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VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients.

ABSTRACT: Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid-forming cells (SFCs) were isolated. The characteristic genes of SFCs were identified through cDNA microarray and validation by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association of their expression with clinicopathologic parameters was analyzed. GSC (4.26-fold), VAV3 (7.05-fold), FOXA2 (12.06-fold), LEF1 (17.26-fold), COMP (21.33-fold), GRIN2A (9.36-fold), CD86 (23.14-fold), PYY (4.18-fold), NKX3-2 (10.35-fold), and PDK4 (74.26-fold) were significantly upregulated in SFCs compared with parental cancer cells. With validation for human ovarian carcinomas, LEF1, PYY, NKX3-2, and WNT3A were significantly upregulated in chemoresistant cancers compared with chemosensitive cancers. Overexpression of LEF1, VAV3, and NKX3-2 was significantly associated with distant metastasis by immunohistochemistry. VAV3 overexpression was an independent poor survival indicator (hazard ratio=15.27, P<0.05) by multivariate Cox analysis. The further functional assay revealed that VAV3 knockdown regulated CSC activation and ovarian cancer cell proliferation and sensitized paclitaxel (PTX)-resistant cancer cells to PTX treatment. Taken together, we identified by high-throughput analysis of CSCs that VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma.

SUBMITTER: Kwon AY

PROVIDER: S-EPMC4499777 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients.

Kwon Ah-Young AY Kim Gwang-Il GI Jeong Ju-Yeon JY Song Ji-Ye JY Kwack Kyu-Beom KB Lee Chan C Kang Hae-Youn HY Kim Tae-Heon TH Heo Jin-Hyung JH An Hee Jung HJ

Stem cells and development 20150409 13

Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid-forming cells (SFCs) were is ...[more]

PMID: 25715123

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Project description:IntroductionIt is believed that ovarian cancer (OC) is the most deadly form of gynecological cancer despite its infrequent occurrence, which makes it one of the most salient public health concerns. Clinical and preclinical studies have revealed that intratumoral CD4+ T cells possess cytotoxic capabilities and were capable of directly killing cancer cells. This study aimed to identify the CD4+ conventional T cells-related genes (CD4TGs) with respect to the prognosis in OC.MethodsWe obtained the transcriptome and clinical data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CD4TGs were first identified from single-cell datasets, then univariate Cox regression was used to screen prognosis-related genes, LASSO was conducted to remove genes with coefficient zero, and multivariate Cox regression was used to calculate riskscore and to construct the CD4TGs risk signature. Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, time-dependent receiver operating characteristics (ROC), decision curve analysis (DCA), nomogram, and calibration were made to verify and evaluate the risk signature. Gene set enrichment analyses (GSEA) in risk groups were conducted to explore the tightly correlated pathways with the risk group. The role of riskscore has been further explored in the tumor microenvironment (TME), immunotherapy, and chemotherapy. A risk signature with 11 CD4TGs in OC was finally established in the TCGA database and furtherly validated in several GEO cohorts.ResultsHigh riskscore was significantly associated with a poorer prognosis and proven to be an independent prognostic biomarker by multivariate Cox regression. The 1-, 3-, and 5-year ROC values, DCA curve, nomogram, and calibration results confirmed the excellent prediction power of this model. Compared with the reported risk models, our model showed better performance. The patients were grouped into high-risk and low-risk subgroups according to the riskscore by the median value. The low-risk group patients tended to exhibit a higher immune infiltration, immune-related gene expression and were more sensitive to immunotherapy and chemotherapy.DiscussionCollectively, our findings of the prognostic value of CD4TGs in prognosis and immune response, provided valuable insights into the molecular mechanisms and clinical management of OC.

Project description:BackgroundBIRC7, which encodes Baculoviral inhibitor of apoptosis (IAP) repeat-containing protein 7, is an oncogene in multiple types of cancer. In this study, we examined the association between BIRC7 expression and the clinicopathological characteristics of prostate cancer, the independent prognostic value of BIRC7 in terms of recurrence-free survival, and the molecular mechanisms of its dysregulation.MethodsData mining was performed using data from The Cancer Genome Atlas. The patients were divided into high and low BIRC7 expression groups according to the Youden index determined by receiver operating characteristic curves for recurrence. Subgroup analysis was performed according to T stages and Gleason score.ResultsBIRC7 was significantly upregulated in prostate cancer tissues (N = 497) than in normal prostate tissues (N = 52). High BIRC7 expression group had lower ratios of overall response rate and medium-grade (Gleason score 6-7) tumors and higher proportions of nodal invasion and recurrence after surgery. Although Kaplan-Meier curves showed that high BIRC7 expression was generally associated with poor recurrence-free survival, the following subgroup analysis only confirmed the association in T3/T4 and medium-grade tumors. Multivariate analysis showed that BIRC7 expression was not an independent indicator of recurrence-free survival in T2 or high-grade tumors, but was independently associated with poor recurrence-free survival in T3/T4 tumors (hazard ratio: 4.249, 95% confidence interval: 1.563-11.546, P = .005) and in medium-grade tumors (hazard ratio: 6.041, 95% confidence interval: 1.763-20.703, P = .004). DNA amplification was associated with significantly upregulated BIRC7 expression. There was also a weak negative correlation between BIRC7 expression and its DNA methylation (Pearson r = -0.23).ConclusionBased on these findings, we infer that BIRC7 upregulation might serve as a valuable biomarker of increased recurrence risk in advanced T stages and medium-grade prostate cancer. Its expression is at least regulated by both copy number alteration and DNA methylation.

Dataset Information

VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients.

Publications

VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients.

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