technical report on research programmes · 2014-11-04 · technical report on research programmes...

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Colorectal Cancer (CRC)

A. Molecular Pathogenesis:

1. Metagenomic analysis of stool samples delineated the landscape of bacterial dysbiosis in CRC.

2. Exome sequencing and targeted capture sequencing has led to the identification of three novel significantly mutated genes in CRC.

3. Single-cell sequencing integrated with functional analysis support that colon cancer could be of biclonal origin and low-prevalence mutations in a cohort may play important pro-tumourigenic roles at the individual level.

4. A novel recurrent disruptive gene fusion was identified in ~8% of CRC patients.

5. MicroRNA-133a serves as a potential tumour suppressor upstream of p53-p21 signalling by targeting RFFL to induce G0/G1-phase cell cycle arrest in CRC.

6. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in CRC by downregulating BMI1.

7. MicroRNA-18 attenuates cellular repair of DNA double-strand breaks by directly suppressing ATM, a key enzyme in DNA damage repair.

Research Progress Summary:

PI:Jun Yu (Department of Medicine and Therapeutics and Institute of Digestive Diseases)

Team:Joseph JY Sung, Francis KL Chan, Henry Chan, Justin Wu, Vincent Wong, Siew Ng, Grace L Fu, Dennis CC Wong, Ye Jin (Department of Medicine and Therapeutics, and Institute of Digestive Diseases); Alfred SL Cheng, William Wu (Institute of Digestive Diseases); Enders KW Ng, James Lau, Simon Ng, Philip Chiu (Department of Surgery, and Institute of Digestive Diseases)

49Technical Report on Research Programmes

8. MicroRNA-7 is a novel miRNA with tumour suppressive function in colon cancer by targeting oncogenic Yin Yang 1 (YY1). YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signalling pathways.

9. Proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition in CRC.

B. Biomarkers:

1. An index calculated from the abundance of 31 bacterial gene markers in stools may be useful for CRC diagnosis in Asian populations.

2. An eight-gene mutation signature that predicts survival outcomes for stratifying CRC patients independent of TNM staging was identified.

3. YY1 serves as an independent prognostic biomarker for CRC patients.

C. Molecular Therapy:

1. MicroRNA-133a may sensitise cells to therapeutics.

2. FK-16, a therapeutic peptide derived from human cathelicidin, induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in CRC cells.

D. Epidemiology:

Siblings of patients with colorectal cancer have a higher prevalence of advanced neoplasms, including colorectal cancer, than siblings of healthy individuals. Screening is indicated in this high-risk population.

Gastric Cancer (GC)


1. ADAMTS9 acts as a functional tumour suppressor in GC through inhibiting oncogenic AKT/mTOR signalling pathway.

2. Chemerin increased invasiveness of GC cells through ERK1/2-dependent up-regulation of VEGF, MMP-7 and IL-6.

3. ZNF545 acts as a functional tumour suppressor in GC by inhibiting rRNA transcription.

4. ZNF331 is identif ied as a multi-functional tumour-suppressor gene in GC.

5. Somatostatin receptor 1 is a novel methylated gene driven by EBV infection in GC cells and acts as a potential tumour suppressor.

6. E p s t e i n - B a r r v i r u s ( E B V ) i n d u c e d a b e r r a n t CpGhypermethylation of genes involving in important cancer-related pathways including mitogen-activated protein kinase signalling, cell adhesion molecules, and Wnt signalling pathway in GC. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A.

B. Biomarkers:

1. Methylation of ADAMTS9 is an independent prognostic factor of GC.

2. Serum level of chemerin was significantly higher in GC patients than healthy subjects. The elevation of serum chemerin level was associated with advanced clinical stages and nonintestinal type of GC.

3. ZNF545 methy la t ion a t ea r l y s tages o f gas t r i c carcinogenesis is an independent prognostic factor.

4. BCL6B methylation may serve as a novel potential non-invasive plasma biomarker for the detection of GC.

C. Molecular Therapy:

Cathelicidin, an antimicrobial peptide, is found to protect against Helicobacter pylori infection and its associated gastritis. Food-grade bacteria could be engineered to deliver cathelicidin.

Hepatocellular Carcinoma (HCC)


1. CITED2 is a direct effector of peroxisome proliferator-activated receptor gamma for tumour suppression in HCC.

2. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human HCC.

3. Full-length Mst1 exhibits a growth promoting activity in HCC cells.

4. Smad7 suppresses HCC cel l growth by inhibit ing proliferation and G1-S phase transition and inducing apoptosis through attenuation of NF-κB and TGFβ signalling. Smad7 acts as a potential tumour suppressor in liver.

