was assayed by hematoxylin-eosin staining. RESULTS: Following adherent cultivation, the majority of cord blood monocytes became rhombic and strongly expressed CD29, but not CD34, CD1 la, or CD11 b. These results supported previously known characteristics of cord blood MSCs. Following differentiation induction, nestin and musashi-1 were expressed on the surface of NSCs, exhibiting strongest expression at 48 hours, and subsequently reducing expression. Cultured cord blood MSCs were not tumorigenic in the nude mice. Cellular morphology displayed no malignant changes between the control and subcutaneous groups. CONCLUSION: MSCs can be isolated from human cord blood, efficiently expanded under culture conditions, differentiated into NSCs following induction, and display no tumorigenicity in nude mice.
基金This article is not an official U.S. Food and Drug Administration guidance or policy statement. No official support or endorsement by the U.S. Food and DrugAdministration is intended or should be inferred.
文摘Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways, particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.
基金supported by Medical Science and Technology Research Foundation of Guangdong Province(2015120104622949)
文摘OBJECTIVE Cervical cancer is the third most malignant tumor in the world.Farnesoid X receptor(FXR) is a member of nuclear receptor superfamily.It is highly expressed in liver,kidney and small intestine,while it showed low expression level in other tissues.It not only plays an important role in the metabolism of bile acids and sugars,but also in the production of chronic inflammation in the early stage of cancer,the proliferation and migration of tumor.Compared with the normal tissue,the expression of FXR in most tumor tissues decreased.But there is no correlation between cervical cancer and FXR.So we aimed to find out the relationship between FXR and cervical cancer.METHODS A clinical study using q PCR,western blot and immunohistochemistry detected the expression of FXR in tumor tissues and normal tissues of clinical patients.FXR was activated by agonists or over-expressed by lentivirus.MTT,clone formation and flow cytometry were used to detect the relationship between FXR and proliferation of cervical cell lines.Tumor growth ability of FXR was detected by nude mice tumorigenicity.The interaction between FXR and CDKN2A-p14^(ARF)-MDM2-p53 pathway was detected by q PCR,Western blot and immunohistochemistry.RESULTS FXR was decreased in cancer tissues compared to normal control.Activation of FXR by agonist or constitutively-over-expression of FXR inhibited cervical cell proliferation.Over-expressed FXR attenuated Caski,Hela and Siha xenograft tumor growth in nude mice compared with control.Over-expression of FXR caused G1 cell-cycle arresting and up-regulated CDKN2A-p14^(ARF)-MDM2-p53 pathway.CONCLUSION FXR inhibits cervical cancer cell proliferation and cervical tumorigenicity which is related to CDKN2A-p14^(ARF)-MDM2-p53 pathway.Activation or overexpression of FXR may be a potential target for the treatment of cervical cancer.
文摘Using Hela cell cultures as positive control and primary canine kidney cell (CKC) or feline kidney cell (FKC) cultures purified in vitro on passage 3 as negative control, the tumorigenicity of Madin-Darby canine kidney (MDCK) cells was tested in >273 nude mice, and colony formation in soft agarose and haemag-glutination under different concentration of plant lectins of these cells were carried out at the same time. Subsequently, very low tumorigenicity strains of MDCK line were successfully selected; these were evaluated for the production of canine or feline combination viral vaccines, free of infectious agents, and of known cytoge-netic and tumorigenic. It is thus evident that MDCK cell of M, JB, JC, WB or H strain can be approved as substrate for the preparation of attenuated viral vaccines, but MDCK cell of YA, YB and KA strains can not be approved as substrate for the preparation of attenuated viral vaccines. The heritable character of these cell sub-lines is comparatively stable, and shows little significant difference between passages.
基金supported by grants from the Ningxia Science and Technological Supporting Project(2015KJHM38)the Ningxia Natural Science Foundation(2019AAC03231).
文摘Mesenchymal stem cells(MSCs)capable of tumour topotaxis have been served as cellular vehicles to deliver anti-tumour agents.As cellular components of the tumour microenvironment,MSCs also affect tumour progression.However,the tumour transformation-related genes of MSCs remain unclear since either tumorigenic or tumour suppressor effects within these cells have been researched.Hence,we aimed to identify potential biomarkers indicative of tumorigenic risk by RNA-seq analysis of human placenta tissue-derived MSCs(hPTMSCs)exposed to the carcinogenic agent,3-methylcholanthrene(3-MC).Twenty-nine tumour transformation-related genes and three pluripotency-related genes were appraised as differentially expressed genes(DEGs)in hPTMSCs.Overexpression of sfrp1 led to reduced cell viability,migration,and colony formation in A549.In contrast,the overexpression of ptgs2 exerted the opposite effect.These results indicate that A549 cells with high ptgs2 expression but low sfrp1 expression may have a more potential tumorigenic capacity.Taken together,this study suggests that ptgs2 and sfrp1 may be tumorigenic risk genes.
