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Deciphering the multi-faceted roles of Shp2 in liver tumorigenesis


Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs) as a positive regulator of signal transduction. Despite its proto-oncogenic role, recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogen. I further investigated the possible multi-faceted roles of Shp2 by examining the effect of hepatocyte specific ablation of Shp2 on oncogene-induced autochthonous liver tumor formation. Despite the induction of hepatic oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins Met/β-catenin or Met/PI3K-p110α. Mechanistically, Shp2 loss inhibited proliferative signaling from oncogenic pathways and triggered cell senescence following exogenous expression of the oncogenes. Further, I demonstrated that the catalytic activity of Shp2 was essential for relay of oncogenic signals from RTK in HCC and that chemical inhibition of Shp2 robustly suppressed HCC driven by RTK. However, in contrast to a tumor-promoting hepatic niche generated by genetic deletion of Shp2 in hepatocytes, pharmacological Shp2 inhibition had a tumor-suppressing effect on liver metastasized tumor progression. Mechanistically, the Shp2 inhibitor enhanced an innate anti-tumor immunity by downregulating inflammatory cytokines, suppressing the CCR5 signaling axis and upregulating interferon-β secretion. Collectively, this dissertation study dissected multi-faceted roles of Shp2 in hepatocarcinogenesis, as well as provided preclinical evidence of anti-tumor activity of Shp2 pharmacological inhibition through both cell-autonomous and nonautonomous mechanisms.

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