Kwan Yuet Ping, Teo Melissa Hui Yen, Lim Jonathan Chee Woei, Tan Michelle Siying, Rosellinny Graciella, Wahli Walter, Wang Xiaomeng
Centre for Vision Research, Duke NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Singapore Eye Research Institute (SERI) The Academia, 20 College Road, Level 6 Discovery Tower, Singapore 169856, Singapore.
Cancers (Basel). 2021 Jun 30;13(13):3279. doi: 10.3390/cancers13133279.
Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host . On the other hand, there was reduced melanoma cell metastasis to the lungs in -deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.
尽管黑色素瘤不太常见，但它是皮肤癌中最致命的一种形式，主要是因为其具有高度转移性。目前，转移性黑色素瘤的治疗选择有限，而且其中许多治疗方法可能会引起严重的副作用。更好地了解转移性黑色素瘤复杂疾病病理生理学背后的分子机制，可能会导致发现新的治疗靶点，并促进靶向治疗药物的开发。在本研究中，我们调查了富含亮氨酸的α-2-糖蛋白1（LRG1）在黑色素瘤发生和发展中的作用。我们首先在人类患者活检组织和小鼠黑色素瘤细胞系中确定了LRG1与黑色素瘤之间的关联，并揭示了转移性黑色素瘤细胞中LRG1表达的显著诱导。然后我们发现，在没有宿主的情况下，肿瘤细胞的生长、增殖和血管生成没有变化。另一方面，在LRG1缺陷的小鼠中，黑色素瘤细胞向肺部的转移减少。LRG1对黑色素瘤细胞迁移、侵袭和黏附的促进作用支持了这一观察结果。从机制上讲，LRG1以EGFR/STAT3依赖的方式介导黑色素瘤细胞的侵袭性。综上所述，我们的研究提供了令人信服的证据，表明LRG1是黑色素瘤转移所必需的，但不是其生长所必需的。靶向LRG1可能为控制恶性黑色素瘤提供一种替代策略。
