Roles for USF-2 in lung cancer proliferation and bronchial carcinogenesis.
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.
Ocejo-Garcia
Marta
M
Cancer Research UK Department of Clinical Oncology, University of Nottingham, Nottingham, UK.
Baokbah
Tourki A S
TA
Ashurst
H Louise
HL
Cowlishaw
Debbie
D
Soomro
Irshad
I
Coulson
Judy M
JM
Woll
Penella J
PJ
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D011230:Precancerous Conditions / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051720:Upstream Stimulatory Factors
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors