REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

Abstract

Subclassification of intraductal papillary mucinous neoplasms of the pancreas (IPMNs), based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia. Regenerating islet-derived family, member 4 (REG4) is associated with the adenoma-carcinoma sequence in colon cancer and it is also associated with intestinal phenotype. Therefore, to identify REG4 expression in IPMNs may be helpful to detect high-grade IPMNs. We also investigated REG4 expression and CDX2 expression in IPMNs. To investigate the expressions of REG4 and CDX2 in IPMNs and in invasive ductal adenocarcinoma derived from IPMN, we used immunohistochemical staining and microdissection-based quantitative real-time reverse transcription-polymerase chain reaction. Among 125 IPMNs, 43 (34%) were positive for REG4 and most of the intestinal-type IPMNs showed its expression (35/38). The positive ratio of REG4 expression in colloid carcinoma (5/7) was significantly higher than that in tubular carcinoma (1/17; P ¼ 0.003). Most of CDX2-positive cases (31/33) expressed REG4 protein, whereas only 12 of 92 CDX2-negative cases did (Po0.001). The levels of REG4 mRNA in intestinal-type IPMN were significantly higher compared to those in gastric-type IPMN or to normal pancreatic ductal epithelium (P ¼ 0.005, P ¼ 0.004, respectively). REG4 expression was observed more frequently in borderline lesions (14/28) and carcinoma (21/45) compared to adenoma (8/52). Using the Ki-67 labeling index, REG4 expression was significantly correlated with proliferative activity in borderline lesions. We conclude that REG4 is involved in the 'intestinal' pathway of carcinogenesis in IPMN. Intraductal papillary mucinous neoplasms (IPMNs) show a wide spectrum of histological differentiation from hyperplasia, adenoma and borderline neoplasm to carcinoma, and the existence of an adenoma-carcinoma sequence is documented. [1][2][3] IPMNs are considered to be precursors of invasive cancer of either tubular ductal adenocarcinoma or colloid (mucinous noncystic) carcinoma. [4][5][6][7] Recently, subclassification of IPMNs, based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia and the intestinal-type associated invasive cancer tends to be colloid carcinoma. [8][9][10][11][12] Meanwhile, most gastric-type IPMNs show low-grade dysplasia and rarely associated with invasive cancer. [8][9][10] IPMNs arising from branch ducts often show gastric-type differentiation and have a less aggressive clinical course. 1,9 Pancreatobiliary-type IPMNs show severe atypia corresponding to in situ carcinoma and is often associated with an invasive tubular type of ductal adenocarcinoma. These findings suggest that each type of IPMN follows a different pathway of carcinogenesis. Adsay et al suggested that the intestinal-type IPMN to colloid carcinoma sequence is a distinct pathway of carcinogenesis involving intestinal-related genes CDX2 an...

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

“…Previous studies have identified markers specific for intestinal-type intraductal papillary mucinous neoplasm, including MUC2, CDX2, and REG4. 31 In the present study, we have identified CLDN4 as a novel marker for intestinal-type intraductal papillary mucinous neoplasm.…”

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

“…These results are consistent with a demonstrated functional impact of Reg IV in pancreatic and some colon cancer cell lines, 23,31 although other studies have failed to show an effect of Reg IV modulation on colon cancer cell growth. 24,32 Although it has been shown that Reg IV expression is significantly correlated to Ki67 staining, 10 to date cell cycle analyses and modulation of cell cycle proteins have not been investigated in the context of Reg IV. We showed upregulation of cell cycle inhibitors, p21 and p27, consistent with the cell cycle profile we observed (Fig.…”

“…Because of the importance of IR in glucose homeostasis, an ideal anti-IGF strategy would target both IGFIR and IR only in tumor cells. 40 Given the restricted expression profile of Reg IV in normal tissues seen by immunohistochemistry, [9][10][11][12][13][14][15][16][17][18] anti-Reg IV therapy might represent a way to target IR activation only in tumors.…”

“…7 The Reg family of proteins have been reported to play a role in pancreatic, gastric, liver and intestinal growth or differentiation. 8 Upregulation of Reg IV has been reported in colorectal, prostate, gallbladder, salivary, gastric and pancreatic cancers [9][10][11][12][13][14][15][16][17][18][19] ; additionally, it is amplified in pancreatic cancer. 20 Reg IV has also been negatively associated with relapse-free survival in prostate cancer and metastasis in both prostate and colorectal cancer.…”

Stathmin 1 promotes the proliferation and malignant transformation of pancreatic intraductal papillary mucinous neoplasms

“…IPMNs can be classified into four types, intestinal, gastric foveolar, oncocytic and pancreatobiliary, based on their histology and expression of mucin proteins. IPMN progresses from benign pancreatic intraductal papillary mucinous adenoma (IPMA) to malignant pancreatic intraductal papillary mucinous carcinoma (IPMC) (2,3), however, the details of this process of carcinogenesis remain to be fully elucidated. In the present study, the factors affecting the carcinogenesis of IPMN were investigated.…”