Lu Wang, Mengxuan Zhu, Ming Ren, Zixu Gao, Yong Zhang, Simin Zhang, Yang Yang, Leqi Qian, Kangjie Shen, Yanlin Li, Jia Feng, Yiteng Ding, Chuanyuan Wei, Jianying Gu
Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
J Oncol. 2022 Oct 11;2022:1419179. doi: 10.1155/2022/1419179. eCollection 2022.
Cutaneous melanoma is a high-grade malignant tumor originating from skin melanocytes with high risk of recurrence and metastasis. Further study on the mechanism of melanoma development is urgently needed. Here, we performed a bioinformatic analysis to identify critical genes in melanoma using public datasets in the Gene Expression Omnibus database. Among these differentially expressed genes, thyroid hormone receptor interactor 13 (TRIP13) has been reported to exert an important role in the development of various tumors, while its role in melanoma remains unclear. We selected TRIP13 as a candidate gene for further study. TRIP13 expression in clinical specimens was evaluated by immunohistochemistry, and its association with patient prognosis was analyzed by the Kaplan-Meier method and log-rank test. MV3 and A2058 melanoma cells were transfected with lentiviral vector to overexpress or knockdown TRIP13 expression level, and then, its biological function was studied using a series of in vitro and in vivo assays. RNA sequencing, co-immunoprecipitation, and mass spectrometry were used to identify the underlying mechanism of TRIP13. The results of this study exhibited that TRIP13 expression was upregulated in melanoma tissue compared with normal tissues, and high levels of TRIP13 were closely correlated with poor prognoses of melanoma patients. Elevated TRIP13 promoted the invasion and migration of melanoma cells in vitro and enhanced lung metastasis in vivo, without an influence on tumor growth. Importantly, elevated TRIP13 promoted the epithelial-mesenchymal transition (EMT) of melanoma cells, indicating a higher metastatic potential of these cells. Mechanically, TRIP13 physically interacted with filamin A (FLNA) and then activated the PI3K/AKT pathway to transcriptional activation of EMT-related genes. The present study revealed that TRIP13 is a novel prognostic biomarker and potential therapeutic target for melanoma treatment.
皮肤黑色素瘤是一种起源于皮肤黑素细胞的高级别恶性肿瘤，具有较高的复发和转移风险。迫切需要对黑色素瘤的发生发展机制进行进一步研究。在此，我们进行了一项生物信息学分析，以利用基因表达综合数据库中的公共数据集来鉴定黑色素瘤中的关键基因。在这些差异表达基因中，甲状腺激素受体相互作用蛋白13（TRIP13）已被报道在多种肿瘤的发生发展中发挥重要作用，但其在黑色素瘤中的作用仍不清楚。我们选择TRIP13作为进一步研究的候选基因。通过免疫组织化学评估临床标本中TRIP13的表达，并采用Kaplan-Meier法和对数秩检验分析其与患者预后的相关性。用慢病毒载体转染MV3和A2058黑色素瘤细胞以过表达或敲低TRIP13的表达水平，然后使用一系列体外和体内实验研究其生物学功能。采用RNA测序、免疫共沉淀和质谱法来确定TRIP13的潜在机制。本研究结果显示，与正常组织相比，黑色素瘤组织中TRIP13的表达上调，且TRIP13的高表达与黑色素瘤患者的不良预后密切相关。TRIP13表达升高促进了黑色素瘤细胞在体外的侵袭和迁移，并增强了体内肺转移，而对肿瘤生长无影响。重要的是，TRIP13表达升高促进了黑色素瘤细胞的上皮-间质转化（EMT），表明这些细胞具有更高的转移潜能。机制上，TRIP13与细丝蛋白A（FLNA）发生物理相互作用，然后激活PI3K/AKT途径以实现EMT相关基因的转录激活。本研究揭示，TRIP13是一种新型的预后生物标志物，也是黑色素瘤治疗的潜在治疗靶点。
