Upregulating SOX9 expression inhibits melanoma cell development, spread

Increased expression of the protein SOX9 may slow melanoma tumor growth and increase its sensitivity to retinoic acid, leading to new treatment approaches for melanoma and other cancers, according to data from an analysis.

Researchers from the National Cancer Institute examined SOX9 expression in normal human skin samples and samples of nevi tissue, primary tumors and metastatic melanoma tumors. As confirmed by immunohistochemistry, SOX9 expression was weak or negative in 95% of the melanoma specimens, but was expressed in normal human melanocytes, with increased expression after UVB exposure.

Researchers used immunohistochemistry of different human tissues to confirm their results. They stained 22 nevi, 56 primary melanomas and 20 metastatic melanomas and found SOX9 expression to be positive in normal skin areas but weak or negative in 81.8% of nevi, 96.4% of primary melanomas and 100% of metastatic melanomas.

To determine whether SOX9 affected PRAME expression in melanoma cells, the researchers conducted an immunoblot analysis of A375 melanoma cells transfected with SOX9, which resulted in a reduction in PRAME protein levels. The researchers cultured A375 cells with or without retinoic acid for 15 days and analyzed their proliferative properties. Compared with controls, SOX9-expressing cells treated with retinoic acid showed a decrease in proliferation; the proliferation of untransfected control cells was unaffected by retinoic acid. Additionally, in B16/F10 melanoma cells, retinoic acid treatment decreased proliferation and enhanced the effect of SOX9 transfection.

SOX9 induced cell cycle arrest by upregulating p21 and MITF expression in melanoma cells. In addition, the researchers reported that PGD2 increases endogenous SOX9 expression.

“Further screening and identification of agents effective in increasing or activating SOX9, such as PGD2 metabolites or specific agonists of the DP1 receptor, and combining them with RA therapy should provide a powerful approach to melanoma therapy,” the researchers wrote. – by Stacey L. Adams

Passeron T. J Clin Invest. 2009;doi:10.1172/JCI34015.

I thought these findings were extremely interesting, especially in the animal model. It's worthwhile to try in the clinical setting in patients who have a minimal disease because the majority of the human melanomas grow rapidly. I'm worried that with upregulation, PGD2 and retinoic acid may not be able to arrest the proliferation process of the melanoma.

– Wen-Jen Hwu, MD

HemOnc Today Editorial Board member