Research Impact
In line with the research directions of SKLLR, our researchers pursue for original and systematic research projects on scientific frontier. The novel and insightful research findings not only provided significant discoveries on liver diseases but also shed lights on the development of better and more effective treatments:
Identification of liver cancer stem cells
Liver cancer is a complicated disease and ranks the fifth most common cancer in the world. A novel concept of cancer biology suggested that cancer initiation is driven by a small population of cells known as “cancer stem cells” (CSCs) or “tumor-initiating cells” (TICs). CSCs are featured by the ability of self-renewal, initiate tumor in vivo and resistant to chemotherapy.
SKLLR is a pioneering team in deciphering the mystery of liver CSCs. We have conducted studies on CD133, a stem cell biomarker. Our findings delineated important signaling pathways in regulating tumorigenesis of liver CSC and highlighted the potential therapeutic option for targeting CD133 (+) liver CSC . [1 – 5] SKLLR identified for the first time that a subset of cancer stem cells, CD24(+), is responsible for chemoresistance, metastasis and tumor recurrence in liver cancer.[6]
Our studies suggested that targeting CD47 is an attractive therapeutic regimen for the treatment of HCC patients.[7, 8] Our studies discovered new knowledge in liver cancer research on the regulation of CSC and establishing targets for selective blocking of CSC functions.
Molecular mechanisms of liver cancer metastasis
Liver cancer (hepatocellular carcinoma, HCC) is a prevalent cancer with an extremely highly mortality rate attributed to HCC metastatic, which is the major cause of tumor recurrence and organ failure. The understanding of cell signaling pathways and cancer metastasis for developing new therapeutic strategies for liver cancer is of crucial importance.
SKLLR has identified many key signaling pathways that involved in regulating liver cancer metastasis. In particular, we are the leading group in the research of the importance and function of DLC1 (Deleted in Liver Cancer 1)/RhoE/microRNA miR-139 in tumor suppressive activities.[9 – 12] Our findings enriched the understanding of the molecular mechanisms of liver cancer metastasis.
An innovative research of SKLLR, breaking the traditional understanding, discovered that antioxidants lead to cancer growth and highlighted the therapeutic benefits of targeting pathways that generate antioxidants.[13] This was a breakthrough discovery on the pathogenesis and therapeutic interventions of liver cancer.
Cancer genomics and epigenomics of liver cancer
Liver carcinogenesis is a multistep process driven by the accumulation of genetic and epigenetic alterations. SKLLR is dedicated to delineate the epigenetics of human HCC. We had comprehensive studies on major mechanisms of epigenetic control with novel findings.
RNA editing is defined as post-transcriptional alteration of RNA sequences and is an additional epigenetic control mechanism. In humans, the most frequent type of RNA editing is conversion of adenosine (A) to inosine (I). Our study identified a close link between A-to-I RNA editing of Antizyme inhibitor 1 (AZIN1) and liver carcinogenesis. Collectively, A-to-I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.[14]
Research teams of SKLLR conducted several studies related to CHD1L (Chromodomain Helicase DNA Binding Protein 1 Like), a chromatin remodelling protein. We revealed the prognostic value of CHD1L and the therapeutic potential of targeting CHDIL in HCC. Research findings of our studies highlighted the clinical and functional significance of CHD1L in liver carcinogenesis.[15 - 17]
Deregulation of histone modifying enzymes is a common trait of human HCC. Our findings of studies on different histone methyltransferases such as SUV39H1 (Suppressor of variegation 3-9 homolog 1), EHZ2 (Enhance of Zeste), SETDB1 (SET domain, bifurcated 1) promoted better understanding on the molecular mechanisms of liver carcinogenesis. [18 – 20]
HBV biology and treatment
Our researchers are world-leading scientists in the development of antiviral treatment for chronic hepatitis B. Our studies focus on the development and monitoring of the long-term antiviral treatment and identification of the importance of occult HBV infection (OBI) in HBV reactivation and development of HCC.
SKLLR is a pioneer group which performed quantitative measurement of cccDNA (covalently closed circular DNA) in chronic hepatitis B patients. Our studies suggested the possibility that cccDNA may be eliminated through long-term antiviral therapy and provoked further research for the verification of this possibility. [22, 23]
Occult HBV infection is especially a life-threating problem in patients with immunosuppressive therapy. SKLLR is a frontier in the research of OBI. Our studies on OBI highlighted the importance of monitoring of HBV markers in patients with immunosuppressive therapy and, more importantly, provided decisive evidence in shaping of treatment strategies in preventing HBV reactivation in these patients. [24 – 28] .
