Yongliang Zhao, Ph.D.

Center for Radiological Research
630 West 168th Street, VC 11-244
New York, N.Y. 10032

Email: yz93@columbia.edu
Tel: 212-305-9514 / Fax: 212-305-3229 

   Current Academic and Professional Appointments  

• Assistant Professor, Department of Radiation Oncology, Center for Radiological Research, College of Physicians & Surgeons of Columbia University

   Research Highlights  

Project 1.  Tumor suppressor function of Big-h3 (TGF-β-induced) examined by in vitro and in vivo models. 

It is well accepted that tumor growth and metastasis is a multistep process involving cell adhesion, proteolytic enzyme degradation of the extracellular matrix (ECM) and motility factors that influence cell migration. Big-h3, also known as TGFBI, was first identified in a human lung adenocarcinoma cell line (A549) treated with TGF-β (Skonier et al, 1992). This gene encodes a highly conserved 683 amino-acid protein that contains a secretary signal sequence and four internal homologous domains, the last of which contains an RGD (Arg-Gly-Asp) motif which can serve as a ligand recognition site for integrins. Big-h3 product has been shown to be a component of ECM in lung and mediate cell adhesion and migration through interacting with integrin via integrin receptors. We have preciously shown that Big-h3 is ubiquitously expressed in human normal tissues, however, downregulation or lost expression of this gene has been found in a variety of human tumor tissues including lung, breast, prostate, and leukemia. In addition, downregulation of Big-h3 expression correlates with tumorigenic phenotype in human cancer cells (Zhao, et al, 2002, 2004 & 2006). CpG island hypermethylation in the promoter region, one of the mechanisms by which tumor suppressor genes are inactivated in human cancers, correlates with the silencing of Big-h3 promoter and its subsequent down-expression (Shao and Zhao, et al, 2006).

To further delineate the function of Big-h3 in vivo, we have generated a unique mouse model system with disruption of Big-h3 gene. The preliminary data showed that mice lacking Big-h3 show a retarded growth, and are prone to spontaneous and carcinogen-induced tumors. In relative to wild type mouse embryonic fibroblasts (MEFs), Big-h3^-/- MEFs display an increased frequency of chromosomal aberration and micronuclei formation, and exhibit an enhanced proliferation and early S-phase entry. Cyclin D1 was upregulated in Big-h3^-/- MEFs that was attributed to aberrant activation of transcription factor CREB (cAMP-response binding protein). Big-h3 reconstitution in Big-h3^-/- cells leads to suppression of phospho-CREB and cyclin D1 expression, and inhibition of cell proliferation. Cyclin D1 upregulation was further identified in most of tumors arising from Big-h3^-/- Mice. Our data provide the first evidence that Big-h3 loss induces genomic instability and functions as a tumor suppressor in vivo.

Project 2. Molecular mechanism of tumor progression in human breast and prostate cancer.

We have established the immortal, non-tumorigenic cell culture models from primary human mammary and prostate epithelial cells using retroviral infection with human telomerase (hTERT). Since hTERT activation has been demonstrated in over 90% of human cancer specimens including prostate and breast, hTERT-immortalized cell systems will be used to study the molecular mechanisms of prostate and mammary tumor progression.

   Selected Publications  

• Zhang Y, Wen GY, Shao GZ, Lin CS, Bhagat G, Balajee AS, Hei TK and Zhao YL. Disruption of TGFBI gene induces genomic instability and predisposes the mice to spontaneous tumor growth. Cancer Res. (In Press).

• Shah JN, Shao G, Hei TK and Zhao Y. Methylation screening of the TGFBI promoter in human lung and prostate cancer by methylation-specific PCR. BMC Cancer 8:284, 2008. [abstract]

• Shao G, Balajee AS, Hei TK and Zhao YL. p16INK4a downregulation is involved in immortalization of primary human prostate epithelial cells induced by telomerase. Mol. Carcinogenesis 47(10):775-83, 2008. [abstract]

• Calaf G, Echiburu-chau C, Zhao YL and Hei TK. BigH3 protein expression as a marker for breast cancer.. Int J of Mol Med. 21(5):561-8, 2008. [abstract]

• Shao G, Berenguer J, Borczuk AC, Powell CA, Hei TK and Zhao YL. Epigenetic inactivation of Betaig-h3 gene in human cancer cells. Cancer Res. 66(9): 4566-73, 2006. [abstract]

• Zhao YL, El-Gabry M and Hei TK. Loss of Betaig-h3 expression is frequent in primary lung carcinoma and related to tumorigenic phenotype in lung cancer cells. Mol. Carcinogenesis 45(2):84-92, 2006. [abstract]

• Piao CQ, Liu L, Zhao YL, Balajee AS, Suzuki M and Hei TK. Immortalization of human airway epithelial cells by ectopic expression of telomerase. Carcinogenesis 26(4):725-31, 2005 (Co-first author). [abstract]

• Zhao YL, Shao G, Piao CQ, Berenguer J and Hei TK. Downregulation of Betaig-h3 gene is involved in the tumorigenic process of human bronchial epithelial cells induced by heavy ion radiation. Radiation Res. 162(6): 655-9, 2004. [abstract]

• Zhao YL, Piao CQ. and Hei TK. Downregulation of Betaig-h3 is causally linked to tumorigenic phenotype in asbestos treated immortalized human bronchial epithelial cells. Oncogene 21:7471-7, 2002. [abstract]

• Zhao YL, Piao CQ. and Hei TK. Overexpression of Betaig-h3 gene downregulates integrin Alpha5Beta1 and suppresses tumorigenicity in radiation-induced tumorigenic human bronchial epithelial cells. British J. of Cancer 86:1923-8, 2002. [abstract]

• Piao CQ, Zhao YL and Hei TK. Analysis of p16 and p21(Cip1) expression in tumorigenic human bronchial epithelial cells induced by asbestos. Oncogene 20(50):7301-6, 2001. [abstract]

• Zhao YL, Piao CQ, Hall EJ and Hei TK. Mechanisms of radiation-induced transformation of human bronchail epithelial cells. Radiation Res. 155(1,Pt2): 230-4, 2001. [abstract]

• Suzuki M, Piao CQ, Zhao YL and Hei TK. Karyotype analysis of tumorigenic human bronchial epithelial cells transformed by chrysolite asbestos using chemically induced premature chromosome condensation technique.. International J. of Mol. Med. 8: 43-47, 2001. [abstract]

• Zhao YL, Piao CQ, Wu LJ, Suzuki M and Hei TK. Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism. Carcinogenesis 21(11): 2005-10, 2000. [abstract]