Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy

Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptosis,pyroptosis,and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy(CRT).Methods:The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT.The associations between genetic variations and overall survival(OS)were evaluated using hazard ratios(HRs)and 95%confidence intervals(CIs)computed using a Cox proportional regression model.Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase(ALOX5)gene and the ALOX5 rs702365 variant.Results:We detected 16 genetic polymorphisms in CASP3,CASP7,TRAILR2,GSDME,CASP4,HO-1,ALOX5,GPX4,and NRF2 that were significantly associated with OS in the additive model(P<0.05).There was a substantial cumulative effect of three genetic polymorphisms(CASP4 rs571407,ALOX5 rs2242332,and HO-1 rs17883419)on OS.Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS.We demonstrated,for the first time,that rs702365[G]>[C]represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.Conclusions:Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

Telomerase-related advances in hepatocellular carcinoma:A bibliometric and visual analysis

BACKGROUND As a critical early event in hepatocellular carcinogenesis,telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma(HCC)patients,and its function in the genesis and treatment of HCC has gained much attention over the past two decades.AIM To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase.METHODS The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to“articles”and“reviews”published in English.A total of 873 relevant publications related to HCC and telomerase were identified.We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications,such as the trends in the publications,citation counts,most prolific or influential writers,and most popular journals;to screen for keywords occurring at high frequency;and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences.VOSviewer was utilized to compile and visualize the bibliometric data.RESULTS A surge of 51 publications on HCC/telomerase research occurred in 2016,the most productive year from 1996 to 2023,accompanied by the peak citation count recorded in 2016.Up to December 2023,35226 citations were made to all publications,an average of 46.6 citations to each paper.The United States received the most citations(n=13531),followed by China(n=7427)and Japan(n=5754).In terms of national cooperation,China presented the highest centrality,its strongest bonds being to the United States and Japan.Among the 20 academic institutions with the most publications,ten came from China and the rest of Asia,though the University of Paris Cité,Public Assistance-Hospitals of Paris,and the National Institute of Health and Medical Research(INSERM)were the most prolific.As for individual contributions,Hisatomi H,Kaneko S,and Ide T were the three most prolific authors.Kaneko S ranked first by H-index,G-index,and overall publication count,while Zucman-Rossi J ranked first in citation count.The five most popular journals were the World Journal of Gastroenterology,Hepatology,Journal of Hepatology,Oncotarget,and Oncogene,while Nature Genetics,Hepatology,and Nature Reviews Disease Primers had the most citations.We extracted 2293 keywords from the publications,120 of which appeared more than ten times.The most frequent were HCC,telomerase and human telomerase reverse transcriptase(hTERT).Keywords such as mutational landscape,TERT promoter mutations,landscape,risk,and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years.CONCLUSION Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer

The mortality rate of gastric cancer worldwide is as high as 70%, despite the development of novel therapeutic strategies. One reason for the high mortality is the rapid and uninhibited spread of the disease, such that the majority of patients are diagnosed at a stage when efficient therapeutic treatment is not available. Therefore, in-depth research is needed to investigate the mechanism of gastric cancer metastasis and invasion to improve outcomes and provide biomarkers for early diagnosis. The mitogen-activated protein kinase(MAPK) signaling pathway is widely expressed in multicellular organisms, with critical roles in multiple biological processes, such as cell proliferation, death, differentiation, migration, and invasion. The MAPK pathway typically responds to extracellular stimulation. However, the MAPK pathway is often involved in the occurrence and progression of cancer when abnormally regulated. Many studies have researched the relationship between the MAPK signaling pathway and cancer metastasis and invasion, but little is known about the important roles that the MAPK signaling pathway plays in gastric cancer. Based on an analysis of published data, this review aims to summarize the important role that the MAP kinases play in the invasion and metastasis of gastric cancer and attempts to provide potential directions for further research and clinical treatment.

