CAV1 promotes HCC cell progression and metastasis through Wnt/β-catenin pathway

PLoS One. 2014 Sep 2;9(9):e106451. doi: 10.1371/journal.pone.0106451. eCollection 2014.

Abstract

Caveolin-1 (CAV1) has significant roles in many primary tumors and metastasis, despite the fact that malignant cells from different cancer types have different profiles of CAV1 expression. There is little information concerning CAV1 expression and role in hepatocellular carcinoma (HCC) progresion and metastasis. The role of CAV1 in HCC progression was explored in this study. We reported that CAV1 was overexpressed in highly invasive HCC cell lines compared with poorly invasive ones. The immunohistochemical staining was obviously stronger in metastatic HCC samples than in the non-metastatic specimens via tissue microarrays. Furthermore, CAV1 overexpression enhanced HCC cell invasiveness in vitro, and promoted tumorigenicity and lung metastasis in vivo. By contrast, CAV1 stable knockdown markedly reduced these malignant behaviors. Importantly, we found that CAV1 could induce EMT process through Wnt/β-catenin pathway to promote HCC metastasis. We also identify MMP-7 as a novel downstream target of CAV1. We have determined that CAV1 acts as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-7 transcription. Together, these studies mechanistically show a previously unrecognized interplay between CAV1, EMT, ERK1/2 and MMP-7 that is likely significant in the progression of HCC toward metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Caveolin 1 / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression*
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • Subcellular Fractions / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism

Substances

  • Caveolin 1
  • beta Catenin

Grants and funding

This work was supported in part by Natural Science Foundation of Shanghai (11ZR1403800), National Key Basic Research Program of China (2013CB910502), National Natural Science Foundation of China (81201534), National Science and Technology Major Project (2012ZX10002012-006) and Shanghai Pujiang Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.