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The Tumor Suppressor Gene WWOX at FRA16D Is Involved in Pancreatic Carcinogenesis

¹ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; ² Areta International srl, Gerenzano, Italy; ³ Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; ⁴ Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan; and ⁵ Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan

Purpose: WWOX (WW domain containing oxidoreductase) is a tumor suppressor gene that maps to the common fragile site FRA16D. We showed previously that WWOX is frequently altered in human lung and esophageal cancers. The purpose of this study was to delineate more precisely the role of WWOX in pancreatic carcinogenesis.

Experimental Design: We analyzed 15 paired pancreatic adenocarcinoma samples and 9 pancreatic cancer cell lines for WWOX alterations. Colony assay and cell cycle analysis were also performed to evaluate the role of the WWOX as a tumor suppressor gene.

Results: Loss of heterozygosity at the WWOX locus was observed in 4 primary tumors (27%). Methylation analysis showed that site-specific promoter hypermethylation was detected in 2 cell lines (22%) and treatment with the demethylating agent 5-aza-2'-deoxycytidine demonstrated an increase in the expression of WWOX. In addition, 2 primary tumor samples (13%) showed promoter hypermethylation including the position of site-specific methylation. Transcripts missing WWOX exons were detected in 4 cell lines (44%) and in 2 tumor samples (13%). Real-time reverse transcription PCR revealed a significant reduction of WWOX expression in all of the cell lines and in 6 primary tumors (40%). Western blot analysis showed a significant reduction of the WWOX protein in all of the cell lines. Furthermore, transfection with WWOX inhibited colony formation of pancreatic cancer cell lines by triggering apoptosis.

Conclusion: These results indicate that the WWOX gene may play an important role in pancreatic tumor development.

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