pathways for Big-h3-regulated cell proliferation and tumor
role of Big-h3 gene in regulating immune response.
of unique signature of signaling dysregulated in cancer
Dr. Ping Lu (Post-Doc Research Scientist)
of Medicine, China Medical University, China, 1986.
Beijing Institute of Radiation Medicine, China, 1995.
Center for Radiological Research, Columbia University, 1998.
Academic and Professional Appointments
Professor, Department of Radiation Oncology, Center for Radiological Research, College of Physicians
& Surgeons of Columbia University
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.
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,
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,
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).
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.
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,
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]
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]
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]