Downregulation of CCN3 expression as a potential mechanism for melanoma progression
Downregulation of CCN3 expression as a potential mechanism for melanoma progression
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DOI：
10.1038/sj.onc.1210896
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发表时间：
2008-04-01
期刊：
影响因子：
8
通讯作者：
Herlyn, M.
中科院分区：
文献类型：
--
作者：
Fukunaga-Kalabis, M.;Martinez, G.;Herlyn, M.
人黑素细胞与角质形成细胞的共培养上调CCN 3，CCN 3是一种对维持皮肤中黑素细胞的正常稳态至关重要的基质细胞蛋白。CCN 3影响黑素细胞生理学的两个基本特征：它抑制黑素细胞增殖并刺激它们粘附到基底膜。在这里，我们报告CCN 3的表达在晚期黑色素瘤中下调。侵袭性黑色素瘤细胞系对CCN 3诱导剂（如白细胞介素-1 β（IL-β））治疗无反应，而侵袭性较低的黑色素瘤细胞系对黑色素细胞的反应相似。免疫染色分析显示，CCN 3存在于接近表皮-真皮界面的黑素瘤细胞中，但不存在于已侵入真皮深处或已转移至淋巴结的黑素瘤细胞中。与我们的预期相反，CCN 3在1205 Lu转移性黑色素瘤细胞中的过表达并不影响它们与IV型胶原的粘附。然而，CCN 3降低了基质金属蛋白酶的转录和活化，并抑制了1205 Lu黑色素瘤细胞的侵袭。这些结果表明，在晚期黑色素瘤细胞中缺乏CCN 3有助于其侵袭性表型。而主要的基质细胞蛋白质，如骨桥蛋白，腱生蛋白或分泌的蛋白质酸性和富含半胱氨酸（CCN），在黑色素瘤细胞中强烈上调; CCN 3是该家族的第一个成员，下调。
Coculture of human melanocytes with keratinocytes upregulates CCN3, a matricellular protein critical to maintenance of normal homeostasis of melanocytes in the skin. CCN3 affects two fundamental features of melanocyte physiology: it inhibits melanocyte proliferation and stimulates their adhesion to the basement membrane. Here we report that expression of CCN3 is downregulated in advanced melanomas. Aggressive melanoma cell lines did not respond to treatment with CCN3 inducers, such as interleukin-1 beta (IL-beta), while less aggressive melanoma cell lines responded similarly to melanocytes. Immunostaining analyses revealed that CCN3 was present in melanoma cells close to the epidermal-dermal interface, but not in melanoma cells that had invaded deep into the dermis or had metastasized to lymph nodes. Contrary to our expectations, overexpression of CCN3 in 1205Lu metastatic melanoma cells did not affect their adhesion to collagen IV. However, CCN3 decreased the transcription and activation of matrix metalloproteinases and suppressed the invasion of 1205Lu melanoma cells. These results suggest that the lack of CCN3 in advanced melanoma cells contributes to their invasive phenotype. Whereas major matricellular proteins, such as osteopontin, tenascin or secreted protein acidic and rich in cysteine (SPARC), are strongly upregulated in melanoma cells; CCN3 is the first member of this family that is downregulated.