Clinical management and treatment for liver cancer
Liver cancer (Hepatocellular carcinoma (HCC) is the 5th leading cancer worldwide, with extremely high incidence in China. Staging of HCC is different from other cancers because in addition to the tumor, the presence of background liver disease such as chronic hepatitis and cirrhosis would also significantly affect patient prognosis.
The research team of SKLLR developed the Asia’s first staging system, named Hong Kong Liver Cancer (HKLC) staging system. [9] The home-grown breakthrough received widespread international recognition. This new HKLC staging system provides better prognostic classification and treatment indications. [29]
Hepatic resection forms the cornerstone for surgical management of HCC. However, many HCC patients are not suitable for this curative treatment. Over the last decade, high-intensity focused ultrasound (HIFU) ablation has emerged as a new form of local ablative therapy. SKLLR conducted various studies to evaluate the outcome of patients with HCC treated by of HIFU. Our works provided valuable experience guiding the use of HIFU in clinical practice for the treatment of unresectable HCC. [30 - 32]
References
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2. Chai S, Tong M, Ng KY, Kwan PS, Chan YP, Fung TM, Lee TK, Wong N, Xie D, Yuan YF, Guan XY, Ma S. Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. Oncotarget. 2014 Jul 30;5(14):5725-35
3. Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, Ng IO, Man K, To KF, Lai PB, Lo CM, Guan XY, Chan KW. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 2012 Mar;55(3):807-20. doi: 10.1002/hep.24739.
4. Tong M, Fung TM, Luk ST, Ng KY, Lee TK, Lin CH, Yam JW, Chan KW, Ng F, Zheng BJ, Yuan YF, Xie D, Lo CM, Man K, Guan XY, Ma. SANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma. Stem Cell Reports. 2015 Jul 14;5(1):45-59. doi: 10.1016/j.stemcr.2015.05.013.
5. Song Y, Pan G, Chen L, Ma S, Zeng T, Man Chan TH, Li L, Lian Q, Chow R, Cai X, Li Y, Li Y, Liu M, Li Y, Zhu Y, Wong N, Yuan YF, Pei D, Guan XY. Loss of ATOH8 Increases Stem Cell Features of Hepatocellular Carcinoma Cells. Gastroenterology. 2015 Oct;149(4):1068-81.e5. doi: 10.1053/j.gastro.2015.06.010.
6. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011 Jul 8;9(1):50-63. doi: 10.1016/j.stem.2011.06.005
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8. Lo J, Lau EY, Ching RH, Cheng BY, Ma MK, Ng IO, Lee TK. NF-κB mediated CD47 upregulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma. Hepatology. 2015 Aug; 62(2):534-45.
9. Ko FC, Chan LK, Sze KM, Yeung YS, Tse EY, Lu P, Yu MH, Ng IO, Yam JW. PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis. Nat Commun. 2013;4:1618. doi: 10.1038/ncomms2604.
10. Chan LK, Ko FC, Sze KM, Ng IO, Yam JW. Nuclear-targeted deleted in liver cancer 1 (DLC1) is less efficient in exerting its tumor suppressive activity both in vitro and in vivo. PLoS One. 2011;6(9):e25547. doi: 10.1371/journal.pone.0025547.
11. Ma W, Wong CC, Tung EK, Wong CM, Ng IO. RhoE is frequently down-regulated in hepatocellular carcinoma (HCC) and suppresses HCC invasion through antagonizing the Rho/Rho-kinase/myosin phosphatase target pathway. Hepatology. 2013 Jan;57(1):152-61. doi: 10.1002/hep.25987.
12. 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 down-regulating Rho-kinase 2. Gastroenterology. 2011 Jan;140(1):322-31. doi: 10.1053/j.gastro.2010.10.006.
13. Xu IM, Lai RK, Lin SH, Tse AP, Chiu DK, Koh HY, Law CT, Wong CM, Cai Z, Wong CC, Ng IO. Transketolase counteracts oxidative stress to drive cancer development. Proc Natl Acad Sci U S A. 2016 Feb; 113(6):E725-34.
14. Chen L, Li Y, Lin CH, Chan TH, Chow RK, Song Y, Liu M, Yuan YF, Fu L, Kong KL, Qi L, Li Y, Zhang N, Tong AH, Kwong DL, Man K, Lo CM, Lok S, Tenen DG, Guan XY. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med. 2013 Feb;19(2):209-16. doi: 10.1038/nm.3043.
