BACKGROUND Mesenchymal stem cells(MSCs)exert anti-oncogenic effects via exosomes containing non-coding RNA(ncRNA),which play important roles in tumor biology.Our preliminary study identified the interaction of the ncR...BACKGROUND Mesenchymal stem cells(MSCs)exert anti-oncogenic effects via exosomes containing non-coding RNA(ncRNA),which play important roles in tumor biology.Our preliminary study identified the interaction of the ncRNA hsa_-circ_0000563(circ563)and the circ563-associated miR-148a-3p in exosomes,as miR-148a-3p and its target metal-regulatory transcription factor-1(MTF-1)are implicated in hepatocellular carcinoma(HCC)progression.AIM To identify the clinical significance,functional implications,and mechanisms of circ563 in HCC.METHODS The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared,and their effects on HCC cells were assessed.Using a dual-luciferase reporter assay,miR-148a-3p was identified as an associated microRNA of circ563,whose role in HCC regulation was assessed in vitro and in vivo.RESULTS The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis.Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression.The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion.Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1.In HCC tissues,circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels.CONCLUSION MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway,while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.展开更多
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colo...BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.展开更多
We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel...We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel associated with irradiation of 60 Gy shrunk the lung tumor. However, soon after,the para-aortic lymph node became swollen. Esophagogastroduodenoscopy revealed three duodenal tumors. Differential diagnosis between malignant lymphoma and metastatic duodenal cancer was endoscopically difficult. The histology of biopsied specimens was poorly differentiated adenocarcinoma. Immunohistochemical analysis revealed a positive reaction for thyroid transcription factor-1 (TTF-1). Thus, we concluded that these were metastatic duodenal tumors from lung adenocarcinoma. Two courses of gemcitabine led to a complete remission in this duodenal metastasisand para-aortic lymph node swelling with only scarring remaining in computed tomography. He is now on the continuous generalized chemotherapy. In conclusion, duodenal metastasis from primary lung adenocarcinoma is rare and hard to diagnose. In such an instance, TTF-1 immunostaining is crucial to obtain the correct diagnosis.展开更多
BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been prop...BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via the c-Myc pathway,which leads to the activation of the UPR pathway,might be a therapeutic target in HCC.展开更多
Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promot...Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promoter inhibited the growth of human lung cancer cells in vitro and in vivo;however,the intervention efficiency needed to be further improved.In this study,we identified the core promoter of TTF-1(from-1299 bp to-871 bp)by 5’deletion assay and screened out the putative transcription factors nuclear factor-1(NF-1)and activator protein-1(AP-1).Further analysis revealed that the expression level of NF-1,but not AP-1,was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer(NSCLC)cells.Moreover,the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter.Of note,we optimized four distinct sequences to form additional NF-1-binding sites(TGGCA)in the sequence of TTF-1 core promoter(termed asTTF-1 promoter),and verified the binding efficiency of NF-1 on theTTF-1 promoter by electrophoretic mobility shift assay(EMSA).As expected,theTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro,accompanied by a reduced transduction of NADH dehydrogenase(ubiquinone)1αsubcomplex 4(NDUFA4)/protein kinase B(Akt)pathway.Consistently,TTF-1 promoter-driven miR-7expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC.Finally,no significant changes were detected in the biological indicators or the histology of some important tissues and organs,including heart,liver,and spleen.On the whole,our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells,providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.展开更多
Objective: To study the correlation of thyroid transcription factor-1 (TTF-1) and Napsin A expression in CT-guided percutaneous puncture tissue with the malignant biology of cancer cells. Methods: The lung tissues tha...Objective: To study the correlation of thyroid transcription factor-1 (TTF-1) and Napsin A expression in CT-guided percutaneous puncture tissue with the malignant biology of cancer cells. Methods: The lung tissues that were obtained from CT-guided percutaneous puncture in Tongchuan People's Hospital between March 2015 and December 2017 were selected and pathologically diagnosed with lung cancer tissues (n=78) and benign tissues (n=40), the RNA was extracted, and then the expression levels of TTF-1, NapsinA, oncogenes and epithelial-mesenchymal transition (EMT) genes were determined. Results: TTF-1, Pim1, C-myc, Nr4a1, KLF4 and N-cadherin mRNA expression levels in lung cancer tissues were significantly higher than those