Accumulation of microtubule associated protein tau promotes hepatocellular carcinogenesis through inhibiting autophagosome-lysosome fusion

Abstract Dysregulated expression of microtubule associated protein tau (MAPT) has been reported in a variety of human cancers. However, whether and how MAPT influences hepatocellular carcinogenesis remains elusive. This study was aimed to investigate the role and the underlying mechanism of MAPT in the proliferation, invasion, migration and sorafenib sensitivity of hepatocellular carcinoma (HCC) cells. An increased level of MAPT was found in the primary tumor samples of HCC compared with the adjacent normal liver tissues, and the increase of MAPT 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 MAPT expression was also correlated with a poorer survival in HCC patients demonstrated by using the GEPIA survival and Kaplan-Meier analysis. Further studies showed that MAPT overexpression promoted the growth, invasion and migration and decreased sorafenib sensitivity in HepG2 and Huh7 cells; MAPT also accelerated growth of xenograft tumors with blockage of autophagosome-lysosome fusion. Finally, overexpressing MAPT inhibited AMPK, which contributed to MAPT-induced promotion of hepatocellular carcinogenesis. In conclusion, our study provides the proof-of-concept evidence validating MAPT as an attractive HCC target.