Truzzi Francesca, Marconi Alessandra, Lotti Roberta, Dallaglio Katiuscia, French Lars E, Hempstead Barbara L, Pincelli Carlo
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy.
J Invest Dermatol. 2008 Aug;128(8):2031-40. doi: 10.1038/jid.2008.21. Epub 2008 Feb 28.
Melanoma is a highly aggressive skin tumor that originates in the epidermis from melanocytes. As melanocytes share with the nervous system a common neuroectodermal origin and express all neurotrophins (NTs), we evaluated the expression and function of NTs and their receptors in melanoma. We report that primary and metastatic melanoma cell lines synthesize and secrete all NTs. Moreover, melanoma cells express the low-affinity (p75NTR) and the high-affinity tyrosine kinase NT receptors (Trk). The inhibition of Trk receptors by either K252a or Trk/Fc chimeras prevents proliferation, indicating that autocrine NTs are responsible for this effect. NT-3, NT-4, and nerve growth factor (NGF) induce cell migration, with a stronger effect on metastatic cell lines. Transfection with p75NTR small interfering RNA (p75NTRsiRNA) or treatment with K252a inhibits NT-induced melanoma cell migration, indicating that both the low- and high-affinity NT receptors mediate this effect. All melanoma cell lines express the p75NTR coreceptor sortilin by which proNGF stimulates migration in melanoma cells, but not in cells transfected with p75NTRsiRNA. These results indicate that NTs, through their receptors, play a critical role in the progression of melanoma.
黑色素瘤是一种高度侵袭性的皮肤肿瘤，起源于表皮中的黑素细胞。由于黑素细胞与神经系统有着共同的神经外胚层起源，并表达所有的神经营养因子（NTs），我们评估了NTs及其受体在黑色素瘤中的表达和功能。我们报告，原发性和转移性黑色素瘤细胞系合成并分泌所有的NTs。此外，黑色素瘤细胞表达低亲和力（p75NTR）和高亲和力酪氨酸激酶NTs受体（Trk）。用K252a或Trk/Fc嵌合体抑制Trk受体可阻止细胞增殖，表明自分泌NTs负责此效应。NT-3、NT-4和神经生长因子（NGF）诱导细胞迁移，对转移性细胞系的作用更强。用p75NTR小干扰RNA（p75NTRsiRNA）转染或用K252a处理可抑制NTs诱导的黑色素瘤细胞迁移，表明低亲和力和高亲和力NTs受体均介导此效应。所有黑色素瘤细胞系均表达p７5NTR共受体sortilin，前体NGF通过该受体刺激黑色素瘤细胞迁移，但不刺激用p75NTRsiRNA转染的细胞迁移。这些结果表明，NTs通过其受体在黑色素瘤进展中起关键作用。