15. Chen L, Yuan YF, Li Y, Chan TH, Zheng BJ, Huang J, Guan XY. Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut. 2011 Apr;60(4):534-43. doi: 10.1136/gut.2010.224071
16. Chan TH, Chen L, Liu M, Hu L, Zheng BJ, Poon VK, Huang P, Yuan YF, Huang JD, Yang J, Tsao GS, Guan XY. Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development. Hepatology. 2012 Feb;55(2):491-505. doi: 10.1002/hep.24709
17. Li Y, Chen L, Chan TH, Liu M, Kong KL, Qiu JL, Li Y, Yuan YF, Guan XY. SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice. Gastroenterology. 2013 Jan;144(1):179-191.e4. doi: 10.1053/j.gastro.2012.09.042
18. Fan DN, Tsang FH, Tam AH, Au SL, Wong CC, Wei L, Lee JM, He X, Ng IO, Wong CM. Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b. Hepatology. 2013 Feb;57(2):637-47. doi: 10.1002/hep.26083
19. Au SL, Wong CC, Lee JM, Wong CM, Ng IO. EZH2-Mediated H3K27me3 Is Involved in Epigenetic Repression of Deleted in Liver Cancer 1 in Human Cancers. PLoS One. 2013 Jun 27;8(6):e68226. doi: 10.1371/journal.pone.0068226
20. Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO, Wong CM. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012 Aug;56(2):622-31. doi: 10.1002/hep.25679
21. Wong CM, Wei L, Law CT, Ho DW, Tsang FH, Au SK, Sze KM, Lee JM, Wong CC, Ng IO. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology. 2016 Feb; 63(2):474-87. doi.org/10.1002/hep.28304.
22. Wong DK, Seto WK, Fung J, Ip P, Huang FY, Lai CL, Yuen MF. Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clin Gastroenterol Hepatol. 2013 Aug;11(8):1004-10. doi: 10.1016/j.cgh.2013.01.026.
23. Lai CL, Wong D, Ip P, Kopaniszen M, Seto WK, Fung J, Huang FY, Lee B, Cullaro G, Chong CK, Wu R, Cheng C, Yuen J, Ngai V, Yuen MF. Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. J Hepatol. 2017 Feb; 66(2):275-81. doi: 10.1016/j.jhep.2016.08.022.
24. Wong DK, Fung J, Lee CK, Seto WK, Leung J, Huang FY, Lin CK, Lai CL, Yuen MF. Intrahepatic hepatitis B virus replication and liver histology in subjects with occult hepatitis B infection. Clin Microbiol Infect. 2016 Mar;22(3):290 e1-3. doi: 10.1016/j.cmi.2015.10.036.
25. Wong DK, Huang FY, Lai CL, Poon RT, Seto WK, Fung J, Hung IF, Yuen MF. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology. 2011 Sep 2;54(3):829-36. doi: 10.1002/hep.24551.
26. Seto WK, Sau-Yan Chan T, Hwang YY, Wong DK, Fung J, Liu KS, Gill H, Lam YF, Lau EH, Cheung KS, Lie AK, Lai CL, Kwong YL, Yuen MF. Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study. Hepatology. 2016 Dec 27. doi: 10.1002/hep.29022.
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28. Wong DK, Seto WK, Cheung KS, Chong CK, Huang FY, Fung J, Lai CL, Yuen MF. Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. Liver Int. 2016 Dec 19. doi: 10.1111/liv.13346.
29. Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014 Jun;146(7):1691-700.e3. doi: 10.1053/j.gastro.2014.02.032.
30. Ng KK, Poon RT, Chan SC, Chok KS, Cheung TT, Tung H, Chu F, Tso WK, Yu WC, Lo CM, Fan ST. High-intensity focused ultrasound for hepatocellular carcinoma: a single-center experience. Ann Surg. 2011 May;253(5):981-7. doi: 10.1097/SLA.0b013e3182128a8b
31. Chan AC, Cheung TT, Fan ST, Chok KS, Chan SC, Poon RT, Lo CM. Survival analysis of high-intensity focused ultrasound therapy versus radiofrequency ablation in the treatment of recurrent hepatocellular carcinoma. Ann Surg. 2013 Apr;257(4):686-92. doi: 10.1097/SLA.0b013e3182822c02.
32. Cheung TT, Fan ST, Chan SC, Chok KS, Chu FS, Jenkins CR, Lo RC, Fung JY, Chan AC, Sharr WW, Tsang SH, Dai WC, Poon RT, Lo CM. High-intensity focused ultrasound ablation: an effective bridging therapy for hepatocellular carcinoma patients. World J Gastroenterol. 2013 May 28;19(20):3083-9. doi: 10.3748/wjg.v19.i20.3083
