Academic Staff > A.L.M. Cheung

 

Annie Lai-Man Cheung ( 張麗雯 )
Associate Professor
B.Sc., Ph.D. (H.K.), CBiol, MIBiol

Department of Anatomy
1/F. Laboratory Block
Faculty of Medicine Building
21 Sassoon Road, Hong Kong

Anatomy Office: (852) 2819-9293 (voice)
Anatomy Office: (852) 2817-0857 (fax)

E-mail: lmcheung@hkucc.hku.hk

Jump to: Research / Publications

Research

Research Interests:

Cancer biology: role and mechanisms of novel oncogenes and tumor suppressor genes in the development and progression of esophageal cancer; identifying and targeting key molecular pathways for cancer therapy; study of mechanisms that drive chromosomal instability in early carcinogenesis.
 

 Current Research Projects:

  1. Role of Id-1 in esophageal cancer

    The helix-loop-helix protein Id-1 is known to promote cellular proliferation in several types of human cancer including esophageal squamous cell carcinoma (ESCC). We previously reported that ectopic expression of Id-1 in ESCC cells leads to activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, which is involved in regulating a wide spectrum of cellular functions including proliferation, survival, angiogenesis, invasion and metastasis. Our recent data show that this activation is mediated by growth factors secreted by the cancer cells, which promote the proliferation, survival, as well migration and invasive potentials of esophageal cancer cells in an autocrine manner. Furthermore, we found that growth factors secreted by Id-1-overexpressing ESCC cells can activate stromal fibroblasts in a paracrine manner to secrete vascular endothelial growth factor (VEGF), which in turn instigates bone marrow-derived vascular progenitor cells to promote tumor angiogenesis and metastasis. Our current aim is to identify key growth factors that mediate the oncogenic function of Id-1. This aspect has important clinical applications since systemic targeting of these growth factors may inhibit esophageal cancer growth and metastasis, and may represent a novel approach in esophageal cancer therapy.

  1. PI3K/AKT pathway as a therapeutic target in human esophageal cancer

Increasing evidence suggests that the PI3K/AKT pathway is involved in cancer development Our previous study showed that PI3K/AKT is constitutively activated in human ESCC cell lines as well as tumor tissues derived from patients, but rarely in normal cells and tissues. To obtain a better understanding of the role of PI3K/AKT signaling pathway in the development and progression of human esophageal cancer, this project investigates the effects of PI3K/AKT inhibition on proliferation, migration and invasive potential of esophageal cancer cells in vitro, and on tumor growth and metastasis in vivo using nude mice tumor xenograft and experimental metastasis models. The PI3K/AKT pathway is also implicated in cancer chemoresistance but the mechanism is not fully understood. It was reported that increased p-AKT (phosphorylated or activated form of AKT) expression during chemotherapy in ESCC patients is associated with poor survival. Since cancer stem cells are thought to be more resistant to chemotherapy, we hypothesize that PI3K/AKT pathway may be differentially activated in esophageal cancer stem cells, and that targeting this pathway using specific inhibitors such as LY294002 and Wortmannin may reduce the population of esophageal cancer cells expressing stem cell markers.

  1. Synergistic effect and molecular mechanisms of green tea (EGCG) and vitamin C in the treatment and prevention of esophageal cancer 

    Carcinogenesis is a multi-stage process that transforms normal epithelial cells to premalignant lesions and on to invasive carcinoma. Increasing attention is focused on the use of non-toxic chemopreventive agents to block or delay the process. In this regard, naturally occurring antioxidants present in the diet and beverages are ideal candidates. Epigallocatechin-3-gallate (EGCG) is the major and most effective component of green tea in preventing and inhibiting experimental carcinogenesis. Vitamin C (ascorbic acid), present in high abundance in many fruits and vegetables, has been shown to be inversely correlated with the development of esophageal cancer. However, both compounds have drawbacks in that EGCG is unstable under physiologic conditions, whereas high dose vitamin C is potentially harmful. Recent studies showed that vitamin C can extend the half-life of EGCG. On the other hand, physiological levels of EGCG can increase the cellular lipid antioxidant activity of vitamin C. We therefore hypothesize that, EGCG and vitamin C may be an ideal combination in the prevention and treatment of human cancer due to their synergistic effects. The aim of this project is to determine the synergistic effects of these two agents in preventing esophageal cancer, and to study the mechanisms involved.

  1. Impact of replication fork stalling on centromeric instability

Centromeres, the integral chromosomal elements where sister chromatids are constricted and the microtubules are attached for chromosome segregation during cell division, are intrinsically predisposed to instability. The frequent occurrence of centromeric aberrations in tumor cells suggests that centromeric instability may contribute to tumor development. In our previous study, we provided first evidence that G2 checkpoint defect promotes centromeric instability. In addition, analysis with confocal microscopy showed that, compared with normal cells, significantly higher percentages of immortalized cells, cancer cells, and fibroblasts from patients with a cancer-prone disorder termed ataxia telangiectasia (A-T) syndrome spontaneously presented large γ-H2AX foci (representing irreparable DNA damage) that were colocalized or juxtaposed with centromeres. Chromatin immunoprecipitation (ChIP) analysis confirmed that cells with G2 checkpoint defect had markedly higher enrichment in centromeric co-precipitation with γ-H2AX compared with normal cells. In contrast, such extents of enrichment were not detected at non-centromeric region. The question remains as to whether centromeric instability can be explained by the late replicating property of centromeres. Based on the features of centromeric DNA replication and the function of G2 checkpoint, we hypothesize that centromeric DNA may be preferentially subject to erroneous replication that fails to be corrected in cells with defective G2 checkpoint, leading to centromeric instability. The aim of this study is to investigate the role of DNA replication fork stalling on centromeric instability

Back to top

Selected Publications

(*Correspondence Author)

  1. Deng W, Tsao SW, Mak GWY, Tsang CM, Ching YP, Guan XY, Huen MSY, Cheung ALM* (2011). Impact of G2 checkpoint defect on centromeric instability. Oncogene 30(11): 1281-1289.