in benign tissues whereas NapsinA, Rb, LKB1, HIPK2 and E-cadherin mRNA expression levels were significantly lower than those in benign tissues;Pim1 and C-myc mRNA expression levels in lung cancer tissues with high TTF-1 expression were significantly higher than those in lung cancer tissues with low TTF-1 expression whereas Rb and LKB1 mRNA expression levels were significantly lower than those in lung cancer tissues with low TTF-1 expression;HIPK2 and E-cadherin mRNA expression levels in lung cancer tissues with high NapsinA expression were significantly higher than those in lung cancer tissues with low NapsinA expression whereas Nr4a1, KLF4 and N-cadherin mRNA expression levels were significantly lower than those in lung cancer tissues with low NapsinA expression. Conclusion: The high expression of TTF-1 and the low expression NapsinA in CT-guided percutaneous puncture tissue can promote the cancer cell proliferation and EMT respectively.展开更多
[Objectives]To study the effect of total flavonoids extracted from Polygonum perfoliatum L.(TFP)on immune-mediated liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide(BCG+LPS)in mice,and to explor...[Objectives]To study the effect of total flavonoids extracted from Polygonum perfoliatum L.(TFP)on immune-mediated liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide(BCG+LPS)in mice,and to explore its action mechanism.[Methods]60 Kunming mice were divided into normal group,model group,control group(bifendate)and TFP low,medium and high dose groups according to random number table method,with 10 mice in each group.On the first day of modeling,mice were injected with 0.2 mL of BCG solution(12.5 mg/mL)through the tail vein,and on the eleventh day,0.2 mL of LPS(37.5μg/mL)were injected into the tail vein to prepare a mouse model of immune-mediated liver injury;from the first day of modeling,the normal group and the model group were administered intragastrically with the corresponding volume of distilled water,and the bifendate group and the TFP high,medium,and low dose groups were administered intragastrically with the corresponding doses once a day for 11 d.After the last time administration,fasting but giving water for 16 h,took blood from eyes,then collected the liver tissue.The levels of alanine transaminase(ALT)and aspartate transaminase(AST)in serum were detected by biochemical method;transforming growth factor-β1(TGF-β1),intercellular adhesion molecule-1(ICAM-1),interleukin-6(IL-6)and interleukin-1β(IL-1β)expression levels in liver tissue were detected by enzyme-linked immunosorbent assay(ELISA);phosphorylated protein tyrosine kinase JAK-2(p-JAK2),phosphorylated signal transducer and activator of transcription 3(p-STAT3)protein expression levels were detected by Western Blot method;the degree of liver tissue lesions was detected by HE staining.[Results]Compared with the model group,the levels of ALT and AST in the serum of mice in each dose group of TFP(high dose 600 mg/kg,medium dose 400 mg/kg,and low dose 200 mg/kg)were reduced,and the activities of T-SOD and GSH-Px were increased;the content or expression ofβ1,ICAM-1,IL-6,IL-1βdecreased,and the expression of p-JAK2 and p-STAT3 protein decreased;pathological sections showed that the degree of inflammatory necrosis and the degree of lesions in the liver tissues of each dose group of TFP were reduced by varying degrees.[Conclusions]TFP has a protective effect on BCG+LPS-induced immune-mediated liver injury in mice.The mechanism may be related to regulating the phosphorylation level of JAK2 and inhibiting the inflammatory reaction,thereby regulating the TGF-β1/STAT3 signaling pathway and improving the immune-mediated liver injury.展开更多
To investigate the regulation of tumor sup-pressor XAF1 gene expression in digestive system cancers,we studied XAF1 gene promoter transcription activity and mRNA level in digestive system cancer cell lines(human hepat...To investigate the regulation of tumor sup-pressor XAF1 gene expression in digestive system cancers,we studied XAF1 gene promoter transcription activity and mRNA level in digestive system cancer cell lines(human hepatoma cell line HepG2,human colon cancer cell line LoVo,and human gastric cancer cell line AGS)and nontumor cell lines(human embryonic liver cell line L02(L02 cells)and human embryonic kidney 293 cells[HEK293 cells])as controls.1395-bp-promoter fragment of XAF1 gene was amplified by polymerase chain reaction(PCR)and cloned into pGL3-basic vector and pEGFP-1 vector to assay its promoter transcription activity.The plasmids were transfected into a variety of cell lines by lipofectamine 2000.The promoter transcription activity was determined by dual-luciferase report assay,and enhanced greenfluorescent protein(EGFP)-positive cells were detected byfluorescence microscope.The expression of XAF1 mRNA in HEK293 and L02 were significantly higher than that in any of the three digestive system cancer cell lines.The dual-luciferase reporter assay showed that the promoter transcription activity in digestive system tumor cell lines transfected with pGL3-XAF1p promoter was apparently lower than that of both HEK293 and L02 cells.Expression of greenfluorescent protein(GFP)under the control of XAF1 promoter in the three digestive system cancer cell lines was lower than that of both HEK293 and L02 cells.The activities of pGL3-XAF1p in the three digestive system cancer cell lines after treatment with heat stress were significantly lower than those in the unstressed cells.The results suggested that remarkably down-regulated XAF1 mRNA expression in digestive system cancer cell lines may be due to loss of transcription activity of XAF1 promoter.展开更多
