MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival. Silencing MELK inhibited cell growth, invasion, stemness and tumorigenicity of HCC cells by inducing apoptosis and mitosis. We further showed that the overexpression of MELK in HCC samples strongly correlated with the cell cycle- and mitosis-related genes which are directly regulated as part of the forkhead transcription factor FoxM1-related cell division program. Together, our data establish MELK as an oncogenic kinase involved in the pathogenesis and recurrence of HCC and could provide a promising molecular target to develop therapeutic strategies for patients with advanced HCC.
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore. Electronic address: xiahp82@gmail.com.
Hongping
H
Xia
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore. Electronic address: kong.shik.nie@nccs.com.sg.
Shik Nie
SN
Kong
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore. Electronic address: chen.jian.xiang@nccs.com.sg.
Jianxiang
J
Chen
Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, PR China. Electronic address: ShiMing@mail.sysu.edu.cn.
Ming
M
Shi
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore. Electronic address: sekar.karthik@nccs.com.sg.
Karthik
K
Sekar
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore. Electronic address: seshachalam.veerabrahma.pratap@nccs.com.sg.
Veerabrahma Pratap
VP
Seshachalam
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore. Electronic address: muthukumar.rajasekaran@nccs.com.sg.
Muthukumar
M
Rajasekaran
Department of General Surgery, Singapore General Hospital, Singapore. Electronic address: brian.goh@sgh.com.sg.
Brian Kim Poh
BKP
Goh
Department of General Surgery, Singapore General Hospital, Singapore; Department of Surgical Oncology, National Cancer Centre, Singapore. Electronic address: dsoopj@nccs.com.sg.
London Lucien
LL
Ooi
Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore. Electronic address: cmrhkm@nccs.com.sg.
Kam M
KM
Hui
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D000066673:Cell Self Renewal; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008938:Mitosis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D015854:Up-Regulation
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
FOXM1; Hepatocellular carcinoma; MELK; Oncogenic kinase; Recurrence