The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.

Professor Cuifen Huang: a great molecular geneticist and the founder of genetic engineering in China

Professor Cuifen Huang(黄翠芬,1921-2011)is a famous molecular geneticist and one of the founders of Genetic Engineering in China(Fig.1).She devoted all her life to researches on genetic engineering of vaccines and polypeptide drugs and studies on molecular tumors.She made tremendous contributions to the development of biotechnology and military medical science in China.She was also the first scientist who cloned and expressed the pro-urokinase gene in China which showed high selective thrombolysis without systemic hemorrhage(Chinese Academy of Engineering,2009).

Professor Haowen Xu:The founder of exercise biochemistry in China

Professor Haowen Xu(许豪文,1935-2004)was a famous sports scientist and the founder of Exercise Biochemistry in China(Fig.1).He dedicated his life to the study of sports science and made tremendous contributions to the formation and growth of the field of Exercise Biochemistry in China.He was the first to use theories of exercise biochemistry and sports medicine to guide athletes'training and competition in China(Yu,2006).