文摘<Abstract>In vitro proliferation and in vivo tumorigenicity of IL-2 and/or IL-3 gene transfected FBL-3erythroleukemia cells were observed to investigate the anti-tumor effect of tumor vaccine. Methods: Leukemiacells were trans fected with IL-2 and/or IL-3 adenovlrus vector. The cytokine expressions were assayed, and the growth characteristics of the transfected FBL-3 cells were studied. Results: High levels of secreted IL-2 and IL-3remained for one week after transfection, and the trans fected leukemia cells became unchanged in growth in vitro and showed weak tumorigenicity in vlvo. The tumorigenicity of FBL-3 cells decreased more significantly when FBL-3 cells were transfected with both IL-2 gene and IL-3 gene than when FBL-3 cells were tran fected with IL-2or IL-3 gene only. The tumor growth was significantly delayed and survival time of the trans fected FBL-3 inoculat ed mice was significantly prolonged. Conclusion: The inhibition of tumor growth is most likely dependent on immune response induced by
基金Natural Science Foundation of China,No.81803069Zhejiang Medical Technology Plan Project,No.2019RC007,No.2019KY007 and No.2021KY047Funds of Science Technology Department of Zhejiang Province,No.LGF21H160033.
文摘Colorectal cancer(CRC)is presently the second most prevalent global mortalityinducing cancer.CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment.In addition,non-neoplastic cell activities within tumor microenvironments for CRC development have been established.However,interleukin(IL)-33,secreted by such cell types,plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment.IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity(ST)2 receptor.Therefore,how to coordinate tumor microenvironment,design and optimize treatment strategies suitable for CRC,based on IL-33/ST2 signal is a challenge.Even though it has established influences upon immunitylinked conditions,IL-33 effects on CRC progression and prevention and related mechanisms are still controversial.Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention.Moreover,IL-33/ST2 signaling is a potential therapeutic target for CRC.
基金supported by Fondation pour la Recherche Médicale(Equipe FRM),SATT Sud Est-Accelerator of Technology Transfer,Association France Parkinson,Fondation de France(Committee Parkinson),COST Action CM1106
文摘Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clinical intervention for disorders such as injuries,diabetes,liver diseases, neurodegeneration and heart failure (Lee et al., 2013; Forbes and Rosenthal, 2014; Tabar and Studer, 2014).
基金supported by the National Natural Science Foundation of China(31970668).
文摘Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations.Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.
基金supported by grants from the National Basic Research Program (973 Program Grant No.2011CB944100 and 2011CB944101)+1 种基金National Natural Science Foundation of China (Grant No. 90919024) awarded to Jun Yu and Knowledge Innovation Program of the Chinese Academy of Sciences (Grant No. KSCX2-EW-R-01-04) to Songnian Husupported by the NIH National Cancer Institute (Grant No.CA127120) to Yongliang Zhao
文摘Immortality and tumorigenicity are two distinct characteristics of cancers. Immortalization has been suggested to precede tumorigenesis. To understand the molecular mechanisms of tumorigenicity and cancer progression in mammary epithelium, we established a tumori- genic cell model by means of heavy-ion radiation of an immortal cell model, which was created by overexpressing the human telomerase reverse transcriptase (hTERT) in normal human mammary epithelial cells. We examined the expression profile of this tumorigenic cell line (T hMEC) using the hTERT-overexpressing immortal cell line (IhMEC) as a control. In-depth RNA-seq data was generated by using the next-generation sequencing (NGS) platform (Life Technologies SOLID3). We found that house-keeping (HK) and tissue-spe- cific (TS) genes were differentially regulated during the tumorigenic process. HK genes tended to be activated while TS genes tended to be repressed. In addition, the HK genes and TS genes tended to contribute differentially to the variation of gene expression at different RPKM (gene expression in reads per exon kilobase per million mapped sequence reads) levels. Based on transcriptome analysis of the two cell lines, we defined 7053 differentially-expressed genes (DEGs) between immortality and tumorigenicity. Differential expression of 20 manually-selected genes was further validated using qRT-PCR. Our observations may help to further our understanding of cellular mechanism(s) in the transition from immortalization to tumorigenesis.
基金This work was supported by the funds from the Natural Science Foundation of Zhejiang Province, China (No. Y207353) and Science Foundation of Zhejiang Province, China for Postdoctors (No. 2006-bsh-34).
文摘Background Cyclin B1 (CLB1) is necessary for mitotic initiation in mammalian cells and plays important roles in cancer development. Therefore, a potential strategy in cancer therapy is to suppress the activity of CLB1 by delivering antisense constructs of CLB1 into tumor cells. In previous CLB1 studies, antisense constructs with a short half life were often used and these constructs might not persistently inhibit CLB1. Methods We successfully created a recombinant plasmid encoding the full-length antisense cDNA of mouse cyclin B1 (AS-mCLB1) and transfected this construct to the murine Lewis lung carcinoma (LL/2) and CT-26 colon carcinoma (CT-26) cells. We isolated clones of LL/2 and CT-26 transfectants with stable expression of AS-mCLB1. Reverse transcriptional polymerase chain reaction (RT-PCR) and Western blot were applied to detect the expression of the mRNA and protein levels of CLB1. To further test the efficacy of this strategy in vivo, AS-mCLBl-expressing LL/2 and CT-26 transfectants were implanted into mice. Results We found the expression of the mRNA and protein levels of CLB1 decrease in these transfectants. The inhibition of CLB1 caused prominent G1 arrest, abnormal morphology, retarded cell growth and an increase in apoptosis. In AS-mCLBl-expressing LL/2 and CT-26 transfectants implanted mice, tumorigenicity was effectively suppressed compared with the controls. In addition, the expression of AS-mCLB1 also significantly increases the survival duration of implanted animals. Conclusion AS-mCLB1 is likely to be useful in future cancer therapy, which may be associated with its ability to down-regulate the expression of CLB1 and then induce G1 arrest and apoptosis in tumor cells.
