Identification of GNA12-driven gene signatures and key signaling networks in ovarian cancer

Ji-Hee Ha; Muralidharan Jayaraman; Mingda Yan; Padmaja Dhanasekaran; Ciro Isidoro; Yong-Sang Song; Danny N Dhanasekaran

doi:10.3892/ol.2021.12980

Identification of GNA12-driven gene signatures and key signaling networks in ovarian cancer

Oncol Lett. 2021 Oct;22(4):719. doi: 10.3892/ol.2021.12980. Epub 2021 Aug 10.

Authors

Ji-Hee Ha^{1

2}, Muralidharan Jayaraman^{1

2}, Mingda Yan¹, Padmaja Dhanasekaran¹, Ciro Isidoro³, Yong-Sang Song⁴, Danny N Dhanasekaran^{1

2}

Affiliations

¹ Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma, OK 73104, USA.
² Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma, OK 73104, USA.
³ Laboratory of Molecular Pathology and NanoBioImaging, Department of Health Sciences, University of Eastern Piedmont, I-17-28100 Novara, Italy.
⁴ Department of Obstetrics and Gynecology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-921, Republic of Korea.

Abstract

With the focus on defining the oncogenic network stimulated by lysophosphatidic acid (LPA) in ovarian cancer, the present study sought to interrogate the oncotranscriptome regulated by the LPA-mediated signaling pathway. LPA, LPA-receptor (LPAR) and LPAR-activated G protein 12 α-subunit, encoded by G protein subunit α 12 (GNA12), all serve an important role in ovarian cancer progression. While the general signaling mechanism regulated by LPA/LPAR/GNA12 has previously been characterized, the global transcriptomic network regulated by GNA12 in ovarian cancer pathophysiology remains largely unknown. To define the LPA/LPAR/GNA12-orchestrated oncogenic networks in ovarian cancer, transcriptomic and bioinformatical analyses were conducted using SKOV3 cells, in which the expression of GNA12 was silenced. Array analysis was performed in Agilent SurePrint G3 Human Comparative Genomic Hybridization 8×60 microarray platform. The array results were validated using Kuramochi cells. Gene and functional enrichment analyses were performed using Database for Annotation, Visualization and Integrated Discovery, Search Tool for Retrieval of Interacting Genes and Cytoscape algorithms. The results indicated a paradigm in which GNA12 drove ovarian cancer progression by upregulating a pro-tumorigenic network with AKT1, VEGFA, TGFB1, BCL2L1, STAT3, insulin-like growth factor 1 and growth hormone releasing hormone as critical hub and/or bottleneck nodes. Moreover, GNA12 downregulated a growth-suppressive network involving proteasome 20S subunit (PSM) β6, PSM α6, PSM ATPase 5, ubiquitin conjugating enzyme E2 E1, PSM non-ATPase 10, NDUFA4 mitochondrial complex-associated, NADH:ubiquinone oxidoreductase subunit B8 and anaphase promoting complex subunit 1 as hub or bottleneck nodes. In addition to providing novel insights into the LPA/LPAR/GNA12-regulated oncogenic networks in ovarian cancer, the present study identified several potential nodes in this network that could be assessed for targeted therapy.

Keywords: G protein subunit α 12; gene expression; genomics; lysophosphatidic acid; ovarian cancer; signaling-network.

Grants and funding

P30 CA225520/CA/NCI NIH HHS/United States