Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612836
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

The role of mechanistic target of rapamycin complex 2-component RICTOR in hepatocellular carcinoma progression and sorafenib-resistance

P Dietrich
1   Biochemistry and Molecular Medicine, Institute of Biochemistry, FAU Erlangen-Nuremberg, Erlangen
,
K Freese
1   Biochemistry and Molecular Medicine, Institute of Biochemistry, FAU Erlangen-Nuremberg, Erlangen
,
V Fritz
1   Biochemistry and Molecular Medicine, Institute of Biochemistry, FAU Erlangen-Nuremberg, Erlangen
,
S Lang
2   University of Regensburg, Department Surgery, Regensburg
,
W Thasler
3   Ludwig-Maximilians-University Munich, Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Munich
,
A Bosserhoff
1   Biochemistry and Molecular Medicine, Institute of Biochemistry, FAU Erlangen-Nuremberg, Erlangen
,
C Hellerbrand
1   Biochemistry and Molecular Medicine, Institute of Biochemistry, FAU Erlangen-Nuremberg, Erlangen
› Author Affiliations
Further Information

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.