  2. Cheung PY, Yip YL, Tsao SW, Ching YP, Cheung ALM* (2011). Id-1 induces cell invasiveness in immortalized epithelial cells by regulating cadherin switching and Rho GTPases. Journal of Cellular Biochemistry 112(1):157-168.

  3. Cheung PY, Deng W, Man C, Tse WW, Srivastava G, Law S, Tsao SW*, Cheung ALM* (2010). Genetic alterations in a telomerase-immortalized human esophageal epithelial cell line: implications for carcinogenesis. Cancer Letters 293(1):41-51.

  4. Li B, Tsao SW, Li YY, Wang X, Ling MT, Wong YC, He QY, Cheung ALM* (2009) Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway. International Journal of Cancer 125(11): 576-2585.

  5. Li B, Li YY, Tsao SW, Cheung ALM* (2009) Targeting NF-κB signaling pathway suppresses tumor growth, angiogenesis, and metastasis of human esophageal cancer. Molecular Cancer Therapeutics 8(9):2635–2644.

  6. Deng W, Tsao SW, Kwok YK, Wong E, Huang XR, Liu S, Tsang CM, Ngan HYS, Cheung ANY, Lan HY, Guan X-Y, Cheung ALM* (2008) TGF-β1 promotes chromosomal instability in HPV16 E6E7-infected cervical epithelial cells. Cancer Research 68(17):7200-7209.

  7. Cheung ALM*, Deng W (2008). Telomere dysfunction, genome instability and cancer. Frontiers in Bioscience 13(1):2075-2090.          

  8. Li B, Cheung PY, Wang X, Tsao SW, Ling MT, Wong YC, Cheung ALM* (2007). Id-1 activation of PI3K/Akt/NFκB signaling pathway and its significance in promoting survival of esophageal cancer cells. Carcinogenesis 28(11): 2313-2320.                        

  9. Deng W, Tsao SW, Guan X-Y, Cheung ALM* (2007). Microtubule breakage is not a major mechanism for resolving end-to-end chromosome fusions generated by telomere dysfunction during the early process of immortalization. Chromosoma 116(6):557-568.

  10. Hui CM, Cheung PY, Ling MT, Tsao SW, Wang X, Wong YC, Cheung ALM* (2006). Id-1 promotes proliferation of p53-deficient esophageal cancer cells. International Journal of Cancer 119:508-514.

  11. Si HX, Tsao SW, Poon CSP, Wong YC, Cheung ALM* (2005). Physical status of HPV-16 in esophageal squamous cell carcinoma. Journal of Clinical Virology 32(1):19-23.

  12. Si HX, Tsao SW, Poon CSP, Cheung ALM* (2004). Human papillomavirus infection and loss of heterozygosity in esophageal squamous cell carcinoma. Cancer Letters 213(2): 231-239.

  13. Deng W, Tsao SW, Guan X-Y, Lucas JN, Si HX, Leung CS, Mak P, Wang LD, Cheung ALM* (2004). Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines. Oncogene 23(56):9090-9101.

  14. Deng W, Tsao SW, Guan X-Y, Lucas JN, Cheung ALM* (2003). The role of short telomeres in inducing preferential chromosomal aberrations in human ovarian surface epithelial cells: a combined telomere Q-FISH and whole-chromosome painting study. Genes, Chromosomes & Cancer 37(1): 92-97.                                            

  15. Deng W, Tsao SW, Lucas JN, Leung CS, Cheung ALM* (2003). A new method for improving metaphase chromosome spreading. Cytometry Part A 51A: 46-51.

  16. Si HX, Tsao SW, Poon CSP, Wang LD, Wong YC, Cheung ALM* (2003). Viral Load of Human Papillomavirus (HPV) in Esophageal Squamous Cell Carcinoma. International Journal of Cancer 103(4):495-500.

  17. Tsao SW, Liu Y, Wang X, Yuen PW, Leung SY, Yuen ST, Pan J, Nicholls JM, Cheung A, Wong YC (2003). Association of downregulation of E-cadherin expression and methylation of E-cadherin gene in nasopharyngeal carcinoma cells. European Journal of Cancer 39:524-531.

  18. Wang X, Jin D-Y, Ng RWM, Feng H, Wong YC, Cheung ALM, Tsao SW (2002). Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Research 62:1662-1668.

  19. Si HX, Tsao SW, Lam KY, Srivastava G, Liu Y, Wong YC, Shen ZY, Cheung ALM* (2001). E-cadherin expression is commonly downregulated by CpG island hypermethylation in esophageal carcinoma cells. Cancer Letters 173(1):71-78.

  20. Cheung ALM*, Graf A-H, Hauser-Kronberger C, Dietze O, Tubbs R, Hacker GW (1999). Detection of human papillomavirus in cervical carcinoma: Comparison of peroxidase-, Nanogold-, and CARD-Nanogold in situ hybridization. Modern Pathology 12(7): 689-696.                   

                                      

 

 

                        

 

 

Back to top
Copyright © 2006 The University of Hong Kong