Hypomethylation of the protein gene product 9.5 promoter region in gallbladder cancer and its relationship with clinicopathological features

Abstract

Protein gene product 9.5 (PGP9.5) is a neurospecific peptide that removes ubiquitin from ubiquitinated proteins and prevents them being targeted for degradation by proteosomes. Its expression is a potential marker of non-small lung cancer, invasive colorectal cancer and esophageal squamous cell carcinoma. Gallbladder (GB) cancer is the most common malignant tumor of the biliary tract and is usually associated with gallstone disease, a late diagnosis, unsatisfactory treatment and a poor prognosis. To understand the role of PGP9.5 in GB cancer, we examined the methylation status of its promoter and its expression in surgical biopsy samples. Formalinfixed, paraffin-embedded tumors and non-neoplastic GB tissues (22 carcinomas, eight adenomas, 26 normal epithelia) were collected from patients who had undergone surgical resection. The methylation status of the promoter region of the PGP9.5 gene was determined by methylation-specific polymerase chain reaction, and the expression of PGP9.5 was examined by immunohistochemistry using tissue microarrays. PGP9.5 promoter was methylated in 84.6% (22/26) of normal GB epithelium, 37.5% ( G allbladder cancer is the most common malignant lesion of the biliary tract and the fifth most common malignant neoplasm of the digestive tract, although it demonstrates pronounced geographic and sex-related variations.(1,2) The etiology of this tumor is complex, but there is a strong association between it and the presence of gallstones related to chronic inflammation.(1) Unfortunately, GB cancer is an aggressive disease with a poor prognosis because of its inherent biology and its often advanced stage at diagnosis. In addition, the symptoms and signs of GB cancer are vague and non-specific, and thus it is difficult to diagnose clinically. Therefore, an understanding of the biological features of GB carcinogenesis is needed to improve its prognosis.Information on the molecular changes involved in GB carcinogenesis is limited.(3) Considerable evidence indicates that mutations of the dominant oncogene (K-ras) and tumor suppressor genes ( p53, p16 and FHIT ) may be involved.(4-7) In addition, genome-wide and specific chromosome arm allelotyping analyses demonstrate that a loss of heterozygosity at multiple sites in the genome is frequent in this neoplasm. (8)(9)(10) Recently, several groups showed that multiple genes, including SHP, 3-OST-2, CDH13, CDH1, CHFR, hMLH, p16, RASSF1A, RUNX3, APC, MGMT, RARβ2, p73 and Reprimo, are hypermethylated in GB tumor tissues, (11)(12)(13)(14) although considerable geographic differences are apparent in methylation patterns of candidate tumor suppressor genes, indicating that gene hypermethylation is a frequent epigenetic event in GB cancer. Moreover, epigenetic transcriptional silencing by promoter hypermethylation is believed to be a common feature in human cancer. (15,16) Hence the delineation of epigenetic alterations that occur in GB cancer may be important for the development of molecular markers of early detection, prognosis and cancer treatment.The ...

Epigenetic Changes in Carcinogenesis of Gallbladder

“…PGP9.5 hypomethylation was found to be inversely correlated with the presence of a gallstone (P=0.015). These results suggest that PGP9.5 promoter hypomethylation could be a reliable marker for GBC and that DNA hypomethylation might play an important role in re-expression of the PGP9.5 gene in GBC [67].…”

“…A study from Korea [67], examined the methylation status of the promoter of PGP9.5 gene and its expression in surgical biopsy samples of 22 GBC, eight adenomas, 26 normal epithelia. Protein gene product 9.5 (PGP9.5) is a neurospecific peptide that removes ubiquitin from ubiquitinated proteins and prevents them being targeted for degradation by proteosomes.…”

Expression of hypoxia-inducible factor-1 alpha (HIF-1α) in patients with the gallbladder carcinoma

“…This carcinoma is an aggressive tumor with a poor prognosis because of its inherent biology and often advanced stage at diagnosis [1,2], despite the recent advances in diagnostic modalities [3,4]. Curative surgical approaches remain the principal treatment associated with improvement in 5-year survival rates, but prognosis is closely correlated with the extent of tumor invasion and lymph node metastasis, suggesting survival is stage dependent (if carcinoma remains within the muscle layer and with no lymph node metastasis, the overall 5-year survival rate is about 90%) [5,6].…”

Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma

“…These 11 genes were selected because it has been reported that their promoters are methylated and their respective target mRNAs are silenced in gastric carcinoma (16)(17)(18)(19)(20)(21) and because some of them are known to be functionally related to metastasis, i.e., ADAM23, membrane adhesion and cell migration, CDH1, cell adhesion, FLNC, organization of actin polymerization and cell motility, ITGA4, cell-extracellular matrix, cell-cell interactions, THBS1, angiogenesis, and TIMP3, extracellular matrix degradation. Corresponding non-neoplastic mucosa and uninvolved lymph node tissues were included for control purposes, because some genes are frequently methylated in chronic gastritis and intestinal metaplasia, and because methylation has also been associated with aging (14).…”