Interleukin-1βis a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease,Parkinson’s disease,stroke an...Interleukin-1βis a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease,Parkinson’s disease,stroke and persistent pain.Activated microglia are the main cellular source of interleukin-1βin the brain.Cathepsin B is associated with the production and secretion of interleukin-1βthrough pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes.The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A,which can stabilize mitochondrial DNA.Therefore,microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging.Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.展开更多
Background Hyperphosphatemia in renal failure has been identified as a major role in the pathogenesis of hyperparathyroidism that is independent of changes in serum calcium and 1,25(OH)203. The aim of this study was...Background Hyperphosphatemia in renal failure has been identified as a major role in the pathogenesis of hyperparathyroidism that is independent of changes in serum calcium and 1,25(OH)203. The aim of this study was to evaluate the expression of parathyroid Pit-1 in hyperphosphatemia-induced secondary hyperparathyroidism (SHPT) of chronic renal failure (CRF) rats. Methods Wistar rats with CRF induced by 5/6 nephrectomy were ramdomly fed with diet containing 1.2% inorganic phosphate (Pi, high phosphate (HP) group, n=-9) or 0.2% Pi (low phosphate (LP) group, n=9) for 10 weeks starting from the fourth week after the surgery. Another 7 nephrectomy rats with HP diet were intraperitoneally injected with phosphonoformic acid (PFA, the specific inhibitor of Pit-l, HP+PFA group) 0.15 g/kg every other day for 10 weeks starting from HP diet. Another 6 HP rats injected with the same amount of normal saline as the control of the HP+PFA group (HP+saline group). At the same time, 9 rats with sham surgery received HP diet as the controls. At the 4th week and 14th week, blood was taken for measurement of serum creatinine (SCr), serum calcium (SCa), serum phosphorus (SPi), 1,25(OH)2D3 and intact parathyroid hormone (iPTH). At the 14th week, two parathroid glands (PTGs) of each rat were removed by microsurgery, one gland for immunohistochemistry analysis of proliferating cell nuclear antigen (PCNA), the other one for detection of Pit-1 by Western blotting, and for the measurement of Pit-1 mRNA and PTH mRNA by real-time quantitative polymerase chain reaction. Results In nephrectomy rats, high dierary phosphate induced a marked increase in serum phosphate, iPTH, PTH mRNA and PCNA parathyroid cells, accompanying Pit-1 and its mRNA in parathyroid gland increased significantly. However, serum Ca and 1,25(OH)2D3 remained unchanged. PFA decreased Pit-1 and its mRNA levels to reduce intact PTH, PTH mRNA and PCNA-positive parathyroid cells. Conclusions Expression of parathyroid Pit-1 in hyperphosphatemia-induced SHPT of CRF rats was upregulated. Pit-1 may mediate the stimulation to parathyroid gland by hyperphosphatemia.展开更多
Objective:To evaluate the expression levels and correlations among the expressions of transforming growth factor-β_1(TGF-β_1),Kunx3 and CD83 in colonic mucosal specimens from IBS patients.Methods:A total of 40 patie...Objective:To evaluate the expression levels and correlations among the expressions of transforming growth factor-β_1(TGF-β_1),Kunx3 and CD83 in colonic mucosal specimens from IBS patients.Methods:A total of 40 patients were selected,who were confirmed as IBS by Rome III standard and 40 healthy volunteers served as control.Colonic mucosal specimens of each subject were collected from colon sigmoideum with biopsy forceps.Runx3,TGF-β_1?and CD83(the marker for immunecompetent mature dendritic cells(DCs)mRNA in the sigmoid colon tissue were measured by real-time fluorescence quantitative PCR.Results:Compared with the control group,CD83 mRNA expressions were higher in patients with IBS than in healthy controls(P<0.05)and were associated with runt-related transcription factor 3(Runx3)mRNA levels(r=-0.361,P<0.05).Meanwhile,Runx3 mRNA levels were associated with TGF-β_1,mRNA expressions in irritable bowel syndrome(IBS)patients(r=0.402,P<0.05).However,there was no correlation between the mRNA expressions of TGF-β_1 and CD83(P>0.05).Conclusions:The increase of abnormal dendritic cells might influence the occurrence and development of IBS.TGF-β_1 signal pathway might not be involved in Runx 3-regulated maturation of dendritic cells in IBS.展开更多
We report a case of pure struma ovarii tumor diagnosed by cytology during laparoscopic surgery. The patient was a 34-year-old Japanese woman, gravida 1, para 1, who had the left adnexal mass, and was pre-operatively d...We report a case of pure struma ovarii tumor diagnosed by cytology during laparoscopic surgery. The patient was a 34-year-old Japanese woman, gravida 1, para 1, who had the left adnexal mass, and was pre-operatively diagnosed as left ovarian endometriotic cyst or mature cystic teratoma by magnetic resonance imaging findings. She underwent laparoscopy, and the content of the left ovarian cystic tumor was found to be yellow gelatinous material, suggesting mature cystic teratoma. The imprint cytology of the tumor showed benign glandular pattern, suggesting struma ovarii. Histopathological findings led us to the diagnosis of pure struma ovarii with positive reactions for thyroglobulin and thyroid transcription factor-1. No metastases or disseminated lesions were detected. The patient has no recurrent signs 7 months after the operation.展开更多
