Dr WONG Chun Ming, Jack
Assistant Professor
BSc HK; MMedSc HK; PhD HK

Cancer epigenetics and molecular pathogenesis of liver cancer

Research Interest

Epigenetic alterations in liver cancer
MicroRNA deregulation in liver cancer
Mechanisms of epigenetic gene regulation
Epigenetic-miRNA regulatory circuitry

Liver cancer (hepatocellular carcinoma, HCC) is one of the most common malignancies worldwide and is particularly prevalent in Asia. Liver cancer is an aggressive cancer associated with a poor prognosis that is often due to late presentation of symptoms and frequent tumor metastasis. However, the molecular mechanisms underlying hepatocarcinogenesis are unclear. In addition to genetic alterations, recent evidences have indicated that epigenetic abnormalities also play a very important role in hepatocarcinogenesis. Epigenetic, as implied by the Greek prefix, Epi- (means “in addition to”), refers to an additional regulatory layer on top of genetic information stored in DNA sequence. DNA methylation and histone modifications are two major epigenetic events that work very closely in regulating chromatin structure and gene expression pattern. We and others have previously shown that epigenetic alterations play a crucial role in silencing tumor suppressor genes in human cancers. We are interested to elucidate the molecular basis and pathological roles of various epigenetic alterations in human HCC. MicroRNA is a class of small non-coding RNA profoundly involved in post-transcriptional gene regulation and recently implicated in human carcinogenesis. We are also interested to study the expression profiles, epigenetic alterations and molecular functions of microRNAs and their roles in liver cancer development and metastasis. Our recent studies particularly focus on delineating the interplay between miRNA and epigenetic machinery and how deregulation of this epigenetic-miRNA regulatory circuit implicated in liver cancer progression and metastasis. We believe that a better knowledge of the underlying molecular mechanisms of hepatocarcinogenesis and cancer metastasis is of crucial importance for the development of new diagnostic tools and therapeutic interventions for this lethal cancer.

Awards received by supervised research postgraduate students:

Au Leung Kuen, Sandy (PhD student), Young Investigator Award, 16th Hong Kong International Congress, Nov 2009, Hong Kong
Au Leung Kuen, Sandy (PhD student), Best Presentation Award, 15th Research Postgraduate Symposium, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Dec 2010, Hong Kong
Fan Ngo-Yin, Dorothy (PhD student), Best Presentation Award, 16th Research Postgraduate Symposium, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Dec 2011, Hong Kong

Major research funding awarded:

Michael Kadoorie Funded Research for Cancer Genetics (2004)
Research Grant Council- General Research Fund (2008, 2011)
Research Grant Council-Collaborative Research Fund (2010)
Seed funding for basic research (2008, 2009, 2010, 2011)

Research articles:

Click here for detail publication list on PubMed

Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO # and Wong CM #. Enhancer of zeste homolog 2 (EZH2) epigenetically silences multiple tumor suppressor miRNAs to promote liver cancer metastasis. Hepatology 2012; In press (# corresponding authors)

Wong CM *#, Wong CC*, Lee JM, Fan DN, Au SL, and Ng IO#. Sequential alterations of miRNA expression in hepatocellular carcinoma development and venous metastasis, Hepatology 2012; 55:1453(*Wong CC and Wong CM contributed equally to this work. # corresponding authors)

Lei ZQ, Li L, Li GJ, Leung CW, Shi J, Wong CM, Lo KC, Chan KW, Mak CS, Chan SB, Chan NM, Leung CH, La PT, and Pong PW. Liver cancer immunoassay with magnetic nanoparticles and MgO-based magnetic tunnel junction sensors. Journal of Applied Physics, 2012; 111, 07E505

Li R, Yang W, Zhang J, Hirankarn N, Pan HF, Mok CC, Chan TM, Wong RW, Mok MY, Lee KW, Wong SN, Leung AM, Li XP, Avihingsanon Y, Lee TL, Ho MH, Lee PP, Wong WH, Wong CM, Ng IO, Yang J, Li PH, Zhang Y, Zhang L, Li W, Baum L, Kwan P, Rianthavorn P, Deekajorndej T, Suphapeetiporn K, Shotelersuk V, Garcia-Barceló MM, Cherny SS, Tam PK, Sham PC, Lau CS, Shen N, Lau YL, Ye DQ. Association of CD247 with systemic lupus erythematosus in Asian Populations. Lupus. 2012; 21: 75

Chan KY*, Wong CM*, Kwan JS*, Lee JM, Cheung KW, Yuen MF, Lai CL, Poon RT, Sham PC, Ng IO. Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection. PLoS ONE. 2011; 6: e28798(*Chan KY, Wong CM and Kwan JS contributed equally to this work)

Wong CC, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO, Wirtz D, Semenza GL. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci U S A. 2011; 108:16369

Zhang Y, Yang W, Mok CC, Chan TM, Wong RW, Mok MY, Lee KW, Wong SN, Leung AM, Lee TL, Ho MH, Lee PP, Wong WH, Yang J, Zhang J, Wong CM, Ng IO, Garcia-Barceló MM, Cherny SS, Tam PK, Sham PC, Lau CS, Lau YL. Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun. 2011; 12:231

Gao P, Wong CC, Tung EK, Lee, JM, Wong CM #, Ng IO #. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J Hepatol, 2011; 54:1177 (# corresponding authors)