基金We thank the National Natural Science Foundation of China(grants No.32171387 and 32071452)Shenzhen Bay Laboratory Open Program(grant No.SZBL2020090501003)the Pearl River Talents Program Local Innovative and Research Teams(grant No.2017BT01S131).
文摘In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine.Of note,considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research.However,tumorigenicity,immunogenicity,and heterogeneity may hamper attempts to deploy this technology therapeutically.This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and howto assess the safety of induced pluripotent stem cells cell therapy products.
基金supported by the Natural Science Foundations of China(81974427)Graduate Research and Innovation Projects of Central South University(2021zzts0931)
文摘The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma(NPC), which is prevalent in southern China and closely related to Epstein-Barr virus(EBV) infection.How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1(LMP1) promoted cyclophilin A(CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis.CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection.
基金the National Natural Science Foundation of China (No. 30371195)Guangdong NaturalScience Foundation (No. 06022672)+1 种基金Guangzhou Science and Technology Foundation (No. 2003Z2-E0191/E0192)Guangzhou Municipal Department of Education (No. 1002)
文摘Objective To analyze the relationship between malignant transformation and abnormal expression of eukaryotic initiation factor 3 (eIF3 p36) in human bronchial epithelial (16HBE) cells induced by cadmium chloride (CdCl2). Methods 16HBE cells were treated several times with different concentrations of CdCl2. Tumorigenic potential of transformed cells was identified by assays for anchorage-independent growth in soft agar and for tumorigenicity in nude mice after the 35th passage. Total RNA was isolated from 16HBE cells induced by CdC12, including non-transformed, Cd-transformed, and Cd-tumorigenic cell lines. Special primers for eIF3 p36 were designed and the expression of eIF3 mRNA in different cell lines was detected with fluorescent quantitative-polymerase chain reaction technique (FQ-PCR). Results The 35th passage of 16HBE cells transformed by CdCl2 exhibited overlapping growth. Compared with the non-transformed cells, colonies of transformed cell lines in soft agar showed statistically significant increases and dose-dependent effects (P〈0.01). All Cd-induced transformed cell lines formed rumors in nude mice within 2 weeks of inoculation, but none of the mice injected with non-transformed cells showed tumors even after 3 weeks. All tumors were pathologically identified as poorly differentiated squamous cell carcinoma. The eIF3 p36 genes in different stages of 16HBE cells transformed by CdCl2 were elevated as compared with the non-transformed control (P〈0.01), and the eIF3 expression increased with the degree of cell malignancy. Conclusion CdCl2 is capable of inducing morphological transformation in 16HBE cells and transformed cells are potentially tumorigenic. Over-expression of eIF3 p36 is positively correlated with malignant transformation of 16HBE cells induced by CdCl2 and may be one of the molecular mechanisms potentially responsible for carcinogenesis due to Cd.
基金Project supported by the National Basic Research Program (973) of China (No. 2004CB518707)the National Natureal Science Foundation of China (No. 30400521)
文摘This article is to summarize the molecular and functional analysis of the gene “suppression of tumorigenicity 13” (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone) of the 70-kDa heat shock proteins (Hsc/Hsp70). By collaborating with other positive co-factors such as Hsp40 and the Hsp70-Hsp90 organizing protein (Hop), or competing with negative co-factors such as Bcl2-associated athanogen 1 (Bag1), Hip facilitates may facilitate the chaperone function of Hsc/Hsp70 in protein folding and repair, and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. Although the nomenclature of ST13 implies a role in the suppression of tumorigenicity (ST), to date available experimental data are not sufficient to support its role in cancer development, except for the possible down-regulation of ST13 in gastric and colorectal cancers. Further investigation of this gene at the physiological level would benefit our understanding of diseases such as endocrinological disorders, cancer, and neurodegeneration commonly associated with protein misfolding.
文摘After more than a decade of controversy on the role of stromal cells in the tumor microenvironment,the emerging data shed light on pro-tumorigenic and potential anti-cancer factors,as well as on the roots of the discrepancies.We discuss the pro-tumorigenic effects of stromal cells,considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells,as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment,and cancer initiating cells'cellular senescence and adaptive metabolism.We summarize the emerging data supporting stromal cell therapeutic potential in cancer,discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects,and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature.