Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas

Abstract

We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(À) IPMAs and 9 (53%) of 17 WWOX(À) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptotic body index. Interestingly, decreased WWOX expression was significantly correlated with loss of SMAD4 expression in these IPMNs. The results indicate that downregulation of WWOX expression by the WWOX regulatory region hypermethylation is critical for transformation of pancreatic duct.

The role of the WWOX gene in leukemia and its mechanisms of action

“…Leukemia is an oligoclonal or monoclonal disease, and its molecular basis remains poorly understood. The WWOX gene was previously identified from chromosome region 16q23.3-24.1 which spans the common fragile site FRA16D (1), and low expression of WWOX has also been reported in various types of cancer (5)(6)(7)(8)(9). The present study also showed that expression of WWOX (mRNA and protein) was frequently reduced or lost in different types of primary leukemia patients and cell lines, but exhibited a high expression level in healthy volunteers.…”

“…The present study also showed that expression of WWOX (mRNA and protein) was frequently reduced or lost in different types of primary leukemia patients and cell lines, but exhibited a high expression level in healthy volunteers. Recent evidence suggests that loss of heterozygosity, as well as epigenetic modification of the promoter by methylation, can reduce WWOX expression in various types of tumor (7,23,24).…”

“…To date, numerous studies have shown either a reduction or loss of WWOX expression in a variety of carcinomas, including breast, esophagus, pancreas and thyroid cancer (5)(6)(7)(8)(9). Significantly, a restoration or upregulation of WWOX in tumors such as lung and breast cancer can sensitize them to apoptosis both in vitro and in vivo (10,11).…”

Reduced expression of the WW domain-containing oxidoreductase in human hematopoietic malignancies

“…WWOX is a tumor suppressor gene that maps to the common fragile site FRA16D and is involved in carcinogenesis and cancer progression in a number of carcinoma types (1,19,20). The bulk of the data documented have shown that the expression of WWOX/WWOX was lost or reduced in various types of solid cancers (2)(3)(4)(5)(6)(7)(8)(9)(10). Similarly, the aberration or absence of WWOX/WWOX expression in primary hematopoietic malignancies has also been reported (11)(12)(13)(14)(15)(16).…”

“…The WWOX gene maps at the 16p23.3-24.1 chromosomal region and spans the second most common fragile site in the human genome, FRA16D (1). Since its discovery, WWOX/WWOX has been shown to exhibit reduced or no expression in a range of neoplastic diseases of varying locations, such as the lungs, breasts, bladder, ovaries, esophagus and pancreas (2)(3)(4)(5)(6)(7). Moreover, abnormal WWOX/WWOX expression profiles had been reported to be associated with a poor prognosis in carcinomas (8)(9)(10).…”