The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors

Abstract

G12 proteins comprise a subfamily of G-alpha subunits of heterotrimeric GTP-binding proteins (G proteins) that link specific cell surface G protein-coupled receptors (GPCRs) to downstream signaling molecules and play important roles in human physiology. The G12 subfamily contains two family members: Gα12 and Gα13 (encoded by the GNA12 and GNA13 genes, respectively) and, as with all G proteins, their activity is regulated by their ability to bind to guanine nucleotides. Increased expression of both Gα12 and Gα13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, Gα12/13 proteins are underappreciated in the field of cancer. As our understanding of G protein involvement in oncogenic signaling has evolved, it has become clear that Gα12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of Gα12/13 proteins is regulated through a series of transcriptional and post-transcriptional mechanisms, several of which are frequently deregulated in cancer. With the ever-increasing understanding of tumorigenic processes driven by Gα12/13 proteins, it is becoming clear that targeting Gα12/13 signaling in a context-specific manner could provide a new strategy to improve therapeutic outcomes in a number of solid tumors. In this review, we detail how Gα12/13 proteins, which were first discovered as proto-oncogenes, are now known to drive several "classical" hallmarks, and also play important roles in the "emerging" hallmarks, of cancer.

Fig. 1. Signaling pathways regulated by Gα12/13 in solid tumors.

Studies of the past decade have shown that Gα12/13 can potentially drive a number of signaling pathways that are implicated in tumorigenesis and metastasis. Some of the key pathways are shown in this figure, with signaling through Rho GTPases depicted in the central axis considered a dominant pathway for most of the biological consequences of Gα12/13 activation. See text for details and definition of acronyms.

Fig. 2. Mechanisms that drive increased expression of Gα12/13 proteins in cancers.

A Expression of Gα12 is dysregulated mainly at the transcriptional level in a c-Jun/AP-1 dependent manner, at least in prostate cancer cells. Gα12 has also been shown to drive the activity of c-Jun in multiple solid tumors, suggesting the possibility of a feed forward loop. Dysregulation of Gα12 expression may also occur at a post transcriptional level, with the loss of at least one miRNA, miR-564 in breast cancer being shown to upregulate Gα12 expression. B Multiple studies indicate that expression of Gα13 is mainly regulated at the post-transcriptional level in solid tumors. Loss of several different miRNAs targeting GNA13 mRNA (miR-182, miR-200a, miR-31, miR-4731-5p, miR-30b-5p) during tumorigenesis and metastasis have been shown to lead to the increased Gα13 protein expression across multiple solid tumors. For both Gα12 and Gα13, the resultant overexpression of Gα12/13 then drives multiple steps of cancer progression. See text for details.

Fig. 3. Schematic representation of the role of Gα12/13 in the hallmarks of cancer.

The diverse roles of Gα12 and Gα13 allow their functions in cancer pathogenesis to be categorized according to the six ‘classical’ hallmarks and two ‘emerging’ hallmarks. Gα12/13 proteins impact the various hallmarks by either inducing oncogenic signaling pathways (labeled red) or suppressing tumor suppressive mechanisms (labeled blue). The degree of impact that Gα12/13 proteins have on each component may vary and this is reflected by the font size of the gene/pathway. See text for details.

Fig. 4. Gα12/13-promoted stemness is a potential mechanism of cancer progression, metastasis and drug resistance in tumors.

Gα12/13 has been shown to drive both EMT-dependent and -independent mechanisms of cancer stem cells/tumor-initiating cells (CSCs/TICs) formations. Both proteins have also been reported to drive EMT and stemness in cancers through multiple signaling mechanisms. CSC-like phenotype induced by Gα12/13 can then contribute to multiple steps in cancer initiation and progression as shown in the figure. See text for details.