The diagnosis of gastric metastasis from lung cancer is relatively rare in living patients.We describe a case of Type 4 tumor-like metastasis due to primary lung cancer diagnosed with immunohistochemical staining whil...The diagnosis of gastric metastasis from lung cancer is relatively rare in living patients.We describe a case of Type 4 tumor-like metastasis due to primary lung cancer diagnosed with immunohistochemical staining while the patient was alive.A 68-year-old man was admitted to our hospital because of epigastric pain.Gastrointestinal endoscopy revealed a Type 4 tumor and the histological examination showed poorly differentiated adenocar-cinoma.His chest X-ray showed mass shadow in the right upper lung field.The resected specimens showed moderately differentiated adenocarcinoma.,The diagnosis of gastric metastasis from lung cancer was made by immunohistochemical staining of the lung and gastric tumors which showed positive staining for Thyroid transcriptional factor-1.Diagnosis of gastric metastasis,especially Type 4 metastasis by lung cancer is diff icult.However,immunohistochemical staining is very helpful for diagnosis of primary lung cancer metastasis at sites such as the gastrointestinal tract which are not normally prone to metastatis.展开更多
BACKGROUND The androgen responsive gene,ELL-associated factor 2(EAF2),expressed in benign prostate tissues,has been shown to play an important role in tumor suppression in a variety of malignant tumors.In addition,som...BACKGROUND The androgen responsive gene,ELL-associated factor 2(EAF2),expressed in benign prostate tissues,has been shown to play an important role in tumor suppression in a variety of malignant tumors.In addition,some scholars found that EAF2 frameshift mutations are associated with intratumor heterogeneity in colorectal cancer(CRC)and inactivation of EAF2 in microsatellite instability-high CRC.However,the molecular mechanism by which EAF2 is involved in CRC invasion and metastasis remains unclear.AIM To determine the clinical value of expression of EAF2 protein in CRC,and to study the effects of EAF2 on the invasion,migration,and angiogenesis of CRC cells in vitro.METHODS In this study,we collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein in patients with advanced CRC.Subsequently,we investigated the effect of EAF2 on the invasion,migration,and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS EAF2 protein was lowly expressed in cancer tissues of patients with advanced CRC.Kaplan-Meier survival analysis showed that the survival rate of the high EAF2 level group was higher than that of the low EAF2 level group.CONCLUSION Our results demonstrated that EAF2,as a tumor suppressor,may inhibit the invasion,metastasis,and angiogenesis of CRC cells by regulating the signal transducer and activator of transcription 3/transforming growth factor-β1 crosstalk pathway,and play a cancer suppressive and protective role in the occurrence and development of CRC.Our findings are of great significance to provide a new idea and theoretical basis for the targeted diagnosis and treatment of CRC.展开更多
Transforming growth factor-β1(TGF-β1)acts as a tumor promoter in advanced prostate cancer(PCa).We speculated that microRNAs(miRNAs)that are inhibited by TGF-β1 might exert anti-tumor effects.To assess this,we ident...Transforming growth factor-β1(TGF-β1)acts as a tumor promoter in advanced prostate cancer(PCa).We speculated that microRNAs(miRNAs)that are inhibited by TGF-β1 might exert anti-tumor effects.To assess this,we identified several miRNAs downregulated by TGF-β1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA.miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue,and its expression level correlated inversely with aggressive clinical pathological features.Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation,migration,and invasion,and promoted apoptosis.The miR-3691-3p target genes E2F transcription factor 3(E2F3)and PR domain containing 1,with ZNF domain(PRDM1)were upregulated in miR-3691-3p-overexpressing PCa cells,and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation,migration,and invasion.Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis.Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p,both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue.Our results indicate that TGF-β1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1.These results provide novel insights into the mechanisms by which TGF-β1 contributes to the progression of PCa.展开更多
Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment.Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct...Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment.Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways.Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes.This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance.展开更多
基金the National Natural Science Foundation of China,No.81972606 and 82271774.
