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TGF-? modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

ABSTRACT: TGF-? has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-?-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-? enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-? receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-?B signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-?-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-? stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-?-targeted therapy of ovarian cancer.

SUBMITTER: Yeung TL

PROVIDER: S-EPMC3745588 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

Yeung Tsz-Lun TL Leung Cecilia S CS Wong Kwong-Kwok KK Samimi Goli G Thompson Melissa S MS Liu Jinsong J Zaid Tarrik M TM Ghosh Sue S Birrer Michael J MJ Mok Samuel C SC

Cancer research 20130703 16

TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated no ...[more]

PMID: 23824740

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Project description:ObjectiveTo explore the regulatory role of miR-4772 in the formation of tumor immune microenvironment in ovarian cancer.MethodsThe optimal cutoff level of PD-L1 expression was calculated based on data from 294 ovarian cancer patients in the TCGA database. The differentially expressed genes (DEGs) between high and low PD-L1 expression groups were screened, and the important DEGs were identified by correlation analysis. WGCNA analysis was performed to select the weighted genes and PD-L1-related miRNAs, from which the hub genes were obtained by intersection analysis. ssGSEA analysis was used to evaluate the effect of PD-L1 and miR-4772 expressions on the tumor immune microenvironment in ovarian cancer. KEGG analysis was used to identify the involved signal pathways, and the interactions between the hub genes were mapped by protein-protein interaction (PPI) analysis. Survival analysis was carried out to identify the survival-related hub genes, and the results were validated using the data of 399 patients with ovarian cancer from GEO database and the sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor.ResultsAccording the optimal cutoff level of PD-L1 expression of 1.31582 (90th quantile), the patients were divided into high- and low-PD-L1 expression groups. A total of 840 DEGs were identified, including 549 significantly up-regulated genes and 291 down-regulated genes. Among them, 20 important DEGs were found to closely correlate with miR-4772 expression, and WGCNA analysis identified 48 weighted genes significantly correlated with miR-4772. Twelve genes were identified as both key DEGs and weighted genes and were treated as the hub genes. ssGSEA analysis showed that both the patients with high PD-L1 expressions and those with high miR-4772 expressions showed more active immune infiltration and functional activity. The 12 hub genes were involved mainly in immune-related signaling pathways, and PPI analysis suggested significant interactions among the hub genes. The two hub genes CD96 and TBX21 showed close correlation with the survival of ovarian cancer patients. The sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor showed that the changes in miR-4772 expression level caused obvious changes in the expressions of the 12 hub genes and PD-L1.ConclusionMiR-4772 plays a regulatory role in the formation of tumor immune microenvironment in ovarian cancer by regulating 12 hub genes.

Dataset Information

TGF-? modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

Publications

TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

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