INSERM, U976, Centre de Recherche sur la Peau, Hôpital Saint-Louis, Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, UMRS976, Paris, France.
Oncogene. 2016 Sep 22;35(38):5070-7. doi: 10.1038/onc.2016.39. Epub 2016 Mar 14.
KIT mutations are frequent in acral, mucosal and chronic sun-damage (CSD) melanoma, but little is known about the mechanisms driving the transformation of KIT-mutated melanocytes into melanoma cells. We showed that exposition of melanocytes harboring the (L576P)KIT mutation to a hypoxic environment induced their transformation into malignant cells. Transformed (L576P)KIT melanocytes showed downregulation of MITF expression characteristic of melanoma initiating cells (MICs). In agreement, these cells were able to form spheres in neural crest cell medium and low-adherence conditions, also a characteristic of MICs. Downregulation of MITF by RNA interference induced transformation of KIT-mutated melanocytes in normoxia and acquisition of a MIC phenotype by these cells. Hence, low level of MITF cooperates with oncogenic KIT to transform melanocytes. Activation of the cAMP pathway in transformed (L576P)KIT melanocytes stimulated MITF expression, and reduced cellular proliferation and sphere formation. These findings highlight the essential role of MITF in revealing the oncogenic activity of KIT in melanocytes and suggest that the cAMP pathway is a therapeutic target in KIT-mutated melanoma.
KIT 突变在肢端、黏膜和慢性日光损伤（CSD）黑素瘤中很常见，但对于驱动 KIT 突变的黑素细胞转化为黑素瘤细胞的机制知之甚少。我们表明，将携带（L576P）KIT 突变的黑素细胞暴露于低氧环境中会诱导其转化为恶性细胞。转化的（L576P）KIT 黑素细胞表现出 MITF 表达下调的特征，这是黑素瘤起始细胞（MICs）的特征。与此一致，这些细胞能够在神经嵴细胞培养基和低黏附条件下形成球体，这也是 MICs 的特征。MITF 的 RNA 干扰下调诱导 KIT 突变黑素细胞在常氧条件下转化，并使这些细胞获得 MIC 表型。因此，MITF 的低水平与致癌性 KIT 共同作用来转化黑素细胞。在转化的（L576P）KIT 黑素细胞中激活 cAMP 途径可刺激 MITF 表达，并减少细胞增殖和球体形成。这些发现强调了 MITF 在揭示 KIT 在黑素细胞中的致癌活性方面的重要作用，并表明 cAMP 途径是 KIT 突变黑素瘤的治疗靶点。
