H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling

Am J Pathol. 2006 Oct;169(4):1427-39. doi: 10.2353/ajpath.2006.051341.

Abstract

H-REV107-1, a known member of the class II tumor suppressor gene family, is involved in the regulation of differentiation and survival. We analyzed H-REV107-1 in non-small cell lung carcinomas, in normal lung, and in immortalized and tumor-derived cell lines. Sixty-eight percent of lung tumors revealed positive H-REV107-1-specific staining. Furthermore, survival analysis demonstrated a significant association of cytoplasmic H-REV107-1 with decreased patient survival. This suggested that H-REV107-1, known as a tumor suppressor, plays a different role in non-small cell lung carcinomas. Knock-down of H-REV107-1 expression in lung carcinoma cells inhibited anchorage-dependent and anchorage-independent growth whereas overexpression of H-REV107-1 induced tumor cell proliferation. Consistent with results of the survival analysis, cytoplasmic localization of the protein was essential for this growth-inducing function. Analysis of signaling pathways potentially involved in this process demonstrated that overexpression of H-REV107-1 stimulated RAS-GTPase activity, ERK1,2 phosphorylation, and caveolin-1 expression in the cell lines analyzed. These results indicate that H-REV107-1 is deficient in its function as a tumor suppressor in non-small cell lung carcinomas and is required for proliferation and anchorage-independent growth in cells expressing high levels of the protein, thus contributing to tumor progression in a subset of non-small cell lung carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Enzyme Activation
  • Humans
  • Immunohistochemistry
  • Intracellular Membranes / chemistry
  • Intracellular Signaling Peptides and Proteins / analysis
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phospholipases A2, Calcium-Independent
  • Prognosis
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / analysis
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / metabolism*
  • ras Proteins / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • Mitogen-Activated Protein Kinase 3
  • PLA2G16 protein, human
  • Phospholipases A2, Calcium-Independent
  • ras Proteins