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DOI: 10.1055/s-0037-1612836
The role of mechanistic target of rapamycin complex 2-component RICTOR in hepatocellular carcinoma progression and sorafenib-resistance
Publication History
Publication Date:
03 January 2018 (online)
Introduction:
Dysregulated mechanistic target of rapamycin (mTOR) signaling is implicated in the progression hepatocellular carcinoma (HCC). In contrast to the rapamycin-sensitive mTORC1 axis, the mTOR complex 2 and the obligate mTORC2 subunit rapamycin-insensitive companion of mTOR (RICTOR) are widely unexplored in HCC. The aim of this study was to analyze the expression and function of RICTOR in HCC.
Methods and Results:
Quantitative RT-PCR analysis and Western Blot analysis revealed significantly increased RICTOR expression in human HCC cell lines (HepG2, Hep3B, PLC and Huh-7) compared to primary human hepatocytes (PHH). Functional in vitro analysis showed that si-RNA mediated RICTOR depletion significantly reduced proliferation, migration clonogenicity and AKT-signaling in HCC cell lines. Immunohistochemical analysis of tissue micro arrays comprising human HCC tissue samples and in silico analysis of TCGA-derived datasets revealed that high RICTOR mRNA and protein expression was correlated with poor survival and enhanced tumor size in HCC patients. Furthermore, we detected increased RICTOR expression in sorafenib-resistant as compared to wild-type HCC-cell lines, and RICTOR-depletion in sorafenib-resistant HCC-cells restored sensitivity for sorafenib-induced growth inhibition and apoptosis.
Conclusions:
RICTOR over-expression promotes different facets of tumorigenicity in HCC including sorafenib-resistance. Therefore, RICTOR appears as a novel diagnostic and therapeutic target in HCC progression and sorafenib-resistance.