UPREGULATION OF SOX9 INHIBITS THE GROWTH OF HUMAN AND MOUSE MELANOMAS AND RESTORES THEIR SENSITIVITY TO RETINOIC ACID.
This study by researchers at the National Cancer Institute (NIH) demonstrated that MatTek’s Melanoma in vitro human skin tissue equivalent can be used to investigate both the efficacy and cytotoxicity of potential malignant melanoma treatments. Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of retinoic acid are mediated by the transcription factor SOX9 in human cancer cell lines. As NCI/NIH researchers have previously shown that SOX9 is expressed in normal melanocytes, here they investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to retinoic acid by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to retinoic acid. Thus, combined treatment with PGD2 and retinoic acid substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and retinoic acid sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.
MEL-FT-A375, Melanoma, Metastasis, S100 protein, SOX9, Transcription factor SOX9, Tumor growth, Tumor invasiveness
PGD2, Retinoic acid, SOX9 lentivirus
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