title: MPHOSPH1: a potential therapeutic target for hepatocellular carcinoma.
abstract: 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 postmitotic 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. Furthermore, 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.
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. Centre for Biomedicine Research, Wuhan Institute of Biotechnology, Wuhan, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yafan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Wuhan the Third Hospital, Wuhan, China.
authors.forename: Anlin
authors.initials: A
authors.lastname: Peng
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gong
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lizi
authors.initials: L
authors.lastname: Huang
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kaige
authors.initials: K
authors.lastname: Ji
authors.affiliation: Departments of Pathology, Neuroscience and Neurology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. Centre for Biomedicine Research, Wuhan Institute of Biotechnology, Wuhan, China. kunhuang2008@hotmail.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D006801:Humans; D016547:Kinesins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000494:pharmacology; D011123:Polyploidy; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C438388:KIF20B protein, human; D016547:Kinesins; D017239:Paclitaxel