Other GI Diseases

1. Cigarette smoking and appendectomy are identified as the strongest environmental risk factors for inflammatory bowel diseases (IBD).

2. A large-scale population-based study was performed to show that IBD can be as severe or more severe in Asia than in the West.

3. The microbiota is substantially altered in IBD, but ethnicity may also play an important role.

4. Systematic review revealed encouraging results of herbal therapy for the treatment of IBD.

5. Endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.

6. Global and deep molecular analysis demonstrate an altered mucosal microbiota composition in irritable bowel syndrome. Probiotic leads to detectable changes in the microbiota, which may contribute to their therapeutic benefit.

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Recognitions:

Awards and Fellowships

Member’s Name Details

Joseph Sung,Francis Chan and Jun Yu

• Establishment of State Key Laboratory of Digestive Disease (July 1st, 2013)

Vincent Wong• Distinguished Research Paper Award for Young Investigators, Hong Kong

College of Physicians 2013

Grants and Consultancy

Details Member’s Name Amount (HK$)

Innovation and Technology Commission (ITC) Innovation & Technology Fund (ITF) (2013 - 2018)Title: Partner State Key Laboratory of Digestive Diseases

Joseph Sung 13,750,000

Research Grant Council (RGC) General Research Fund (GRF) (2010 - 2013)Title: Randomized trial of proton-pump inhibitor plus a COX-

2 selective NSAID versus proton-pump inhibitor plus nonselective NSAID in patients with high ulcer risk

Francis Chan 1,840,000

Research Grant Council (RGC) General Research Fund (GRF) (2013 - 2015)Title: Continuation of clopidogrel and the risk of

colonoscopicpolypectomy bleeding: A double-blind, randomized trial

Francis Chan 1,200,000

Shenzhen Virtual University Park Support Scheme, Shenzhen (1/7/2012 - 30/6/2014)Title: State Key Laboratory of Cancer Biology (CUHK Joint

Research Base in Shenzhen)

Jun Yu 1,000,000

Shenzhen Municipal Science and Technology R & D Funding of Basic Research Programs, China (2013 - 2015)Title: Whole-exome sequencing in colon cancer to identify key

genetic alterations and to clarify their clinical implication

Jun Yu RMB 500,000

SH Ho Foundation, Hong Kong (2012 - 2018)Title: Microbe, colorectal cancer and obesity

Jun Yu 5,000,000


Innovation & Technology Commission-Innovation and Technology Support Programme (1/8/2013 – 31/7/2014)Title: Development of Novel Hypermethylated Genes as

Prognostic Biomarkers for Gastric Cancer.

Jun Yu 775,997

Food and Health Bureau - Health and Medical Research Fund (2012 – 2014)Title: Elucidating the role of autophagy in hepatitis B virus

X protein (HBx)-mediated liver infl ammation and carcinogenesis

William Wu 994,040

Food and Health Bureau - Health and Medical Research Fund (1/2/2013 – 31/1/2015)Title: Elucidation of the Modulating Role of Autophagy in

Helicobacter Pylori Colonization and the Associated Gastritis.

William Wu 999,552

Research Grants Council (RGC) - General Research Fund (GRF) (1/1/2013 – 31/12/2014)Title: Factors associated with incident nonalcoholic fatty liver

disease in the general population: A follow-up study with proton-magnetic resonance spectroscopy and transient elastography.

Vincent Wong 850,000

Food and Health Bureau - Health and Medical Research Fund (1/2/2012 – 31/12/2013)Title: Liver fi brosis progression in patients with chronic

hepatitis B: A prospective study with paired transient elastography examination

Vincent Wong 891,776

Food and Health Bureau - Health and Medical Research Fund (1/10/2012 – 31/1/2014)Title: The Application of Transcutaneous Electric Nerve

Stimulation on Acupoints (Acu-TENS) for Pain Relief during Colonoscopy: A Prospective, Randomized, Placebo-Controlled Study

Simon Ng 368,490

Research Grants Council (RGC) - General Research Fund (GRF) (1/11/2012 – 31/10/2014)Title: Robotics-assisted laparoendoscopic single site access

surgery: from animal study to clinical application.

Enders Ng 804,134

Technology and Innovation Project Fund, ShenzhenTitle: MicroRNA-based detection of colorectal cancer: key

technology development project InvestigatorsJun Yu RMB 4,000,000

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1. Bai, A. H., & Cheng, A. S. (2013). Alliance ofepigenetic forces for the activation of oncogenicWnt/β-catenin signalling. Journal of Gastroenterologyand Hepatology, 28(3), 383-385.