文摘BACKGROUND Mesenchymal stem cells(MSCs)exert anti-oncogenic effects via exosomes containing non-coding RNA(ncRNA),which play important roles in tumor biology.Our preliminary study identified the interaction of the ncRNA hsa_-circ_0000563(circ563)and the circ563-associated miR-148a-3p in exosomes,as miR-148a-3p and its target metal-regulatory transcription factor-1(MTF-1)are implicated in hepatocellular carcinoma(HCC)progression.AIM To identify the clinical significance,functional implications,and mechanisms of circ563 in HCC.METHODS The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared,and their effects on HCC cells were assessed.Using a dual-luciferase reporter assay,miR-148a-3p was identified as an associated microRNA of circ563,whose role in HCC regulation was assessed in vitro and in vivo.RESULTS The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis.Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression.The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion.Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1.In HCC tissues,circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels.CONCLUSION MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway,while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.
基金the Natural Science Foundation of Liaoning Province,No.2023-MS-149.
文摘BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
文摘We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel associated with irradiation of 60 Gy shrunk the lung tumor. However, soon after,the para-aortic lymph node became swollen. Esophagogastroduodenoscopy revealed three duodenal tumors. Differential diagnosis between malignant lymphoma and metastatic duodenal cancer was endoscopically difficult. The histology of biopsied specimens was poorly differentiated adenocarcinoma. Immunohistochemical analysis revealed a positive reaction for thyroid transcription factor-1 (TTF-1). Thus, we concluded that these were metastatic duodenal tumors from lung adenocarcinoma. Two courses of gemcitabine led to a complete remission in this duodenal metastasisand para-aortic lymph node swelling with only scarring remaining in computed tomography. He is now on the continuous generalized chemotherapy. In conclusion, duodenal metastasis from primary lung adenocarcinoma is rare and hard to diagnose. In such an instance, TTF-1 immunostaining is crucial to obtain the correct diagnosis.
文摘BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via the c-Myc pathway,which leads to the activation of the UPR pathway,might be a therapeutic target in HCC.
基金the National Natural Science Foundation of China(Nos.32160178,82160503,31760258,and 81960509)the Project of the Guizhou Provincial Department of Science and Technology(Nos.QKH-JC-2018-1428,QKHZC-2020-4Y156,and QKH-JC-ZK-2022-624)+1 种基金the Collaborative Innovation Center of Chinese Ministry of Education(No.2020-39)the Program for Excellent Young Talents of Zunyi Medical University(No.15ZY-001),China。
文摘Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promoter inhibited the growth of human lung cancer cells in vitro and in vivo;however,the intervention efficiency needed to be further improved.In this study,we identified the core promoter of TTF-1(from-1299 bp to-871 bp)by 5’deletion assay and screened out the putative transcription factors nuclear factor-1(NF-1)and activator protein-1(AP-1).Further analysis revealed that the expression level of NF-1,but not AP-1,was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer(NSCLC)cells.Moreover,the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter.Of note,we optimized four distinct sequences to form additional NF-1-binding sites(TGGCA)in the sequence of TTF-1 core promoter(termed asTTF-1 promoter),and verified the binding efficiency of NF-1 on theTTF-1 promoter by electrophoretic mobility shift assay(EMSA).As expected,theTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro,accompanied by a reduced transduction of NADH dehydrogenase(ubiquinone)1αsubcomplex 4(NDUFA4)/protein kinase B(Akt)pathway.Consistently,TTF-1 promoter-driven miR-7expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC.Finally,no significant changes were detected in the biological indicators or the histology of some important tissues and organs,including heart,liver,and spleen.On the whole,our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells,providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.
文摘Objective: To study the correlation of thyroid transcription factor-1 (TTF-1) and Napsin A expression in CT-guided percutaneous puncture tissue with the malignant biology of cancer cells. Methods: The lung tissues that were obtained from CT-guided percutaneous puncture in Tongchuan People's Hospital between March 2015 and December 2017 were selected and pathologically diagnosed with lung cancer tissues (n=78) and benign tissues (n=40), the RNA was extracted, and then the expression levels of TTF-1, NapsinA, oncogenes and epithelial-mesenchymal transition (EMT) genes were determined. Results: TTF-1, Pim1, C-myc, Nr4a1, KLF4 and N-cadherin mRNA expression levels in lung cancer tissues were significantly higher than those in benign tissues whereas NapsinA, Rb, LKB1, HIPK2 and E-cadherin mRNA expression levels were significantly lower than those in benign tissues;Pim1 and C-myc mRNA expression levels in lung cancer tissues with high TTF-1 expression were significantly higher than those in lung cancer tissues with low TTF-1 expression whereas Rb and LKB1 mRNA expression levels were significantly lower than those in lung cancer tissues with low TTF-1 expression;HIPK2 and E-cadherin mRNA expression levels in lung cancer tissues with high NapsinA expression were significantly higher than those in lung cancer tissues with low NapsinA expression whereas Nr4a1, KLF4 and N-cadherin mRNA expression levels were significantly lower than those in lung cancer tissues with low NapsinA expression. Conclusion: The high expression of TTF-1 and the low expression NapsinA in CT-guided percutaneous puncture tissue can promote the cancer cell proliferation and EMT respectively.
