Researchers have shown that the tumor suppressor gene H-REV107-1 may actually stimulate tumor progression in some non-small cell lung carcinomas. The related report by Nazarenko et al., "H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling," appears in the October issue of The American Journal of Pathology.
Tumor suppressor genes function by regulating normal cell growth and proliferation. When a tumor suppressor gene is turned off, by mutation, deletion, or blocked expression, cell growth can proceed without safeguards, contributing to cancer cell proliferation. However, this appears not to be the case in some non-small cell lung carcinomas (NSCLC), in which a tumor suppressor (H-REV107-1) actually promotes cancer cell growth.
Nazarenko et al. found H-REV107-1 expression in a portion of human NSCLC samples examined. When they further characterized this expression in relation to normal lung tissue, H-REV107-1 was found in nonproliferating and proliferating cells in normal lung tissue, localized mainly to the nucleus. In cultured NSCLC cells, however, H-REV107-1 was found in either the cytoplasm or both the cytoplasm and nucleus.
The group then examined whether cellular localization of H-REV107-1 in NSCLC tumor samples is linked with tumor behavior. Strikingly, cytoplasmic localization correlated with decreased patient survival (24 months versus 41 months for nuclear localization). These data suggested that cytoplasmic H-REV107-1 stimulates cell growth. This was then confirmed by suppression of H-REV107-1 RNA, which inhibited cell proliferation, and overexpression of H-REV107-1 protein, which stimulated cell growth pathways and increased proliferation.
These data demonstrate that H-REV107-1 exerts pro-growth functions within a subset of NSCLC cells in a location-dependent manner. Similar reverse functions have been identified for other tumor suppressors, but the correlation between H-REV107-1 expression and NSCLC patient survival is quite striking. The exact mechanisms that regulate H-REV107-1 activity are currently being investigated.
The possibility of using H-REV107-1 as a novel prognostic indicator of tumor aggressiveness is appealing. Lung cancer is responsible for more deaths than any other cancer, with only 15% of patients reaching 5-year survival, and non-small cell lung cancer accounts for 75% of all lung cancer.
This work was supported by Deutsche Krebshilfe and by the Berliner Programm zur Frauenfoerderung im Bereich der Natur-und Technikwissenschaften.
Work was directed by Dr. Christine Sers from the Institute of Pathology, Charité University Medicine Berlin, Germany.
Citation: Nazarenko I, Kristiansen G, Fonfara S, Guenther R, Gieseler C, Kemmner W, Schafer R, Petersen I, Sers C. H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling. Am J Pathol 2006 169:1427-1439
The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.
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