Liu Xuemin, Hao Zhiwei, He Huanhuan, Wang Xuan, Wang Wenqi, Shu Xiji, Sun Binlian, Hu Zhiyong, Hu Shaobo, Hou Xiaoying, Xiao Yue, Zhou Hongyan, Liu Yuchen, Wang Jianzhi, Fu Zhengqi
Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, 8 Sanjiaohu Road, Wuhan, 430056, China.
Cancer Institute, School of Medicine, Jianghan University, Wuhan, 430056, China.
Mol Cell Biochem. 2024 Dec 24. doi: 10.1007/s11010-024-05193-9.
Dysregulated expression of microtubule-associated protein tau (MAPT) has been reported in a variety of human cancers. However, whether and how Tau influences hepatocellular carcinogenesis remains elusive. This study was aimed to investigate the role and the underlying mechanism of Tau in the proliferation, invasion, migration and sorafenib sensitivity of hepatocellular carcinoma (HCC) cells. An increased level of Tau was found in the primary tumor samples of HCC compared with the adjacent normal liver tissues, and the increase of Tau was positively correlated with p62 evidenced by the data obtained from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and human samples from HCC patients. The high Tau expression was also correlated with a poorer survival in HCC patients demonstrated by using the GEPIA survival analysis and OncoLnc database. Further studies showed that Tau overexpression promoted the growth, invasion and migration and decreased sorafenib sensitivity in HepG2 and Huh7 cells; Tau also accelerated growth of xenograft tumors with blockage of autophagosome-lysosome fusion. Finally, overexpressing Tau inhibited AMPK, which contributed to Tau-induced promotion of hepatocellular carcinogenesis. In conclusion, our study provides the proof-of-concept evidence validating Tau as an attractive HCC target.
在多种人类癌症中均有报道微管相关蛋白tau（MAPT）表达失调。然而，Tau是否以及如何影响肝细胞癌发生仍不清楚。本研究旨在探讨Tau在肝癌（HCC）细胞增殖、侵袭、迁移及索拉非尼敏感性方面的作用及潜在机制。与相邻正常肝组织相比，在HCC的原发肿瘤样本中发现Tau水平升高，且通过癌症基因组图谱（TCGA）、基因表达谱交互分析（GEPIA）以及HCC患者的人类样本数据证明，Tau的升高与p62呈正相关。通过GEPIA生存分析和OncoLnc数据库表明，HCC患者中Tau高表达也与较差的生存率相关。进一步研究表明，Tau过表达促进HepG2和Huh7细胞的生长、侵袭和迁移，并降低其对索拉非尼的敏感性；Tau还通过阻断自噬体-溶酶体融合加速异种移植瘤的生长。最后，过表达Tau抑制AMPK，这促成了Tau诱导的肝细胞癌发生促进作用。总之，我们的研究提供了概念验证证据，证实Tau是一个有吸引力的HCC靶点。