基金Natural Science Foundation Project of Guangxi(2017GXNSFAA 198326)。
文摘[Objectives]To study the effect of total flavonoids extracted from Polygonum perfoliatum L.(TFP)on immune-mediated liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide(BCG+LPS)in mice,and to explore its action mechanism.[Methods]60 Kunming mice were divided into normal group,model group,control group(bifendate)and TFP low,medium and high dose groups according to random number table method,with 10 mice in each group.On the first day of modeling,mice were injected with 0.2 mL of BCG solution(12.5 mg/mL)through the tail vein,and on the eleventh day,0.2 mL of LPS(37.5μg/mL)were injected into the tail vein to prepare a mouse model of immune-mediated liver injury;from the first day of modeling,the normal group and the model group were administered intragastrically with the corresponding volume of distilled water,and the bifendate group and the TFP high,medium,and low dose groups were administered intragastrically with the corresponding doses once a day for 11 d.After the last time administration,fasting but giving water for 16 h,took blood from eyes,then collected the liver tissue.The levels of alanine transaminase(ALT)and aspartate transaminase(AST)in serum were detected by biochemical method;transforming growth factor-β1(TGF-β1),intercellular adhesion molecule-1(ICAM-1),interleukin-6(IL-6)and interleukin-1β(IL-1β)expression levels in liver tissue were detected by enzyme-linked immunosorbent assay(ELISA);phosphorylated protein tyrosine kinase JAK-2(p-JAK2),phosphorylated signal transducer and activator of transcription 3(p-STAT3)protein expression levels were detected by Western Blot method;the degree of liver tissue lesions was detected by HE staining.[Results]Compared with the model group,the levels of ALT and AST in the serum of mice in each dose group of TFP(high dose 600 mg/kg,medium dose 400 mg/kg,and low dose 200 mg/kg)were reduced,and the activities of T-SOD and GSH-Px were increased;the content or expression ofβ1,ICAM-1,IL-6,IL-1βdecreased,and the expression of p-JAK2 and p-STAT3 protein decreased;pathological sections showed that the degree of inflammatory necrosis and the degree of lesions in the liver tissues of each dose group of TFP were reduced by varying degrees.[Conclusions]TFP has a protective effect on BCG+LPS-induced immune-mediated liver injury in mice.The mechanism may be related to regulating the phosphorylation level of JAK2 and inhibiting the inflammatory reaction,thereby regulating the TGF-β1/STAT3 signaling pathway and improving the immune-mediated liver injury.
基金supported by grants from the National Natural Sciences Foundation of China(Grant No.30872237)Research Fund for the Doctoral Program of Higher Education of China(No.20070487007)the National Program for Basic Research(973 project)of China(No.2007CB512900).
文摘To investigate the regulation of tumor sup-pressor XAF1 gene expression in digestive system cancers,we studied XAF1 gene promoter transcription activity and mRNA level in digestive system cancer cell lines(human hepatoma cell line HepG2,human colon cancer cell line LoVo,and human gastric cancer cell line AGS)and nontumor cell lines(human embryonic liver cell line L02(L02 cells)and human embryonic kidney 293 cells[HEK293 cells])as controls.1395-bp-promoter fragment of XAF1 gene was amplified by polymerase chain reaction(PCR)and cloned into pGL3-basic vector and pEGFP-1 vector to assay its promoter transcription activity.The plasmids were transfected into a variety of cell lines by lipofectamine 2000.The promoter transcription activity was determined by dual-luciferase report assay,and enhanced greenfluorescent protein(EGFP)-positive cells were detected byfluorescence microscope.The expression of XAF1 mRNA in HEK293 and L02 were significantly higher than that in any of the three digestive system cancer cell lines.The dual-luciferase reporter assay showed that the promoter transcription activity in digestive system tumor cell lines transfected with pGL3-XAF1p promoter was apparently lower than that of both HEK293 and L02 cells.Expression of greenfluorescent protein(GFP)under the control of XAF1 promoter in the three digestive system cancer cell lines was lower than that of both HEK293 and L02 cells.The activities of pGL3-XAF1p in the three digestive system cancer cell lines after treatment with heat stress were significantly lower than those in the unstressed cells.The results suggested that remarkably down-regulated XAF1 mRNA expression in digestive system cancer cell lines may be due to loss of transcription activity of XAF1 promoter.
