Tang Bo, Zhang Yi, Wang Wei, Qi Guangying, Shimamoto Fumio
Department of Health Sciences, Hiroshima Shudo University Hiroshima 731-3195, Japan.
Am J Cancer Res. 2020 Jul 1;10(7):2100-2113. eCollection 2020.
PARP6 belongs to the mono-ADP-ribosyltransferase family and has been shown to be involved in the genesis and development of some tumours. However, the role of PARP6 in hepatocellular carcinoma (HCC) development remains to be fully elucidated. In the current study, we demonstrated that PARP6 was expressed at a low level in HCC cells and was negatively related to the degree of tumour differentiation. Additionally, silencing PARP6 led to an increase in the proliferation, invasion and migration ability of HCC cells in both and assays. Conversely, an elevation in the PARP6 expression level had the opposite effect. Through gene chip analysis combined with experimental verification, we confirmed that PARP6 can inhibit the expression of XRCC6 by inducing degradation and thus affect the Wnt/β-Catenin signalling pathway, which contributes to the suppression of HCC. Further mechanistic investigation demonstrated that the ubiquitin ligase HDM2 can interact with PARP6 and XRCC6, and mediated the regulatory effect of PARP6 on XRCC6 degradation. Taking together, PARP6 appears to inhibit HCC progression through the XRCC6/Wnt/β-catenin signal axis and could be used as a biomarker for the clinical monitoring of HCC development.
PARP6属于单ADP核糖基转移酶家族，已被证明参与某些肿瘤的发生和发展。然而，PARP6在肝细胞癌（HCC）发展中的作用仍有待充分阐明。在本研究中，我们证明PARP6在肝癌细胞中低表达，且与肿瘤分化程度呈负相关。此外，在体外和体内实验中，沉默PARP6均导致肝癌细胞增殖、侵袭和迁移能力增强。相反，PARP6表达水平升高则产生相反的效果。通过基因芯片分析并结合实验验证，我们证实PARP6可通过诱导降解来抑制XRCC6的表达，从而影响Wnt/β-连环蛋白信号通路，进而抑制肝癌。进一步的机制研究表明，泛素连接酶HDM2可与PARP6和XRCC6相互作用，并介导PARP6对XRCC6降解的调控作用。综上所述，PARP6似乎通过XRCC6/Wnt/β-连环蛋白信号轴抑制肝癌进展，并可作为肝癌发展临床监测的生物标志物。