2. Cheung, K. F., Zhao, J., Hao, Y., Li, X., Lowe, A. W.,Cheng, A. S., Sung, J. J., & Yu, J. (2013). CITED2is a novel direct effector of peroxisome proliferator-activated receptor γ in suppressing hepatocellularcarcinoma cell growth. Cancer, 119(6), 1217-1226.

3. Dong, C. G., Wu, W. K., Feng, S. Y., Yu, J., Shao, J. F.,& He, G. M. (2013). Suppressing the malignantphenotypes of glioma cells by lentiviral deliveryof small hairpin RNA targeting hypoxia-induciblefactor-1alpha. International Journal of Clinical andExperimental Pathology, 6(11), 2323-2332.

4. Dong, Y., Zhao, J., Wu, C. W., Zhang, L., Liu, X.,Kang, W., Leung, W. W., Zhang, N., Chan, F. K.,Sung, J. J., Ng, S. S., & Yu, J. (2013). Tumorsuppressor functions of miR-133a in colorectalcancer. Molecular Cancer Research, 11 (9 ) ,1051-1060.

5. Du, W., Wang, S., Zhou, Q., Li, X., Chu, J., Chang, Z.,Tao, Q., Ng, E. K., Fang, J., Sung, J. J., & Yu, J.(2013). ADAMTS9 is a functional tumor suppressorthrough inh ib i t ing AKT/mTOR pathway andassociated with poor survival in gastric cancer.Oncogene, 32(28), 3319-3328.

6. Fan, Q., He, M., Deng, X., Wu, W. K., Zhao, L., Tang, J.,Wen, G., Sun, X., & Liu, Y. (2013). Derepressionof c-Fos caused by MicroRNA-139 down-regulation contributes to the metastasis of humanhepatocellular carcinoma. Cell Biochemistry andFunction, 31(4), 319-324.

7. Li, Z., Shen, J., Wu, W. K., Yu, X., Liang, J., Qiu, G.,& Liu, J. (2013). The role of leptin on the organizationand expression of cytoskeleton elements in nucleuspulposus cells. Journal of Orthopaedic Research,31(6), 847-857.

8. Ng, S. C., Bernstein, C. N., Vatn, M. H., Lakatos, P. L.,Loftus, E. V.Jr., Tysk, C., O'Morain, C., Moum, B., &Colombel, J. F. (2013). Geographical variability andenvironmental risk factors in inflammatory boweldisease. Gut, 62(4), 630-649.

9. Ng, S. C., Lam, E. F., Lam, T. T., Chan, Y., Law, W.,Tse, P. C., Kamm, M. A., Sung, J. J., Chan, F. K.,& Wu, J. C. (2013). Effect of probiotic bacteria onthe intestinal microbiota in irritable bowel syndrome.Journal of Gastroenterology and Hepatology, 28(10),1624-1631.

10. Ng, S. C., Lam, Y. T., Tsoi, K. K., Chan, F. K.,Sung, J. J., & Wu, J. C. (2013). Systematic review:the effi cacy of herbal therapy in infl ammatory boweldisease. Alimentary Pharmacology & Therapeutics,38(8), 854-863.

11. Ng, S. C., Lau, J. Y., Chan, F. K., Suen, B. Y.,Leung, W. K., Tse, Y. K., Ng, S. S., Lee, J. F., To, K. F.,Wu, J. C., & Sung, J. J. (2013). Increased risk ofadvanced neoplasms among asymptomatic siblingsof patients with colorectal cancer. Gastroenterology,144(3), 544-550.

12. Ng, S. C., Tang, W., Ching, J. Y., Wong, M., Chow, C. M., Hui, A. J., Wong, T. C., Leung, V. K., Tsang, S. W.,Yu, H. H., Li, M. F., Ng, K. K., Kamm, M. A., Studd, C.,Bell, S., Leong, R., de Silva, H. J., Kasturiratne, A.,M u f e e n a , M . N . , L i n g , K . L . , O o i , C . J . ,Tan , P. S . , Ong, D . , Goh, K . L . , H i lm i , I . ,P i s e s p o n g s a , P. , M a n a t s a t h i t , S . ,R e r k n i m i t r, R . , A n i w a n , S . , Wa n g , Y. F. ,Ouyang, Q., Zeng, Z., Zhu, Z., Chen, M. H., Hu, P. J.,Wu, K., Wang, X., Simadibrata, M., Abdullah, M.,Wu, J. C., Sung, J. J., & Chan, F. K. (2013).Inc idence and phenotype o f i n f l ammatorybowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study.Gastroenterology, 145(1), 158-165.