Genetic Polymorphism of PSCA and Risk of Advanced Precancerous Gastric Lesions in a Chinese Population

Objective： To evaluate the relationship between the genetic polymorphism of prostate stem cell antigen （PSCA） and the risk of advanced precancerous gastric lesions including intestinal metaplasia（IM） and dysplasia（Dys）, a population-based study was conducted in Linqu County, a high-risk area of gastric cancer （GC） in China. Methods： The prevalence of gastric lesions including superficial gastritis（SG）, chronic atrophic gastritis（CAG）, IM and Dys was determined by histopathologic examination. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） technique. The effects of PSCA genetic variant on the risks of IM and Dys were calculated by unconditional logistic regression. Results： Multivariate analysis revealed subjects carrying PSCA rs2294008 CT/TT genotype were associated with an increased risk of IM （OR=1.38, 95% CI=1.11-1.71） and Dys （OR=1.75, 95% CI=1.36-2.26）, especially for subjects with H.pylori infection （IM： OR=1.34, 95% CI=1.05-1.71; Dys： OR=1.82, 95% CI=1.37-2.42）. Furthermore, H. pylori infection and PSCA rs2294008 CT/TT genotype were observed to jointly elevate the risk of IM （OR=3.32, 95% CI=2.33-4.71） and Dys （OR=4.58, 95% CI=2.99-7.04）. Conclusion： This study suggested that PSCA rs2294008 might have an impact on the risk of IM or Dys among the high risk population of GC.

Research progress of the role of HGF/c-Met in the proliferation, invasion, angiogenesis and metastasis of cancer

The HGF/c-Met pathway plays an important role in the proliferation, invasion, angiogenesis, and metastasis of tumors. With the successful development of small molecule c-Met kinase inhibitors, this signal pathway has become the focus of oncology research. In this review, we discuss the basic mechanism, targeted therapy, and early results of clinical trials of the HGF/c-Met pathway.

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma

BACKGROUND Spindle and kinetochore-associated complex subunit 3(SKA3)is a malignancyassociated gene that plays a critical role in the regulation of chromosome separation and cell division.However,the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma(HCC)has not been fully elucidated.AIM To investigate the molecular mechanisms underlying the role of SKA3 in HCC.METHODS SKA3 expression,clinicopathological,and survival analyses were performed using multiple public database platforms,and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples.Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC.Furthermore,the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis(ssGSEA)algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC.The response to chemotherapeutic drugs was evaluated by the R package“pRRophetic”.RESULTS We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC.Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival.GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair.Moreover,patients with high SKA3 expression had significantly decreased ratios of CD8+T cells,natural killer cells,and dendritic cells.Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib,sunitinib,paclitaxel,doxorubicin,gemcitabine,and vx-680.CONCLUSION High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC.SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

A single nucleotide polymorphism in the matrix metalloproteinase 2 promoter is closely associated with high risk of nasopharyngeal carcinoma in Cantonese from southern China

Matrix metalloproteinase 2(MMP2) has been shown to play an important role in several steps of cancer development.The-1306C/T polymorphism of the MMP2 gene displays a strikingly lower promoter activity than the T allele,and the CC genotype in the MMP2 promoter has been reported to associate with the development of several cancers.To assess the contribution of the MMP2-1306C/T polymorphism to the risk of nasopharyngeal carcinoma(NPC),we conducted a case-control study and analyzed MMP2 genotypes in 370 patients with NPC and 390 frequency-matched controls using real-time PCR-based TaqMan allele analysis.We found that subjects with the CC genotype had an increased risk(OR = 1.55,95% CI = 1.05-2.27) of developing NPC compared to those with the CT or TT genotypes.Furthermore,we found that the risk of NPC was markedly increased in subjects who were smokers(OR = 15.04,95% CI = 6.65-33.99),heavy smokers who smoked ≥20 pack-years(OR = 18.66,95% CI = 7.67-45.38),or young(<60 years) at diagnosis(OR = 1.52,95% CI = 1.01-2.29).Our results provide molecular epidemiological evidence that the MMP2-1306C/T promoter polymorphism is associated with NPC risk,and this association is especially noteworthy in heavy smokers.

Comparison of dimension reduction-based logistic regression models for case-control genome-wide association study:principal components analysis vs.partial least squares

With recent advances in biotechnology, genome-wide association study （GWAS） has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistical strategy is traditional logistical regression （LR） based on single-locus analysis. However, such a single-locus analysis leads to the well-known multiplicity problem, with a risk of inflating type I error and reducing power. Dimension reduction-based techniques, such as principal component-based logistic regression （PC-LR）, partial least squares-based logistic regression （PLS-LR）, have recently gained much attention in the analysis of high dimensional genomic data. However, the perfor- mance of these methods is still not clear, especially in GWAS. We conducted simulations and real data application to compare the type I error and power of PC-LR, PLS-LR and LR applicable to GWAS within a defined single nucleotide polymorphism （SNP） set region. We found that PC-LR and PLS can reasonably control type I error under null hypothesis. On contrast, LR, which is corrected by Bonferroni method, was more conserved in all simulation settings. In particular, we found that PC-LR and PLS-LR had comparable power and they both outperformed LR, especially when the causal SNP was in high linkage disequilibrium with genotyped ones and with a small effective size in simulation. Based on SNP set analysis, we applied all three methods to analyze non-small cell lung cancer GWAS data.

