Roles for USF-2 in lung cancer proliferation and bronchial carcinogenesis

J Pathol. 2005 Jun;206(2):151-9. doi: 10.1002/path.1775.

Abstract

The upstream stimulatory factors USF-1 and USF-2 dimerize to regulate transcription through E-box motifs in target genes. Although widely expressed, they can mediate tissue-specific transcription and we previously reported that USF-2 can enhance transcription of arginine vasopressin, a neuropeptide growth factor in small cell lung cancer. Here we determine the expression and role of USF-2 in lung cancer subtypes and examine USF-2 distribution in the bronchial epithelium. For a panel of 12 cell lines and 10 frozen human tumour samples, immunoblotting demonstrated that USF-2 expression was more frequent and abundant in small cell lung cancer than in non-small cell lung cancer. An immunohistochemical study of 108 formalin-fixed and paraffin-embedded human samples was undertaken to localize USF-2 expression and included 44 small cell and 32 non-small cell lung cancers, and 32 samples with bronchial dysplasia. USF-2 was restricted to ciliated cells in normal bronchial epithelium, but was more strongly expressed in dysplastic epithelium (72%) and certain lung cancer types, including small cell lung cancer (71%), squamous cell carcinoma (69%) and a large cell neuroendocrine carcinoma, but was less common in adenocarcinoma (11%). In a small series, expression was assessed adjacent to positively staining tumours; in phenotypically normal bronchial tissues, USF-2 was more highly expressed at 1 cm than at 5 cm from the tumour. Transient USF-2 overexpression in non-small cell lung cancer cell lines significantly stimulated in vitro cell proliferation; this response was most apparent for NCI-H460 (p < 0.005), reducing the mean cell doubling time from 19 to 16 h. Dominant-negative USF-2 mutants had no significant effect on cell growth. Taken together, these data suggest that USF-2 represents a relatively early molecular marker for the development of bronchial dysplasia and non-adenocarcinoma lung cancer. USF may also play a role in bronchial carcinogenesis, perhaps through promoting cell proliferation, although the genes through which this is regulated remain to be determined.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Bronchi / metabolism
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Female
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology
  • Precancerous Conditions / metabolism
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured
  • Up-Regulation
  • Upstream Stimulatory Factors

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Transcription Factors
  • USF1 protein, human
  • Upstream Stimulatory Factors