Spi-B-Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors

Cancer Res. 2017 Sep 15;77(18):4809-4822. doi: 10.1158/0008-5472.CAN-17-0020. Epub 2017 Jul 28.

Abstract

Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage-restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B-expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809-22. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary
  • Animals
  • Apoptosis
  • Biomarkers, Tumor
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / secondary*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / secondary
  • Cell Proliferation
  • Claudin-2 / genetics
  • Claudin-2 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intercellular Junctions
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Prognosis
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / secondary
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Claudin-2
  • DNA-Binding Proteins
  • Transcription Factors
  • SPIB protein, human