Aberrantly activated Gli2-KIF20A axis is crucial for growth of hepatocellular carcinoma and predicts poor prognosis

// Chao Shi 1 , Dengliang Huang 1 , Nonghua Lu 2 , Dan Chen 1 , Minhong Zhang 1 , Yehong Yan 3 , Libin Deng 4 , Quqin Lu 5 , Hua Lu 6 , Shiwen Luo 1 1 Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 2 Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 3 Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 4 Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China 5 Department of Epidemiology and Biostatistics, School of Public Health, Nanchang University, Nanchang, Jiangxi, China 6 Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA Correspondence to: Shiwen Luo, email: shiwenluo@ncu.edu.cn Keywords: glioma-associated oncogene 2, Forkhead box M1, kinesin family member 20A, transcriptional regulation, hepatocellular carcinoma Received: January 29, 2016 Accepted: March 14, 2016 Published: March 28, 2016 ABSTRACT Glioma-associated oncogene 2 (Gli2), a primary transcriptional regulator of Hedgehog (Hh) signaling, is essential for hepatocellular carcinoma (HCC) growth and survival. However, the underlying molecular mechanism and crucial downstream targets of Gli2 in human HCC are not fully understood. Here, we report the identification of kinesin family member 20A (KIF20A) as a novel downstream target of Gli2, which is important for HCC proliferation and tumor growth. Inhibition of Hh signaling leads to a remarkable decrease of KIF20A expression in HCC cells, whereas overexpression of Gli2 elevates KIF20A expression by activating Forkhead Box M1 (FoxM1)-MMB complex-mediated transcription of this kinesin gene. Gli2-induced HCC cell growth requires enhanced expression of KIF20A, and knockdown of Gli2 or KIF20A represses the proliferation of HCC cells in vitro and in vivo . Correlated with these results, analyses of clinical HCC samples show that Gli2, FoxM1 and KIF20A are highly elevated in primary HCC samples and represent significant risk factors for HCC recurrence and survival. Conclusion: KIF20A is an important downstream target gene of Hh signaling. And, the Gli2-KIF20A axis is essential for the proliferation and growth of human HCC cells. Our study also suggests Gli2-KIF20A axis as a potential target for future therapeutic intervention and as an independent prognostic biomarker for HCC.