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[Cancer Research 62, 2715-2720, May 1, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Expression of Several Genes in the Human Chromosome 3p21.3 Homozygous Deletion Region by an Adenovirus Vector Results in Tumor Suppressor Activities in Vitro and in Vivo1

Lin Ji2, Masahiko Nishizaki, Boning Gao, David Burbee, Masashi Kondo, Craig Kamibayashi, Kai Xu, Nancy Yen, E. Neely Atkinson, Bingliang Fang, Michael I. Lerman, Jack A. Roth and John D. Minna

Section of Thoracic Molecular Oncology, Departments of Thoracic and Cardiovascular Surgery [L. J., M. N., K. X., N. Y., B. F., J. A. R.] and Biomathematics [E. N. A.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390 [B. G., D. B., M. K., C. K., J. D. M.]; and Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [M. I. L.]

A group of candidate tumor suppressor genes (designated CACNA2D2, PL6, 101F6, NPRL2, BLU, RASSF1, FUS1, HYAL2, and HYAL1) has been identified in a 120-kb critical tumor homozygous deletion region (found in lung and breast cancers) of human chromosome 3p21.3. We studied the effects of six of these 3p21.3 genes (101F6, NPRL2, BLU, FUS1, HYAL2, and HYAL1) on tumor cell proliferation and apoptosis in human lung cancer cells by recombinant adenovirus-mediated gene transfer in vitro and in vivo. We found that forced expression of wild-type FUS1, 101F6, and NPRL2 genes significantly inhibited tumor cell growth by induction of apoptosis and alteration of cell cycle processes in 3p21.3 120-kb region-deficient (homozygous) H1299 and A549 cells but not in the 3p21.3 120-kb region-heterozygous H358 and the normal human bronchial epithelial cells. Intratumoral injection of Ad-101F6, Ad-FUS1, Ad-NPRL2, and Ad-HYAL2 vectors or systemic administration of protamine-complexed vectors significantly suppressed growth of H1299 and A549 tumor xenografts and inhibited A549 experimental lung metastases in nu/nu mice. Together, our results, coupled with other studies demonstrating a tumor suppressor role for the RASSSF1A isoform, suggest that multiple contiguous genes in the 3p21.3 120-kb chromosomal region may exhibit tumor suppressor activity in vitro and in vivo.




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Copyright © 2002 by the American Association for Cancer Research.