Yang J, Yang W, Hirankarn N, Ye DQ, Zhang Y, Pan HF, Mok CC, Chan TM, Wong RW, Mok MY, Lee KW, Wong SN, Leung AM, Li XP, Avihingsanon Y, Rianthavorn P, Deekajorndej T, Suphapeetiporn K, Shotelersuk V, Baum L, Kwan P, Lee TL, Ho MH, Lee PP, Wong WH, Zeng S, Zhang J, Wong CM, Ng IO, Garcia-Barceló MM, Cherny SS, Tam PK, Sham PC, Lau CS, Lau YL. ELF1 is associated with systemic lupus erythematosus in Asian populations. Hum Mol Genet. 2011; 20:601

Wong CM, Wong CC, Ng YL, Au SL, Ng IO. Transcriptional repressive H3K9 and H3K27 methylations contribute to DNMT1-mediated DNA methylation recovery. PLoS ONE, 2011, 6: e16702

Wong CC *, Wong CM *, Tung EK, Au SL, Lee, JM, Poon RT, Man K, Ng IO. The microRNA MiR-139 suppresses metastasis and progression of hepatocellular carcinoma by downregulating Rho-kinase 2. Gastroenterology. 2011; 140:332. (*Wong CC and Wong CM contributed equally to this work.)

Liang L, Wong CM, Ying Q, Fan DN, Huang S, Ding J, Yao J, Yan M, Li J, Yao M, Ng IO, He X. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology. 2010; 52:1731

Ko FC, Yeung YS, Wong CM, Chan LK, Poon RT, Ng IO, Yam JW. Deleted in liver cancer 1 isoforms are distinctly expressed in human tissues, functionally different and under differential transcriptional regulation in hepatocellular carcinoma. Liver Int. 2010: 30:139-48

Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Leung AM, Li XP, Avihingsanon Y, Wong CM, Lee TL, Ho MH, Lee PP, Chang YK, Li PH, Li RJ, Zhang L, Wong WH, Ng IO, Lau CS, Sham PC, Lau YL; Asian Lupus Genetics Consortium. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010; 6:e1000841

Wong CC, Wong CM, Tung EKK, Man K, and Ng IO. Rho-kinase 2 (ROCK2) is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology. 2009; 48:1583

Tung EKK, Wong CM, Yau TO, Lee JM, Ching YP and Ng IO. HAI-2 is epigenetically down-regulated in human hepatocellular carcinoma and its Kunitz domain type 1 is critical for its anti-invasive function. Int J Cancer. 2009; 124:1811

Wong CC, Wong CM, Ko FC, Chan LK, Ching YP, Yam JW, Ng IO. Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PLoS ONE. 2008; 3:e2779

Lee JM, Wong CM and Ng IO. Hepatitis B virus-associated multistep hepatocarcinogenesis: a stepwise increase in allelic alterations. Cancer Res. 2008; 68:5988-96

Wong CM, Ng YL, Lee JM, Wong CC, Cheung OF, Chan CY, Tung EK, Ching YP, Ng IOL. Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma. Hepatology 2007; 45: 1129-1138

Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY, Ng IO. Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proc Natl Acad Sci U S A. 2005; 102:15207-15212

Wong CM*, Yam JW*, Ching YP, Yau TO, Leung TH, Jin DY, Ng IO. Rho GTPase activating protein DLC1 (deleted in liver cancer) suppresses cell proliferation and invasion in hepatocellular carcinoma. Cancer Res 2005; 65: 8861-8868(*Wong CM and Yam JWP contributed equally to this work.)

Chin KT, Zhou HJ, Wong CM, Lee JM, Chan CP, Qiang BQ, Yuan JG, Ng IO, Jin DY. The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma. Nucleic Acids Res 2005; 33:1859-1873

Yau TO, Chan CY, Chan KL, Lee JM, Wong CM, Fan ST, Ng IO. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 2005; 24:1607-1614

Chan CF, Yau TO, Jin DY, Wong CM, Fan ST, Ng IO. Evaluation of nuclear factor-kB, urokinase-type plasminogen activator (uPA) and HBx and their clinicopathological significance in hepatocellular carcinoma. Clin Cancer Res 2004; 10: 4140-4149

Pang R, Yuen J, Yuen MF, Lai CL, Lee TK, Man K, Poon RT, Fan ST, Wong CM, Ng IO, Kwong YL, Tse E. Pin1 overexpression and b-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Oncogene 2004; 23: 4182-4186

Wong CM, Lee JM, Ching YP, Jin DY, Ng IO. Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res. 2003; 63: 7646-7651

Ching YP*, Wong CM*, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO. Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J. Biol. Chem. 2003; 278:10824-10830. (*Ching YP and Wong CM contributed equally to this work.)

Wong CM, Lee JM, Lau TC, Fan ST, Ng IO. Clinicopathological significance of loss of heterozygosity on chromosome 13q in hepatocellular carcinoma. Clin. Cancer Res. 2002; 8: 2266-2272

Wong CM, Fan ST, Ng IO. ß-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance. Cancer 2001; 92: 136-145.

Review articles:

Wong CM, Kai AK, Tsang FH, Ng IO. Regulation of hepatocarcinogenesis by microRNAs. Front Biosci (Schol Ed). 2012; In press

Wong CC, Wong CM, Au SL, Ng IO. RhoGTPases and Rho-Effectors in Hepatocellular Carcinoma Metastasis: ROCK N' Rho Move It. Liver Int. 2010; 30:642

Yam JY, Wong CM, Ng IO. Molecular and functional genetics of hepatocellular carcinoma. Front Biosci (Schol Ed). 2010; 2:117-34

Wong CM and Ng IOL. Molecular pathogenesis of hepatocellular carcinoma. Liver Int. 2008; 28:160-174.

Book chapters:

Wong CM, Yam JW and Ng IO, Molecular Pathogenesis of Hepatocellular, In: Wang XW et al. (eds), Molecular Genetics of Liver Neoplasia, Cancer Genetics, Springer, 2010