A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family are widely implicated in tissue remodeling events manifested in cancer development. ADAMTS1, the most fully characterized ADAMTS, plays conflicting roles in different cancer types; however, the role of ADAMTS1 in renal cell carcinoma (RCC) remains unclear. Herein, we found that ADAMTS1 is highly expressed in RCC tissues compared to normal renal tissues, and its expression was correlated with an advanced stage and a poor prognosis of RCC patients. In vitro, we observed higher expression of ADAMTS1 in metastatic (m)RCC cells compared to primary cells, and manipulation of ADAMTS1 expression affected cell invasion and clonogenicity. Results from protease array showed that ADAMTS1 is modulated by melatonin through mechanisms independent of the MT1 receptor in mRCC cells, and overexpression of ADAMTS1 relieved the invasion/clonogenicity and growth/metastasis inhibition imposed by melatonin treatment in vitro and in an orthotopic xenograft model. The human microRNA (miR) OneArray showed that miR‐181d and miR‐let‐7f were induced by melatonin and, respectively, targeted the 3’‐UTR and non‐3'‐UTR of ADAMTS1 to suppress its expression and mRCC invasive ability. Clinically, RCC patients with high levels of miR‐181d or miR‐let‐7f and a low level of ADAMTS1 had the most favorable prognoses. In addition, ubiquitin/proteasome‐mediated degradation of ADAMTS1 can also be triggered by melatonin. Together, our study indicates that ADAMTS1 may be a useful biomarker for predicting RCC progression. The novel convergence between melatonin and ADAMTS1 post‐transcriptional and post‐translational regulation provides new insights into the role of melatonin‐induced molecular regulation in suppressing RCC progression.

中文翻译：

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褪黑激素触发的 ADAMTS1 转录后和翻译后修饰协同延缓肾细胞癌的肿瘤发生和转移。

具有血小板反应蛋白基序 (ADAMTS) 家族的去整合素和金属蛋白酶广泛参与癌症发展中表现出的组织重塑事件。ADAMTS1 是表征最充分的 ADAMTS，它在不同的癌症类型中扮演着相互矛盾的角色；然而，ADAMTS1 在肾细胞癌 (RCC) 中的作用仍不清楚。在此，我们发现与正常肾组织相比，ADAMTS1 在 RCC 组织中高表达，其表达与 RCC 患者的晚期和不良预后相关。在体外，我们观察到转移性 (m)RCC 细胞中 ADAMTS1 的表达高于原代细胞，并且 ADAMTS1 表达的操作影响细胞侵袭和克隆形成。蛋白酶阵列的结果表明，ADAMTS1 受褪黑激素的调节，其机制与 mRCC 细胞中的 MT1 受体无关，ADAMTS1 的过表达减轻了褪黑激素治疗在体外和原位异种移植模型中施加的侵袭/克隆形成和生长/转移抑制。人类微小RNA（miR）OneArray显示miR-181d和miR-let-7f由褪黑激素诱导，分别靶向ADAMTS1的3'-UTR和非3'-UTR以抑制其表达和mRCC侵袭能力。临床上，具有高水平 miR-181d 或 miR-let-7f 和低水平 ADAMTS1 的 RCC 患者具有最有利的预后。此外，泛素/蛋白酶体介导的 ADAMTS1 降解也可由褪黑激素触发。总之，我们的研究表明 ADAMTS1 可能是预测 RCC 进展的有用生物标志物。