基金founded by JSPS KAKENHI,No.24390416,JP15H05015,15K15684 and JP16H01304(all to HN)
文摘Interleukin-1βis a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease,Parkinson’s disease,stroke and persistent pain.Activated microglia are the main cellular source of interleukin-1βin the brain.Cathepsin B is associated with the production and secretion of interleukin-1βthrough pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes.The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A,which can stabilize mitochondrial DNA.Therefore,microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging.Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.
文摘Background Hyperphosphatemia in renal failure has been identified as a major role in the pathogenesis of hyperparathyroidism that is independent of changes in serum calcium and 1,25(OH)203. The aim of this study was to evaluate the expression of parathyroid Pit-1 in hyperphosphatemia-induced secondary hyperparathyroidism (SHPT) of chronic renal failure (CRF) rats. Methods Wistar rats with CRF induced by 5/6 nephrectomy were ramdomly fed with diet containing 1.2% inorganic phosphate (Pi, high phosphate (HP) group, n=-9) or 0.2% Pi (low phosphate (LP) group, n=9) for 10 weeks starting from the fourth week after the surgery. Another 7 nephrectomy rats with HP diet were intraperitoneally injected with phosphonoformic acid (PFA, the specific inhibitor of Pit-l, HP+PFA group) 0.15 g/kg every other day for 10 weeks starting from HP diet. Another 6 HP rats injected with the same amount of normal saline as the control of the HP+PFA group (HP+saline group). At the same time, 9 rats with sham surgery received HP diet as the controls. At the 4th week and 14th week, blood was taken for measurement of serum creatinine (SCr), serum calcium (SCa), serum phosphorus (SPi), 1,25(OH)2D3 and intact parathyroid hormone (iPTH). At the 14th week, two parathroid glands (PTGs) of each rat were removed by microsurgery, one gland for immunohistochemistry analysis of proliferating cell nuclear antigen (PCNA), the other one for detection of Pit-1 by Western blotting, and for the measurement of Pit-1 mRNA and PTH mRNA by real-time quantitative polymerase chain reaction. Results In nephrectomy rats, high dierary phosphate induced a marked increase in serum phosphate, iPTH, PTH mRNA and PCNA parathyroid cells, accompanying Pit-1 and its mRNA in parathyroid gland increased significantly. However, serum Ca and 1,25(OH)2D3 remained unchanged. PFA decreased Pit-1 and its mRNA levels to reduce intact PTH, PTH mRNA and PCNA-positive parathyroid cells. Conclusions Expression of parathyroid Pit-1 in hyperphosphatemia-induced SHPT of CRF rats was upregulated. Pit-1 may mediate the stimulation to parathyroid gland by hyperphosphatemia.
基金supported by Key Science and Technology Project of Hainan Province(Grant No.ZDXM20100042)
文摘Objective:To evaluate the expression levels and correlations among the expressions of transforming growth factor-β_1(TGF-β_1),Kunx3 and CD83 in colonic mucosal specimens from IBS patients.Methods:A total of 40 patients were selected,who were confirmed as IBS by Rome III standard and 40 healthy volunteers served as control.Colonic mucosal specimens of each subject were collected from colon sigmoideum with biopsy forceps.Runx3,TGF-β_1?and CD83(the marker for immunecompetent mature dendritic cells(DCs)mRNA in the sigmoid colon tissue were measured by real-time fluorescence quantitative PCR.Results:Compared with the control group,CD83 mRNA expressions were higher in patients with IBS than in healthy controls(P<0.05)and were associated with runt-related transcription factor 3(Runx3)mRNA levels(r=-0.361,P<0.05).Meanwhile,Runx3 mRNA levels were associated with TGF-β_1,mRNA expressions in irritable bowel syndrome(IBS)patients(r=0.402,P<0.05).However,there was no correlation between the mRNA expressions of TGF-β_1 and CD83(P>0.05).Conclusions:The increase of abnormal dendritic cells might influence the occurrence and development of IBS.TGF-β_1 signal pathway might not be involved in Runx 3-regulated maturation of dendritic cells in IBS.