13. Ng, Y. K., Lau, W. S., Lui, V. W., Cheng, A. S., Ng, P. K.,Tsui, S. K., Cheung, Y. S., & Lai, P. B. (2013). Full-length Mst1 exhibits growth promoting function inhuman hepatocellular carcinoma cells. FEBS Letters,587(5), 496-503.

14. Otani, K., Li, X., Arakawa, T., Chan, F. K., & Yu, J.(2013). Epigenetic-mediated tumor suppressorgenes as diagnostic or prognostic biomarkersin gastric cancer. Expert Review of MolecularDiagnostics, 13(5), 445-455.

15. Prideaux, L., Kang, S., Wagner, J., Buckley, M.,Mahar, J. E., De Cruz, P., Wen, Z., Chen, L., Xia, B.,van Langenberg, D. R., Lockett, T., Ng, S. C.,Sung, J. J., Desmond, P., McSweeney, C., Morrison, M.,Kirkwood, C. D., & Kamm, M. A. (2013). Impact ofethnicity, geography, and disease on the microbiotain hea l th and in f lammatory bowel d isease.Infl ammatory Bowel Diseases, 19(13), 2906-2918.

16. Ren, S. X., Shen, J., Cheng, A. S., Lu, L., Chan, R. L.,Li, Z. J., Wang, X. J., Wong, C. C., Zhang, L.,Ng, S. S., Chan, F. L., Chan, F. K., Yu, J., Sung, J. J.,Wu, W. K., & Cho, C. H. (2013). FK-16 derived fromthe anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death incolon cancer cells. PLoS One, 8(5), e63641.

Publications:


17. Tai, E. K., Wu, W. K., Wang, X. J., Wong, H. P., Yu, L.,Li, Z. J., Lee, C. W., Wong, C. C., Yu, J., Sung, J. J.,Ga l lo , R. L . , & Cho, C. H. (2013) . In t rarecta ladministration of mCRAMP-encoding plasmid reversesexacerbated colitis in Cnlp-/- mice. Gene Therapy, 20(2),187-193.

18. Tang, C. M., & Yu, J. (2013). Hypoxia-induciblefactor-1 as a therapeutic target in cancer. Journal ofGastroenterology and Hepatology, 28(3), 401-405.

19. Wang, J., Zhao, J., Chu, E. S., Mok, M. T., Go, M. Y.,Man, K., Heuchel, R., Lan, H. Y., Chang, Z., Sung, J. J.,& Yu , J . ( 2013 ) . I nh ib i to r y ro l e o f Smad7 i nhepatocarcinogenesis in mice and in vitro. The Journalof Pathology, 230(4), 441-452.

20. Wang, S., Cheng, Y., Du, W., Lu, L., Zhou, L., Wang, H.,Kang, W., Li, X., Tao, Q., Sung, J. J., & Yu, J. (2013).Zinc-finger protein 545 is a novel tumour suppressorthat acts by inhibiting ribosomal RNA transcription ingastric cancer. Gut, 62(6), 833-841.

21. Wang, X. J., Yu, J., Wong, S. H., Cheng, A. S., Chan, F. K.,Ng, S. S., Cho, C. H., Sung, J. J., & Wu, W. K. (2013).A nove l c rossta lk between two major prote indegradation systems: Regulation of proteasomal activityby autophagy. Autophagy, 9(10), 1500-1508.

22. Wong, S. H., & Ng, S. C. (2013). What can we learn frominflammatory bowel disease in developing countries?Current Gastroenterology Reports, 15(3), 313.

23. Wong, S. H., Sung, J. J., Chan, F. K., To, K. F., Ng, S. S.,Wang, X. J., Yu, J., & Wu, W. K. (2013). Genome-wide association and sequencing studies on colorectalcancer. Seminars in Cancer Biology, 23(6, Part B),502-511.

24. Wu, C. W., Dong, Y. J., Liang, Q. Y., He, X. Q., Ng, S. S.,Chan, F. K., Sung, J. J., & Yu, J. (2013). MicroRNA-18aattenuates DNA damage repair through suppressing theexpression of ataxia telangiectasia mutated in colorectalcancer. PLoS One, 8(2), e57036.

25. Wu, W. K., & Sung, J. J. (2013). Focus on gastrointestinaland liver cancers. Seminars in Cancer Biology, 23(6,Part B), 469-470.

