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

• Published in: BMC cancer Vol. 19; no. 1; p. 343
• Main Authors: Cao, Hui, Xu, Zhong, Wang, Jingxiao, Cigliano, Antonio, Pilo, Maria G, Ribback, Silvia, Zhang, Shu, Qiao, Yu, Che, Li, Pascale, Rosa M, Calvisi, Diego F, Chen, Xin
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.04.2019; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; Aged; AKT protein; Angiogenesis; Animal models; Animals; Breast cancer; c-Met; Cancer; Carcinoma; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Clonal deletion; CRISPR; Development and progression; Disease Models, Animal; Drug therapy; Female; Gastroenterology; Genetic aspects; Glucocorticoids; Health aspects; Hepatocellular carcinoma; Humans; Kinases; Lipogenesis; Liver - pathology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Metabolism; Mice; Mice, Knockout; Middle Aged; mTOR; Mutation; PIK3CA mutants; Plasmids; Protein Domains - genetics; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Pten; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Regorafenib; RNA, Small Interfering - metabolism; SGK3; Signal Transduction; Sorafenib; Steroids (Organic compounds); Tumorigenesis; Tumors; China; mTOR; Liver cancer; SGK3; c-Met; Pten; PIK3CA mutants
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-019-5551-2

Hepatocellular 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). We investigated the functional contribution of SGK3 in mediating activated PIK3CA mutant or loss of Pten induced HCC development using Sgk3 knockout mice. We 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. Altogether, our data suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development.