The Therapeutic Effect And Molecular Mechanism Of Targeting KIF20B In Hepatocellular Carcinoma

Liver cancer is a common cancer,which causes 800,000 deaths annually worldwide.Hepatocellular carcinoma(HCC)is the most common tumor type in the liver,accounting for approximately 75% of primary liver cancer.Clinically,HCC is not sensitive to chemotherapy drugs and lacks effective drug treatment.Therefore,it is urgent to find new targets and effective treatment strategies for HCC.Kinesin family member 20B(KIF20B),the member of the kinesins superfamily(KIFs),which share a highly conserved motor domain that enables its microtubule-dependent plus-end motion ability through its ATPase activity.KIF20 B is a microtubule-associated protein,which plays a critical role in cytokinesis and specifically phosphorylation at M-phase.Previously,the oncogenicity of KIF20 B has been demonstrated in several cancers;however,the exact mechanism underlying its tumorigenic effects remain unclear.Herein,we showed the overexpression of KIF20 B in human hepatocellular carcinoma(HCC)and reported a negative correlation between KIF20 B level and the prognosis of patients.Furthermore,we applied Ad-shKIF20 B,a recombinant adenoviral vector expressing shRNAs against KIF20 B,to HCC cell lines,the results showed that reducing KIF20 B blockaded mitotic exit of HCC cells at telophase,which is independent of the spindle assembly checkpoint,and reducing KIF20 B also promoted apoptosis.Importantly,reducing KIF20 B acts synergistically with microtubule-associated agents(MTAs)to HCC cells.In conclusion,we found a novel mechanism in HCC treatment that blocking cytokinesis by KIF20 B inhibition increases the efficacy of MTA.Our results indicated that reducing KIF20 B blockaded mitotic exit at telophase,whereas MTA mainly suppressed mitosis at metaphase.Together,we suggested a dual-mitotic suppression approach against HCC by combining MTA with KIF20 B inhibition,which simultaneously blocks mitosis at both metaphase and telophase.There are some advantages of the approach.On one hand,the cells that escaped from metaphase inhibition(triggered by MTA)would be re-trapped in the telophase arrest by KIF20 B inhibition,resulting in increasing the efficacy of MTA.On the other hand,MTA will further increase the cytotoxic effect of KIF20 B inhibition through microtubule poison characteristics,thus generating enhanced or even synergistic efficacy.Our study of anti-HCC through targeting KIF20 B will provide new ideas for the subsequent study of liver cancer and other MTA-insensitive solid tumors from the perspective of mitosis.