26. Wu, W. K., Wang, X. J., Cheng, A. S., Luo, M. X., Ng, S. S.,To, K. F., Chan, F. K., Cho, C. H., Sung, J. J., & Yu, J.(2013). Dysregulation and crosstalk of cellular signallingpathways in colon carcinogenesis. Critical Reviews inOncology/Hematology, 86(3), 251-277.

27. Yang, Q., Gao, J., Xu, L., Zeng, Z., Sung, J. J., & Yu, J.(2013). Promoter hypermethylation of BCL6B gene is

a potential plasma DNA biomarker for gastric cancer. Biomarkers, 18(8), 721-725.

28. Yu, J., Liang, Q. Y., Wang, J., Cheng, Y., Wang, S.,Poon, T. C., Go, M. Y., Tao, Q., Chang, Z., & Sung, J. J.(2013). Zinc-finger protein 331, a novel putative tumorsuppressor, suppresses growth and invasiveness ofgastric cancer. Oncogene, 32(3), 307-317.

29. Yu, J., Shen, J., Sun, T. T., Zhang, X., & Wong, N. (2013).Obesity, insulin resistance, NASH and hepatocellularcarcinoma. Seminars in Cancer Biology, 23(6, Part B),483-491.

30. Yu, X., Li, Z., Shen, J., Wu, W. K., Liang, J., Weng, X.,& Qiu, G. (2013). MicroRNA-10b promotes nucleuspulposus cell proliferation through RhoC-Akt pathwayby targeting HOXD10 in intervetebral disc degeneration.PLoS One, 8(12), e83080.

31. Yu, Z., & Cheng, A. S. (2013). Epigenetic deregulationof microRNAs: new opportunities to target oncogenicsignalling pathways in hepatocellular carcinoma. CurrentPharmaceutical Design , 19(7), 1192-1200.

32. Zeng, Z., Zhu, Z., Yang, Y., Ruan, W., Peng, X., Su, Y.,Peng, L., Chen, J., Yin, Q., Zhao, C., Zhou, H., Yuan, S.,Hao, Y., Qian, J., Ng, S. C., Chen, M., & Hu, P. (2013).Incidence and clinical characteristics of inflammatorybowel disease in a developed region of GuangdongProvince, China: A prospective population-based study.Journal of Gastroenterology and Hepatology, 28(7),1148-1153.

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33. Zhang, L., Yu, J., Wong, C. C., Ling, T. K., Li, Z. J.,Chan, K. M., Ren, S. X., Shen, J., Chan, R. L.,Lee, C. C., Li, M. S., Cheng, A. S., To, K. F., Gallo,R. L., Sung, J. J., Wu, W. K., & Cho, C. H. (2013).Cathelicidin protects against Helicobacter pyloricolonization and the associated gastritis in mice.Gene Therapy , 20(7), 751-760.

34. Zhang, N., Li, X., Wu, C. W., Dong, Y., Cai, M.,Mok, M. T., Wang, H., Chen, J., Ng, S. S., Chen, M.,Sung, J. J., & Yu, J. (2013). microRNA-7 is anovel inhibitor of YY1 contributing to colorectaltumorigenesis. Oncogene, 32(42), 5078-5088.

35. Zhao, J., Liang, Q., Cheung, K. F., Kang, W., Dong, Y.,Lung, R. W. M., Tong, J. H., To, K. F., Sung, J. J.,& Yu, J. (2013). Somatostatin Receptor 1, a novelEBV-associated CpG hypermethylated gene,contributes to the pathogenesis of EBV-associated

gastric cancer. British Journal of Cancer, 108(12), 2557-2564.

36. Zhao, J., Liang, Q., Cheung, K. F., Kang, W., Lung, R.W., Tong, J. H., To, K. F., Sung, J. J., & Yu, J. (2013).Genome-wide identification of Epstein-Barr virus-driven promoter methylation profi les of human genesin gastric cancer cells. Cancer, 119(2), 304-312.

37. Zhao, J., Ng, S. C., Lei, Y., Yi, F., Li, J., Yu, L., Zou, K.,Dan, Z., Dai, M., Ding, Y., Song, M., Mei, Q.,Fang, X., Liu, H., Shi, Z., Zhou, R., Xia, M., Wu, Q.,Xiong, Z., Zhu, W., Deng, L., Kamm, M. A., & Xia, B.(2013). F i rst prospect ive, populat ion-basedinflammatory bowel disease incidence study inmainland of China: the emergence of "western"disease. Inflammatory Bowel Diseases, 19(9),1839-1845.

technical report on research programmes · 2014-11-04 · technical report on research programmes...

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