The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc., Changzhou, China.
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Cancer Lett. 2021 Oct 28;519:237-249. doi: 10.1016/j.canlet.2021.07.033. Epub 2021 Jul 26.
Melanoma is a highly metastatic cancer that requires effective and targeted curative therapy. Annexin A10 (ANXA10), a member of the annexin family, is a calcium- and phospholipid-binding protein. Considerable evidence indicates that ANXA10 is involved in tumour progression, but little is known about its role in melanoma development. In this study, we find that ANXA10 expression is significantly upregulated, and correlates with melanoma progression. ANXA10 knockout profoundly reduces cell migration and the metastatic activity of melanoma. In addition, ANXA10 knockout induces the N- to E-cadherin switch by upregulating SMAD6, an inhibitory SMAD in the TGF-β/SMAD pathway. The negative regulation of SMAD6 by ANXA10 is dependent on PKD1. ANXA10 interacts with PKD1 and inhibits E3 ligase TRIM41-targeted PKD1 degradation. In B16F10 melanoma cells, protein levels of ANXA10 and PKD1 are inversely correlated with SMAD6 level, but correlated with cell migration. Interestingly, ANXA10 and SMAD6 levels are inversely correlated in clinical samples of melanoma progression. Our findings suggest that the ANXA10-PKD1-SMAD6 axis is a new target for therapeutic strategies against melanoma metastasis.
黑色素瘤是一种高度转移性癌症，需要有效的靶向治疗。膜联蛋白 A10（ANXA10）是 annexin 家族的一员，是一种钙和磷脂结合蛋白。大量证据表明，ANXA10 参与肿瘤的进展，但对其在黑色素瘤发展中的作用知之甚少。在这项研究中，我们发现 ANXA10 的表达显著上调，并与黑色素瘤的进展相关。ANXA10 敲除显著降低了黑色素瘤细胞的迁移和转移活性。此外，ANXA10 敲除通过上调 TGF-β/SMAD 通路中的抑制性 SMAD SMAD6 诱导 N-到 E-钙粘蛋白转换。ANXA10 对 SMAD6 的负调控依赖于 PKD1。ANXA10 与 PKD1 相互作用并抑制 E3 连接酶 TRIM41 靶向的 PKD1 降解。在 B16F10 黑色素瘤细胞中，ANXA10 和 PKD1 的蛋白水平与 SMAD6 水平呈负相关，但与细胞迁移呈正相关。有趣的是，在黑色素瘤进展的临床样本中，ANXA10 和 SMAD6 水平呈负相关。我们的研究结果表明，ANXA10-PKD1-SMAD6 轴是针对黑色素瘤转移的治疗策略的新靶点。
