B7-H3, an immunoregulatory protein, is known to play a role in tumor progression. For many cancer types observed correlations between high B7-H3 expression and poor prognosis has been attributed to its involvement in antitumor immunity. However, here we demonstrate a non-immunological alternative function of B7-H3 in cancer metastasis. Since advanced malignant melanoma is a disease with a poor survival rate and a broad pattern of metastasis, we used this disease as a model in our studies. We found that shRNA silencing of B7-H3 reduced the in vitro migratory potential and matrigel invasiveness of MDA-MB-435 and FEMX-I melanoma cells. In an experimental metastasis model in vivo, B7-H3 silencing of MDA-MB-435 cells resulted in reduced metastatic capacity and significantly increased the median symptom-free survival of nude mice (147 vs. 65 days, p <0.001) and rats (53 vs. 42 days, p=0,025) injected with MDA-MB-435 cells. Furthermore, a smaller fraction of mice had microscopically detectable metastases compared to control animals, and the pattern of metastases was slightly different between the two groups but with the brain as the predominant organ. Immunohistochemistry on samples from two melanoma patients showed strong B7-H3 staining in both a primary tumor and metastases. Notably, the metastasis-associated proteins, MMP-2, Stat3 and the level of secreted IL-8 were reduced in the B7-H3 knock-down cell variants, whereas TIMP-1 and-2 levels were increased. Taken together, our findings indicate a novel role for B7-H3 in regulation of metastatic capacity of melanoma cells and that it might be a potential therapeutic target for anti-metastasis therapy. © 2011 Wiley-Liss, Inc.

Copyright © 2011 Wiley-Liss, Inc.

PMID: 21671471 [PubMed - as supplied by publisher] Source: National Library of Medicine.