Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts

Cancer Lett. 2018 Aug 10;429:66-77. doi: 10.1016/j.canlet.2018.04.038. Epub 2018 May 8.

Abstract

Cholesterol plays a vital role in modulating the action of membrane proteins critical to cellular function. The effect of serum cholesterol on the prognosis of hepatocellular carcinoma (HCC) patients remains uncertain. Here, we report that high levels of cholesterol predict good survival and low disease recurrence after surgery. Cholesterol could significantly suppress migration and invasion of HCC cells and restrain metastasis of HCC in mice. High levels of cholesterol promoted CD44 translocation into lipid rafts and attenuated CD44-Ezrin binding, which are crucial for cell migration and cancer metastasis. The suppressive effect of cholesterol on HCC metastasis was abolished by the downregulation of CD44 or its palmitoylation inhibitor, which blocked CD44 localization in lipid rafts. Furthermore, pharmacologically promoting CD44 retention inside lipid rafts obviously attenuated HCC migration and invasion, providing a potential therapeutic strategy to prolong the survival of HCC patients.

Keywords: CD44; Cholesterol; HCC; Lipid raft; Metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / blood
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cholesterol / blood*
  • Cholesterol / pharmacology
  • Female
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Liver Neoplasms / blood
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Membrane Microdomains / metabolism*
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Metastasis

Substances

  • Hyaluronan Receptors
  • Cholesterol