Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma

Am J Pathol. 2018 Feb;188(2):378-391. doi: 10.1016/j.ajpath.2017.10.016. Epub 2017 Nov 22.

Abstract

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 G1/S phase transition by activating Wnt signaling. Mechanistically, MUC13 bound to β-catenin and increased its phosphorylation at Ser552 and Ser675 sites, which subsequently promoted nuclear translocation of β-catenin and up-regulation of its downstream target genes Axin2, c-Myc, and CyclinD1. Knockdown of AKT with shRNA in MUC13-overexpressing cells nullified the elevated phosphorylation of β-catenin by MUC13. In clinical HCC samples, nuclear translocation of β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / physiology*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle / physiology
  • Cell Division
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Heterografts
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Nude
  • Middle Aged
  • Mucins / biosynthesis
  • Mucins / genetics
  • Mucins / physiology*
  • Neoplasm Transplantation
  • Phosphorylation
  • Prognosis
  • Up-Regulation
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / metabolism

Substances

  • Biomarkers, Tumor
  • CTNNB1 protein, mouse
  • MUC13 protein, human
  • Mucins
  • beta Catenin