Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid
Thierry Passeron, … , Yoshinori Miyamura, Vincent J. Hearing
Thierry Passeron, … , Yoshinori Miyamura, Vincent J. Hearing
Published March 9, 2009
Citation Information: J Clin Invest. 2009;119(4):954-963. https://doi.org/10.1172/JCI34015.
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Research Article Oncology

Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Abstract

Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we 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 RA 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 RA. Thus, combined treatment with PGD2 and RA 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 RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

Authors

Thierry Passeron, Julio C. Valencia, Takeshi Namiki, Wilfred D. Vieira, Hélène Passeron, Yoshinori Miyamura, Vincent J. Hearing

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Figure 6

Combined treatment with PGD2 and RA inhibits melanoma growth in human ex vivo and in mouse models.

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Combined treatment with PGD2 and RA inhibits melanoma growth in human ex...
(A) A375 melanoma cells were included in a human reconstructed skin model and were treated with PGD2 (0.5 μg/μl) and/or RA (10–7 M) for 10 days. H&E staining of melanoma cells shows a clear proliferation, with some invasiveness of the dermis in the untreated control samples and in RA-treated samples. RA had no effect on tumor growth, but decreased tumor size was observed in melanoma reconstructed skins treated with PGD2, while a marked further decrease in proliferation was noted in samples treated with a combination of PGD2 and RA. Scale bar: 100 μm. (B) A375 and B16/F10 melanoma cells were injected subcutaneously into nude and C57BL/6 mice, respectively. After 8 days, mice were treated intraperitoneally with BW245C and/or RA 3 times a week for 3 weeks. The graphs show the mean tumor diameters observed after treatment in B16/F10 melanoma–challenged mice (left) and in A375 melanoma–challenged mice (right). *P < 0.05, **P < 0.01.