Cui Yankang, Miao Chenkui, Liu Shouyong, Tang Jingyuan, Zhang Jing, Bu Hengtao, Wang Yuhao, Liang Chao, Bao Meiling, Hou Chao, Wu Jiajin, Chen Xiaochao, Zhang Xiang, Wang Zengjun, Liu Bianjiang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
Mol Ther Nucleic Acids. 2021 Nov 10;26:1336-1350. doi: 10.1016/j.omtn.2021.11.004. eCollection 2021 Dec 3.
Seminoma is the most common subtype of testicular germ cell tumor, with an increasing incidence worldwide. Clusterin (CLU) expression was found to be downregulated in testicular seminoma in our previous study. We now expanded the sample size, and further indicated that CLU expression correlates with tumor stage. Tcam-2 cell line was used to investigate the CLU function in testicular seminoma, and CLU was found to inhibit the proliferation and metastasis abilities. Besides, extracellular matrix protein COL15a1 was demonstrated as the downstream of CLU to affect the epithelial-mesenchymal transition (EMT) process via competitively binding to DDR1 with COL1A1 and inhibiting the phosphorylation of PYK2. MEF2A was found to interact with CLU and bind to the promoter of COL15a1 and so upregulate its expression. This is the first study using testicular xenografts to simulate testicular seminoma metastatic and proliferative capacities. In conclusion, CLU acts as a tumor suppressor to inhibit the metastasis of testicular seminoma by interacting with MEF2A to upregulate COL15a1 and blocking the EMT process.
精原细胞瘤是睾丸生殖细胞肿瘤最常见的亚型，在全球范围内发病率呈上升趋势。在我们之前的研究中发现，簇集素（CLU）在睾丸精原细胞瘤中的表达下调。我们现在扩大了样本量，并进一步表明CLU表达与肿瘤分期相关。利用Tcam-2细胞系研究CLU在睾丸精原细胞瘤中的功能，发现CLU可抑制其增殖和转移能力。此外，细胞外基质蛋白COL15a1被证明是CLU的下游分子，通过与COL1A1竞争性结合DDR1并抑制PYK2的磷酸化来影响上皮-间质转化（EMT）过程。发现MEF2A与CLU相互作用并结合到COL15a1的启动子上，从而上调其表达。这是第一项利用睾丸异种移植来模拟睾丸精原细胞瘤转移和增殖能力的研究。总之，CLU作为一种肿瘤抑制因子，通过与MEF2A相互作用上调COL15a1并阻断EMT过程来抑制睾丸精原细胞瘤的转移。
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