MPHOSPH1: a potential therapeutic target for hepatocellular carcinoma

MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation, in a manner associated with an accumulation of multinucleated polyploid cells, induction of post-mitotic apoptosis and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Further, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC.