MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma
MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma
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MPHOSPH1：肝细胞癌的潜在治疗靶点
DOI：
10.1158/0008-5472.can-14-1279
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Huang, Kun
中科院分区：
文献类型：
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作者：
Liu, Xinran;Zhou, Yafan;Huang, Kun
MPHOSPH1是一种关键的激酶蛋白，在细胞分裂中起作用。在这里，我们发现MPHOSPH1在肝细胞癌（HCC）细胞中过表达，这是增殖所必需的。用肿瘤选择性shrna表达腺病毒（Ad-shMPP1）减弱MPHOSPH1的表达足以阻止HCC细胞的增殖，这种增殖与多核多倍体细胞的积累、有丝分裂后细胞凋亡的诱导以及对紫杉醇细胞毒性的敏感性增加有关。机制研究表明，MPHOSPH1的衰减稳定了p53，阻断了STAT3的磷酸化，延长了有丝分裂停滞。在小鼠肝癌皮下异种移植模型中，肿瘤注射Ad-shMPP1抑制MPHOSPH1的表达和肿瘤生长，其方式与诱导细胞凋亡相关。与单用紫杉醇相比，Ad-shMPP1联合紫杉醇可提高抗肿瘤效果。此外，尾静脉注射Ad-shMPP1可抑制原位肝结节的形成，预防肝功能障碍。综上所述，我们的研究结果确定MPHOSPH1是HCC的致癌驱动因子和候选治疗靶点。(c) 2014年aacr。
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. (C) 2014 AACR.