GNAi2/gip2-Regulated Transcriptome and Its Therapeutic Significance in Ovarian Cancer

Abstract

Increased expression of GNAi2, which encodes the α-subunit of G-protein i2, has been correlated with the late-stage progression of ovarian cancer. GNAi2, also referred to as the proto-oncogene gip2, transduces signals from lysophosphatidic acid (LPA)-activated LPA-receptors to oncogenic cellular responses in ovarian cancer cells. To identify the oncogenic program activated by gip2, we carried out micro-array-based transcriptomic and bioinformatic analyses using the ovarian cancer cell-line SKOV3, in which the expression of GNAi2/gip2 was silenced by specific shRNA. A cut-off value of 5-fold change in gene expression (p < 0.05) indicated that a total of 264 genes were dependent upon gip2-expression with 136 genes coding for functional proteins. Functional annotation of the transcriptome indicated the hitherto unknown role of gip2 in stimulating the expression of oncogenic/growth-promoting genes such as KDR/VEGFR2, CCL20, and VIP. The array results were further validated in a panel of High-Grade Serous Ovarian Carcinoma (HGSOC) cell lines that included Kuramochi, OVCAR3, and OVCAR8 cells. Gene set enrichment analyses using DAVID, STRING, and Cytoscape applications indicated the potential role of the gip2-stimulated transcriptomic network involved in the upregulation of cell proliferation, adhesion, migration, cellular metabolism, and therapy resistance. The results unravel a multi-modular network in which the hub and bottleneck nodes are defined by ACKR3/CXCR7, IL6, VEGFA, CYCS, COX5B, UQCRC1, UQCRFS1, and FYN. The identification of these genes as the critical nodes in GNAi2/gip2 orchestrated onco-transcriptome establishes their role in ovarian cancer pathophysiology. In addition, these results also point to these nodes as potential targets for novel therapeutic strategies.

FYN: emerging biological roles and potential therapeutic targets in cancer

“…Integrins are involved in triggering FAK-Y397 phosphorylation, and a portion of FAK is located in the lipid raft/fossa structural domain where it interacts with FYN leading to elevated levels of FYN phosphorylation and elevated activity [ 63 ]. Microarray transcriptomic and bioinformatic analysis of ovarian cancer identified FYN as a key downstream target in the transcriptome of GNAi2/gip2 regulated tumor progression [ 64 ].…”

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

“…Lysophosphatidic acid (LPA), a lipid growth factor highly secreted in the ovarian tumor microenvironment [13], exerts several pro-tumorigenic activities such as (i) reprogramming toward a glycolytic shift that associates with the pheno-conversion of ovarian normal fibroblasts into cancer-associated fibroblasts (CAFs) [14] and with the enhanced proliferation of ovarian cancer cells [15], (ii) upregulating the oncogenic/growth-promoting transcriptome [16,17], (iii) promoting EMT and invasiveness [18,19], (iv) stimulating the secretion of pro-inflammatory and angiogenic factors (such as TNF-α, IL-6, IL-8, VEGF, etc.) [20,21], and (v) promoting therapy resistance either by supporting an immunosuppressive phenotype or by protecting tumor cells from apoptosis [21].…”

A Signature of N6-methyladenosine Regulator-Related Genes Predicts Prognoses and Immune Responses for Head and Neck Squamous Cell Carcinoma

“…The pleiotropic protein p62/ SQSTM1 is subjected to degradation during autophagy, and its expression has been demonstrated to increase in primary HNSCC tumors. CYCS encodes the core component protein of the mitochondrial electron transport chain, which is also involved in the initiation of apoptosis and various tumor processes (40,41). Although the mechanisms of some of these genes in HNSCC were not clear in the present study, studies have also confirmed that they could be involved in the occurrence and development of tumors in other cancers.…”