Role of MetallothioneinlH in Cisplatin Resistance of Non-Small Cell Lung Cancer Cells

Objective： Despite platinum-based adjuvant chemotherapy has improved greatly patients＇ outcomes, drug resistance poses a major impediment to the successful use of such an effective agent. Metallothioneins（MTs） are known to play putative roles in cancer cell proliferation, apoptosis, differentiation, drug resistance and prognosis. The present studiy was to investigte the role of metallethioeinlH（MTIH） in cisplatin resistance of human non-small cell lung cancer（NSCLC） cell lines in vitro or its possible molecular mechanisms. Methods： MTIH mRNA expression in A549 and A549/DDP cells was detected by RT-PCR. A recombinant eukaryotic expression plasmid pcDNA3.1（-）-MT1H was constructed and transfected into A549 cells which express no MTIH. MT1H siRNA was transfected into A549/DDP cells which express MTIH highly. MTIH expression was detected by RT-PCR and Immunoblot. The chemosensitivity to cisplatin was assessed by MTT assay. Apoptosis rate was determined by Tunel and FCM. Bcl-2 and Bax were determined by immunohistochemistry. Results： MT1H mRNA was expressed in A549/DDP but not in A549. After transfection of MT1H, MT1H expression was enhanced and the chemosensitivity to cisplatin was decreased in A549 cells. Inversely, after transfection of MT1H siRNA, MT1H expression was decreased and the chemosensitivity to cisplatin was increased in A549/DDP. The apoptosis rate induced by cisplatin was increased and Bcl-2 was down-regulated but Bax showed little change in A549/DDP cells interferred with MT1H siRNA. Conclusion： MT1H overexpression can promote drug resistance in A549 cells . Down-regulation of MTIH interfered with siRNA can effectively reverses the drug resistance in A549/DDP cells by down-regulating the expression of Bcl-2 and increasing cisplatin induced apoptosis. SiRNA targeting MT1H combined with chemotherapy may be a very promising strategy for treatment of lung cancer.

Detection of piRNA-54265 in human serum:evidence and significance

Dear Editor,An increasing number of studies have shown that PIWIinteracting RNAs(piRNAs)are aberrantly expressed in many types of human cancer and involved in regulating the malignant progression,piRNAs would be expected to serve as molecular biomarkers for cancer screening and early diagnosis.In a previous study,we have identified the presence of piRNA-54265 in human serum[1].Further research has demonstrated that it is a promising and specific blood molecularmarker for colorectal cancer(CRC)[2].In these studies,we have developed a stem-loop primer reverse transcription-quantitative PCR(RT-qPCR)approach to determine the piRNA-54265 levels,which included the reverse transcription of piRNA-54265 to cDNA using a stem-loop primer and the quantitative detection of cDNA by PCR with the primers and probe specific for piR-54265[2].

Roles and implications of mRNA N^(6)-methyladenosine in cancer

RNA N^(6)-methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics,garnering increased attention.To date,m^(6)A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes.Recent evidence suggests that aberrant m^(6)A modification is a hallmark of cancer,and it plays a critical role in cancer development and progression through multiple mechanisms.Here,we review the biological functions of mRNA m^(6)A modification in various types of cancers,with a particular focus on metabolic reprogramming,programmed cell death and tumor metastasis.Furthermore,we discuss the potential of targetingm^(6)Amodification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m^(6)A modification in tumor immunity and immunotherapy.Finally,we summarize the development of different m^(6)A detection methods and their advantages and disadvantages.

Mutations in the DNA polymerase binding pathway affect the immune microenvironment of patients with small-cell lung cancer and enhance the efficacy of platinum-based chemotherapy

Background:Small-cell lung cancer(SCLC)is characterized by its high malignancy and is associated with a poor prognosis.In the early stages of the disease,platinum-based chemotherapy is the recommended first-line treatment and has demonstrated efficacy.However,SCLC is prone to recurrence and is generally resistant to chemotherapy in its later stages.Methods:Here,we collected samples from SCLC patients who received platinum-based chemotherapy,performed genomic and transcriptomic analyses,and validated our results with publicly available data.Results:SCLC patients with DNA polymerase binding pathway mutations had an improved prognosis after platinum chemotherapy compared with patients without such mutations.Patients in the mutant(MT)group had higher infiltration of T cells,B cells,and M1 macrophages compared with patients without DNA polymerase binding pathway mutations.Conclusions:DNA polymerase binding pathway mutations can be used as prognostic markers for platinum-based chemotherapy in SCLC.

Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression

Epithelial-mesenchymal transition(EMT)and proliferation play important roles in epithelial cancer formation and progression,but what molecules and how they trigger EMT is largely unknown.Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma(ESCC)from mice and humans to decipher these critical issues.By investigating spatiotemporal gene expression patterns and cell–cell interactions,we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRC/ERK/AKT signaling.The aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions,which expands to the whole epithelial layer and strengthens along the cancer development and progression.Functional analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressedΔNP63 due to TP53 mutation,the culprit in human ESCC tumorigenesis.Our results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation.

Organoid co-culture models of the tumor microenvironment promote precision medicine

In recent years,the three-dimensional(3D)culture system has emerged as a promising preclinical model for tumor research owing to its ability to replicate the tissue structure and molecular characteristics of solid tumors in vivo.This system offers several advantages,including high throughput,efficiency,and retention of tumor heterogeneity.Traditional Matrigel-submerged organoid cultures primarily support the long-term proliferation of epithelial cells.One solution for the exploration of the tumor microenvironment is a reconstitution approach involving the introduction of exogenous cell types,either in dual,triple or even multiple combinations.Another solution is a holistic approach including patient-derived tumor fragments,air-liquid interface,suspension 3D culture,and microfluidic tumor-on-chip models.Organoid co-culture models have also gained popularity for studying the tumor microenvironment,evaluating tumor immunotherapy,identifying predictive biomarkers,screening for effective drugs,and modeling infections.By leveraging these 3D culture systems,it is hoped to advance the clinical application of therapeutic approaches and improve patient outcomes.

Prognostic Significance of Tumor-infiltrating CD8^＋ or CD3^＋ T Lymphocytes and Interleukin-2 Expression in Radically Resected Non-small Cell Lung Cancer

Background：Altered immunoresponse is associated with tumorigenesis and cancer progression.This study assessed the levels of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and interleukin-2 （IL-2） protein in radically resected non-small cell lung cancer （NSCLC） tissues to predict overall survival （OS） of the patients.Methods：Paraffin-embedded tissue specimens from 129 NSCLC patients were retrospectively collected for immunostaining of CD8^＋,CD3^＋,and IL-2 expression.Clinicopathological and survival data were collected and analyzed using the Chi-squared test,Kaplan-Meier curves,and the log-rank test or the Cox regression model.Results：The data showed a significant inverse association between CD8^＋ T lymphocyte levels and IL-2 expression （r =-0.927; P =0.000） and between the levels of CD8^＋ and CD3^＋ T lymphocytes （r =-0.722; P =0.000）,but a positive association between CD3^＋ T lymphocyte levels and IL-2 expression （r =0.781; P =0.000） in NSCLC tissues.Furthermore,the levels of CD3^＋ and CD8^＋ T lymphocytes and IL-2 expression were associated with tumor stage （P =0.023,0.006,and 0.031,respectively） and the level of CD8^＋ T lymphocytes was associated with the patient gender （P =0.024）.In addition,the levels of CD8^＋ T lymphocytes were associated with an unfavorable 5-year OS,whereas patients with high levels of CD3^＋ T lymphocytes in tumor lesions and IL-2-expressing tumors had significantly better 5-year OS rates than patients with low levels.Conclusions：The levels of CD8^＋ T cells in tumor lesions and IL-2 expression were both independent predictors of OS for these NSCLC patients.Thus,the detection of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and IL-2 expression could be useful to predict the prognosis of radically resected NSCLC patients.

Characterization of Distinct T Cell Receptor Repertoires in Tumor and Distant Non-tumor Tissues from Lung Cancer Patients

T cells and T cell receptors(TCRs)play pivotal roles in adaptive immune responses against tumors.The development of next-generation sequencing technologies has enabled the analysis of the TCRb repertoire usage.Given the scarce investigations on the TCR repertoire in lung cancer tissues,in this study,we analyzed TCRb repertoires in lung cancer tissues and the matched distant non-tumor lung tissues(normal lung tissues)from 15 lung cancer patients.Based on our results,the general distribution of T cell clones was similar between cancer tissues and normal lung tissues;however,the proportion of highly expanded clones was significantly higher in normal lung tissues than in cancer tissues(0.021%±0.002%vs.0.016%±0.001%,P=0.0054,Wilcoxon signed rank test).In addition,a significantly higher TCR diversity was observed in cancer tissues than in normal lung tissues(431.37±305.96 vs.166.20±101.58,P=0.0075,Mann-Whitney U test).Moreover,younger patients had a significantly higher TCR diversity than older patients(640.7±295.3 vs.291.8±233.6,P=0.036,Mann-Whitney U test),and the higher TCR diversity in tumors was significantly associated with worse cancer outcomes.Thus,we provided a comprehensive comparison of the TCR repertoires between cancer tissues and matched normal lung tissues and demonstrated the presence of distinct T cell immune microenvironments in lung cancer patients.

Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN (≥149.97 ng/mL), MMP7 (≥2.28 ng/mL), and PSG9 (≥45.59 ng/mL) were prognostic indicators of reduced OS (P<0.001, P<0.001, and P=0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P=0.008) and DFS (P=0.038). Plasma OPN+MMP7+PSG9 elevation in combination was a prognostic factor for OS (P<0.001). OPN was demonstrated to be a risk factor-associated OS in stage I patients with HCC and patients with low α-fetoprotein levels (<20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer

Background Although chemotherapy is one of the most important treatments of breast cancer,it is limited by significant inter-individuval variations in response and toxicity.The metabolism of epirubicin （EPI） and cyclophosphamide （CTX） is mainly mediated by cytochrome P450s （CYPs） and glutathione S-transferases （GSTs）.It has been well-known that the activities of these enzymes are polymorphic in population due to their genetic polymorphisms.The aim of this research was to examine the effects of genetic polymorphisms in CYP3A,GSTP1 and MDR1 genes on treatment response and side-effects of breast cancer patients receiving EPI/CTX chemotherapy.Methods One hundred and twenty patients with stage Ⅱ or Ⅲ invasive breast cancer were recruited and treated with three to four cycles of EPI 80 mg/m2 and CTX 600 mg/m2 every two weeks.The AJCC TNM staging system （sixth edition）was used to evaluate the pathological response of primary tumor and axillary lymph nodes.The genotypes of gene polymorphisms were determined by using PCR-restriction fragment length polymorphism methods.Results Patients carrying GSTP1 105 lle/Val or 105 lle/lle genotype were more likely to have good response （OR,0.40;95% CI,0.16-0.96;P=0.024） and light toxicity （OR,0.35;95% Cl,0.13-0.78;P=0.006） than those carrying 105Val/Val genotypes.The response to the treatment was not correlated with estrogen receptor,progesterone receptor and Her2/neu status of tumors.No correlation was found between toxicity effect and patient＇s age,tumor staging,menopause status,and dose intensity of the drugs.Conclusion GSTP1 polymorphism was associatiated with the chemotherapy response or adverse effects of EPI and CTX regimens.

Expression of cytochrome P4502E1 in human liver: relationship between genotype and phenotype in Chinese

Polymorphic cytochrome P4502E1 (CYP2E1) plays an important role in the metabolic activation of many carcinogens. We have previously shown that the c1/c1 genotype recognized by Rsa I in the 5′-regulatory region of the CYP2E1 may be a susceptibility factor for developing esophageal cancer and lung cancer in Chinese. The present study was to investigate the relationship between the Rsa I genotype and the expression of CYP2E1 in human livers. A total of 50 liver specimens were genotyped for CYP2E1 and assayed for CYP2E1 protein contents and functional activity by using specific antibody in immunoblot and a probe substrate, p-nitrophenol. A considerable interindividual variation in CYP2E1 protein (20-fold) and functional activity (56-fold) was observed among these liver samples. However, when they were categorized according to genotype, the mean content of CYP2E1 protein was significantly higher among individuals with the c1/c1 genotype than that among those having c1/c2 or c2/c2 genotype [124.0±83.9 pmol/mg (n = 28) versus 65.5±38.9 pmol/mg (n = 22), P＜0.01 . The mean activity of CYP2E1 towards p-nitrophenol for the c1/c1 genotype was also higher than that for the variant genotypes (198.4±27.8 pmol/min/mg versus 101.2±18.1 pmol-1·min-1·mg-1, P＜0.01 . Also, the protein levels and functional activity showed a significant correlation (r = 0.68, P＜0.01 . These results demonstrate an association between the Rsa I genotype and the phenotype of CYP2E1 in our samples, and the data are compatible with the assumption that CYP2E1 c1/c1 genotype is a susceptibility factor for certain cancers in Chinese.

NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma

Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.