Functional role of SGK3 in PI3K/Pten driven liver tumor development

Hui Cao,Zhong Xu,Shu Zhang,Silvia Ribback,Antonio Cigliano,Rosa M Pascale,Diego F Calvisi,Li Che,Jingxiao Wang,Maria G Pilo,Xin Chen,Yu Qiao

doi:10.1186/s12885-019-5551-2

Abstract

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. The PI3K cascade is one of the major signaling pathways underlying HCC development and progression. Activating mutations of PI3K catalytic subunit alpha (PIK3CA) and/or loss of Pten often occur in human HCCs. Serum and glucocorticoid kinase 3 (SGK3) belongs to the SGK family of AGK kinases and functions in parallel to AKT downstream of PI3K. Previous studies have shown that SGK3 may be the major kinase responsible for the oncogenic potential of PIK3CA helical domain mutants, such as PIK3CA(E545K), but not kinase domain mutants, such as PIK3CA(H1047R).MethodsWe investigated the functional contribution of SGK3 in mediating activated PIK3CA mutant or loss of Pten induced HCC development using Sgk3 knockout mice.ResultsWe found that ablation of Sgk3 does not affect PIK3CA(H1047R) or PIK3CA(E545K) induced lipogenesis in the liver. Using PIK3CA(H1047R)/c-Met, PIK3CA(E545K)/c-Met, and sgPten/c-Met murine HCC models, we also demonstrated that deletion of Sgk3 moderately delays PIK3CA(E545K)/c-Met driven HCC, while not affecting PIK3CA(H1047R)/c-Met or sgPten/c-Met HCC formation in mice. Similarly, in human HCC cell lines, silencing of SGK3 reduced PIK3CA(E545K) -but not PIK3CA(H1047R)- induced accelerated tumor cell proliferation.ConclusionAltogether, our data suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development.

Highlights

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide
Constructs and reagents The constructs used for mouse injection, including pT3-EF1α-PI3K catalytic subunit alpha (PIK3CA)(H1047R), pT3-EF1α-PIK3CA(E545K), pT3-EF1α-c-Met, PX330-sgPten, and pCMV/sleeping beauty transposase, were described previously [20, 21, 23,24,25]. pLenti-PIK3CA(H1047R) and pLentiPIK3CA(E545K) constructs were subcloned into pLenti vector by the Gateway PCR cloning strategy (Invitrogen)
To determine whether Serum and glucocorticoid kinase 3 (SGK3) is required for activated PIK3CA mutant induced hepatic steatosis in vivo, we hydrodynamically transfected PIK3CA(H1047R) and PIK3CA(E545K) constructs, which we will refer here to as H1047R and E545K, into the Sgk3+/+ or Sgk3−/− mouse liver

Summary

Introduction

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. The multi-kinase inhibitors Sorafenib and Regorafenib have been approved for patients with advanced HCC over the last decade [2, 3]. They can extend patients’ survival by approximately three months. As one of the most important intracellular signaling pathways, the Phosphoinositide-3-Kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently altered in human cancers [4, 5], including HCC [6]. Deregulation of genes involved in the PI3K pathway, including mutations of the PI3K catalytic subunit alpha (PIK3CA) and loss of Pten, is frequently found in cancer [7]. Similar to other tumor types, recent genome-wide studies have revealed that both mutations of PIK3CA and deletion/downregulation of Pten occur in human HCCs [9]

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Discussion

Conclusion