Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation

Cell Physiol Biochem. 2017;42(2):729-742. doi: 10.1159/000477890. Epub 2017 Jun 15.

Abstract

Background/aims: Elevated serum cholesterol levels were linked to a higher risk of colorectal adenoma and colorectal cancer (CRC), while the effect of cholesterol on CRC metastasis has not been widely studied.

Methods: CRC patients were enrolled to evaluate the association between low-density lipoprotein cholesterol (LDL) and CRC metastases, and LDL receptor (LDLR) level of the CRC tissue was assessed by immunohistochemistry. The effects of LDL on cell proliferation, migration and stemness were assessed in CRC cells in vitro, and the effects of high fat diet (HFD) on tumor growth and intestinal tumorigenicity were investigated in vivo. ROS assays, gene expression array analysis and western blot were used to explore the mechanisms of LDL in CRC progression.

Results: The level of LDL was positively correlated with liver metastases, and a higher level of LDL receptor (LDLR) expression was associated with advanced N and M stages of CRC. In vitro, LDL promoted the migration and sphere formation of CRC cells and induced upregulated expression of "stemness" genes including Sox2, Oct4, Nanog and Bmi 1. High-fat diet (HFD) significantly enhanced tumor growth in vivo, and was associated with a shorter intestinal length in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Furthermore, LDL significantly elevated reactive oxygen species (ROS) levels and Whole Human Genome Microarray found 87 differentially expressed genes between LDL-treated CRC cells and controls, which were largely clustered in the MAP kinase (MAPK) signaling pathway.

Conclusions: LDL enhances intestinal inflammation and CRC progression via activation of ROS and signaling pathways including the MAPK pathway. Inflammation is strongly associated with cancer initiation, and the role of LDL in intestinal tumorigenicity should be further explored.

Keywords: Cholesterol; Colorectal cancer; Metastasis; ROS.

MeSH terms

  • Aged
  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cholesterol / metabolism*
  • Cholesterol, LDL / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Diet, High-Fat
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Proteins / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics

Substances

  • Cholesterol, LDL
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Cholesterol