Protocadherin 17 Acts as a Tumour Suppressor Inducing Tumour Cell Apoptosis and Autophagy, and Is Frequently Methylated in Gastric and Colorectal Cancers

J Pathol. 2013 Jan;229(1):62-73. doi: 10.1002/path.4093.

Abstract

Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ∼95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis* / drug effects
  • Autophagy*
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Caspase 3 / metabolism
  • Cell Proliferation
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • DNA Methylation*
  • Down-Regulation
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • HCT116 Cells
  • Humans
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microtubule-Associated Proteins / metabolism
  • Promoter Regions, Genetic
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Time Factors
  • Transfection
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • ATG12 protein, human
  • ATG5 protein, human
  • Antimetabolites, Antineoplastic
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Biomarkers, Tumor
  • Cadherins
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Tumor Suppressor Proteins
  • protocadherin 17, human
  • CASP3 protein, human
  • Caspase 3
  • Fluorouracil