Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma
Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma
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MUC13（一种不良预后预测因子）的过表达通过激活肝细胞癌中的 Wnt 信号转导促进细胞生长
DOI：
10.1016/j.ajpath.2017.10.016
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发表时间：
2018-02-01
影响因子：
6
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Dai, Yongdong;Liu, Lulu;Guan, Xin-Yuan
最近RNA测序显示粘蛋白13（MUC 13）在肝细胞癌（HCC）组织中高表达。为了解MUC 13在肝癌中的临床病理意义，采用定量PCR和免疫组化方法检测其在癌组织和癌旁组织中的表达。通过体外和体内测定确定MUC 13的癌蛋白作用。在168例原发性HCC病例中检测到74例（44%）MUC 13过表达，并且与肿瘤大小（P = 0.027）、分期（P = 0.006）、包膜（P = 0.044）、静脉浸润（P = 0.024）和预后不良（P = 0.004）显著相关。功能研究表明，MUC 13通过促进细胞生长、集落形成、细胞迁移和裸鼠肿瘤形成而具有强的致癌活性。RNA干扰可有效抑制MUC 13的促癌作用。MUC 13通过激活Wnt信号通路促进细胞G（1）/S期转变。从机制上讲，MUC 13结合β-连环蛋白并增加其在Ser 552和Ser 675位点的磷酸化，这随后促进β-连环蛋白的核转位及其下游靶基因Axing 2、c-Myc和CyclinDl的上调。在MUC 13过表达细胞中用sh RNA敲低AKT使MUC 13引起的β-连环蛋白磷酸化水平升高无效。在临床HCC样本中，β-连环蛋白核转位与MUC 13过表达显著相关（P = 0.001）。MUC 13的过表达通过激活Wnt信号通路在HCC的发生和发展中起关键作用。
Recently RNA sequencing revealed high mucin 13 (MUC13) expression in hepatocellular carcinoma (HCC) tissues. To understand the clinicopathologic significance of MUC13 in HCC, quantitative PCR and immunohistochemistry were used to detect its expression in paired tumor tissues and nontumor tissues. The oncoprotein role of MUC13 was determined by in vitro and in vivo assays. Overexpression of MUC13 was detected in 74 of 168 primary HCC cases (44%) and was significantly associated with tumor size (P = 0.027), stage (P = 0.006), encapsulation (P = 0.044), venous invasion (P = 0.024), and poor outcome (P = 0.004). Functional studies demonstrated MUC13 had strong oncogenic activity by promoting cell growth, colony formation, cell migration, and tumor formation in nude mice. The pro-oncogenic effect of MUC13 were effectively inhibited by RNA interference. MUC13 promoted cellular G(1)/S phase transition by activating Wnt signaling. Mechanistically, MUC13 bound to beta-catenin and increased its phosphorylation at Ser552 and Ser675 sites, which subsequently promoted nuclear translocation of beta-catenin and up-regulation of its downstream target genes Axing2, c-Myc, and CyclinDl. Knockdown of AKT with sh RNA in MUC13-overexpressing cells nullified the elevated phosphorylation of beta-catenin by MUC13. In clinical HCC samples, nuclear translocation of beta-catenin was significantly associated with MUC13 overexpression (P = 0.001). Overexpression of MUC13 plays a critical role in the development and progression of HCC by activating Wnt signaling.