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Suppression of Tumorigenesis and Induction of p15^ink4b by Smad4/DPC4 in Human Pancreatic Cancer Cells¹

Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 [J. B. F.], and Departments of Surgical Oncology [B. P., T. B., A. M. G., S. F., D. B. E., T. W., K. D. R.], Gastrointestinal Medical Oncology [J. L. A.], Molecular and Cellular Oncology [P. J. C.], and Biostatistics [D. A., K. W.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: The tumor suppressor gene Smad4/DPC4, a key transcription factorin transforming growth factor ß (TGF-ß) signaling cascades,is inactivated in 50% of pancreatic adenocarcinomas. We seek to determine the role of Smad4/DPC4 in the suppression of tumor cell growth and in the regulation of TGF-ß-mediated expression of cell-cycle regulatory genes p15^ink4b and p21^waf1.

Experimental Design: Smad4/DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4/DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4/DPC4 is not expressed. Expression of the TGF-ß downstream target gene p21^waf1, regulation of the p15^ink4b promoter, anchorage-independent growth, and tumorigenesis were examined.

Results: We demonstrate that expression of Smad4/DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression of Smad4/DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15^ink4b, p21^waf1, and TGF-ß-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified Smad4 binding element (SBE) located in the region between -356 and -329 bp of the p15^ink4b promoter. The p15^ink4b promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates that p15^ink4b is one of the downstream target genes regulated by Smad/DPC4.

Conclusion: These results explain the role of Smad4/DPC4 in TGF-ß-mediated inhibition of cell proliferation in vitro and in vivo. Moreover, these results suggest that Smad4/DPC4-mediated tumor suppression and induction of TGF-ß-regulated cell-cycle-inhibitory genes may depend on additional factors that are absent in CFPac-1 cells.

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