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Determinant role for the gep oncogenes, G?12/13, in ovarian cancer cell proliferation and xenograft tumor growth.

ABSTRACT: Recent studies have shown that the gip2 and gep oncogenes defined by the ?-subunits of Gi2 and G12 family of G proteins, namely G?i2 and G?12/13, stimulate oncogenic signaling pathways in cancer cells including those derived from ovarian cancer. However, the critical ?-subunit involved in ovarian cancer growth and progression in vivo remains to be identified. Using SKOV3 cells in which the expressions of individual G?-subunits were silenced, we demonstrate that the silencing of G?12 and G?13 drastically attenuated serum- or lysophosphatidic acid-stimulated proliferation. In contrast, the invasive migration of these cells were reduced only by the silencing of G?i2 or G?13. Analyses of the xenograft tumors derived from these G?-silenced cells indicated that only the silencing of G?13 drastically reduced xenograft tumor growth and prolonged the survival of the mice. Similar, but albeit reduced, effect was seen with the silencing of G?12. On the contrary, the silencing of G?i2 or G?q failed to exert such effect. Thus, our studies establish for the first time that G?12/13, the putative gep oncogenes, are the determinant ?-subunits involved in ovarian cancer growth in vivo and their increased oncogenicity can be correlated with its ability to stimulate both proliferation and invasive migration.

SUBMITTER: Ha JH

PROVIDER: S-EPMC4575922 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Determinant role for the gep oncogenes, Gα12/13, in ovarian cancer cell proliferation and xenograft tumor growth.

Ha Ji Hee JH Gomathinayagam Rohini R Yan Mingda M Jayaraman Muralidharan M Ramesh Rajagopal R Dhanasekaran Danny N DN

Genes & cancer 20150701 7-8

Recent studies have shown that the gip2 and gep oncogenes defined by the α-subunits of Gi2 and G12 family of G proteins, namely Gαi2 and Gα12/13, stimulate oncogenic signaling pathways in cancer cells including those derived from ovarian cancer. However, the critical α-subunit involved in ovarian cancer growth and progression in vivo remains to be identified. Using SKOV3 cells in which the expressions of individual Gα-subunits were silenced, we demonstrate that the silencing of Gα12 and Gα13 dra ...[more]

PMID: 26413218

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Project description:The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates.

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Dataset Information

Determinant role for the gep oncogenes, G?12/13, in ovarian cancer cell proliferation and xenograft tumor growth.

Publications

Determinant role for the gep oncogenes, Gα12/13, in ovarian cancer cell proliferation and xenograft tumor growth.

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