文摘We report a case of pure struma ovarii tumor diagnosed by cytology during laparoscopic surgery. The patient was a 34-year-old Japanese woman, gravida 1, para 1, who had the left adnexal mass, and was pre-operatively diagnosed as left ovarian endometriotic cyst or mature cystic teratoma by magnetic resonance imaging findings. She underwent laparoscopy, and the content of the left ovarian cystic tumor was found to be yellow gelatinous material, suggesting mature cystic teratoma. The imprint cytology of the tumor showed benign glandular pattern, suggesting struma ovarii. Histopathological findings led us to the diagnosis of pure struma ovarii with positive reactions for thyroglobulin and thyroid transcription factor-1. No metastases or disseminated lesions were detected. The patient has no recurrent signs 7 months after the operation.
文摘The diagnosis of gastric metastasis from lung cancer is relatively rare in living patients.We describe a case of Type 4 tumor-like metastasis due to primary lung cancer diagnosed with immunohistochemical staining while the patient was alive.A 68-year-old man was admitted to our hospital because of epigastric pain.Gastrointestinal endoscopy revealed a Type 4 tumor and the histological examination showed poorly differentiated adenocar-cinoma.His chest X-ray showed mass shadow in the right upper lung field.The resected specimens showed moderately differentiated adenocarcinoma.,The diagnosis of gastric metastasis from lung cancer was made by immunohistochemical staining of the lung and gastric tumors which showed positive staining for Thyroid transcriptional factor-1.Diagnosis of gastric metastasis,especially Type 4 metastasis by lung cancer is diff icult.However,immunohistochemical staining is very helpful for diagnosis of primary lung cancer metastasis at sites such as the gastrointestinal tract which are not normally prone to metastatis.
基金Supported by the Natural Science Foundation of Liaoning Province,No.2019-BS-279.
文摘BACKGROUND The androgen responsive gene,ELL-associated factor 2(EAF2),expressed in benign prostate tissues,has been shown to play an important role in tumor suppression in a variety of malignant tumors.In addition,some scholars found that EAF2 frameshift mutations are associated with intratumor heterogeneity in colorectal cancer(CRC)and inactivation of EAF2 in microsatellite instability-high CRC.However,the molecular mechanism by which EAF2 is involved in CRC invasion and metastasis remains unclear.AIM To determine the clinical value of expression of EAF2 protein in CRC,and to study the effects of EAF2 on the invasion,migration,and angiogenesis of CRC cells in vitro.METHODS In this study,we collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein in patients with advanced CRC.Subsequently,we investigated the effect of EAF2 on the invasion,migration,and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS EAF2 protein was lowly expressed in cancer tissues of patients with advanced CRC.Kaplan-Meier survival analysis showed that the survival rate of the high EAF2 level group was higher than that of the low EAF2 level group.CONCLUSION Our results demonstrated that EAF2,as a tumor suppressor,may inhibit the invasion,metastasis,and angiogenesis of CRC cells by regulating the signal transducer and activator of transcription 3/transforming growth factor-β1 crosstalk pathway,and play a cancer suppressive and protective role in the occurrence and development of CRC.Our findings are of great significance to provide a new idea and theoretical basis for the targeted diagnosis and treatment of CRC.
基金This study was supported by Shanghai Changning District Committee of Science and Technology(CNKW2016Y01)Shanghai Tongren Hospital Project(TRYJ201501)+3 种基金Suzhou Science and Technology Development Program(SYS201717)the Second Affiliated Hospital of Soochow University Advance Research Program of the Natural Science Foundation of China Grants(SDFEYGJ1705)Open project of Jiangsu State Key Laboratory of Radiation Medicine and Projection(GJS1963)the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Transforming growth factor-β1(TGF-β1)acts as a tumor promoter in advanced prostate cancer(PCa).We speculated that microRNAs(miRNAs)that are inhibited by TGF-β1 might exert anti-tumor effects.To assess this,we identified several miRNAs downregulated by TGF-β1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA.miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue,and its expression level correlated inversely with aggressive clinical pathological features.Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation,migration,and invasion,and promoted apoptosis.The miR-3691-3p target genes E2F transcription factor 3(E2F3)and PR domain containing 1,with ZNF domain(PRDM1)were upregulated in miR-3691-3p-overexpressing PCa cells,and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation,migration,and invasion.Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis.Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p,both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue.Our results indicate that TGF-β1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1.These results provide novel insights into the mechanisms by which TGF-β1 contributes to the progression of PCa.
基金Efforts are supported by the Department of Defense Grants(W81XWH-18-1-0618,W81XWH-15-1-0558)VA Merit Review(1I01BX002494)to Gupta S.Kushwaha PP acknowledges financial support from University Grants Commission,India in the form of CSIR-UGC Senior Research fellowshipKumar S acknowledges Department of Science and Technology,India,and University Grants Commission,India for providing financial support in the form of DST-SERB Grant[EEQ/2016/000350]and UGC-BSR Research Start-Up-Grant[No.F.30-372/2017(BSR)]respectively.
文摘Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment.Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways.Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes.This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance.