Expression and localization of Reg IV in human neoplastic and non‐neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma

Oue, Naohide; Mitani, Yoshitsugu; Aung, Phyu P.; Sakakura, Chouhei; Takeshima, Yukio; Kaneko, Mayumi; Noguchi, Tsuyoshi; Nakayama, Hirofumi; Yasui, Wataru

doi:10.1002/path.1827

Cited by 118 publications

(192 citation statements)

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“…Immunohistochemical Patterns of REG4 Expression in IPMNs According to Morphological Phenotype REG4 expression was detected in islet cells of Langerhans as previously reported, 14 and these were considered to be internal positive controls. However, REG4 expression was not detected in normal pancreatic ductal epithelium, acini and stromal fibroblasts.…”

Section: Resultsmentioning

confidence: 92%

“…15,18 REG4 is also detected in goblet cells of intestinal metaplasia of the stomach, which is associated with CDX2. 14 The proliferative activity of the goblet cells is higher in the intestinal metaplasia of the stomach compared to those in the small intestine and colon. 19 The biological and clinical significance of the occurrence of the 'intestinal' pathway of carcinogenesis of IPMN remains controversial.…”

mentioning

confidence: 99%

“…REG4 is also expressed in gastrointestinal carcinoma. [14][15][16][17] REG4 is involved in the carcinogenesis of colon cancer and is associated with proliferative function. 15,18 REG4 is also detected in goblet cells of intestinal metaplasia of the stomach, which is associated with CDX2.…”

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confidence: 99%

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

et al. 2009

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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...

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Section: Resultsmentioning

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

et al. 2009

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“…Quantitative reverse transcription-polymerase chain reaction (PCR) analysis revealed that approximately 50% of GCs overexpress the REG4 gene . Although various normal tissues express REG4 (Hartupee et al, 2001), the levels of expression are much lower in normal tissues than in cancerous tissues (Oue et al, 2005). We reported previously that Reg IV is expressed in GC cells but not stromal cells.…”

Section: Introductionmentioning

confidence: 85%

“…Reg IV was expressed in 30% of GC tissues and was associated with both the intestinal mucin phenotype and neuroendocrine differentiation. In CRC, expression of Reg IV was observed in 36% of cases and was associated with tumor stage (Oue et al, 2005). Furthermore, because it is a secreted protein, Reg IV may be a serum biomarker for GC; however, the concentration of Reg IV in serum has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy

et al. 2007

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Serum olfactomedin 4 (GW112, hGC‐1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

Oue

Sentani

Noguchi

et al. 2009

Intl Journal of Cancer

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Gastric cancer (GC) is 1 of the most common human cancers. Early detection remains the most promising approach to improving long‐term survival of patients with GC. We previously performed Serial Analysis of Gene Expression (SAGE) on 4 primary GCs and identified several GC‐specific genes including Reg IV. Of these genes, olfactomedin 4 (OLFM4, also known as GW112 or hGC‐1) is a candidate gene for cancer‐specific expression. In this study, we examined the expression of olfactomedin 4 in human GC by immunohistochemistry. We also assessed serum olfactomedin 4 levels in GC patients by enzyme‐linked immunosorbent assay. 94 (56%) of 167 GC cases were positive for olfactomedin 4 by immunostaining. Olfactomedin 4 staining was observed more frequently in stage I/II cases than in stage III/IV cases. The serum olfactomedin 4 concentration in presurgical GC patients (n = 123, mean ± SE, 36.3 ± 3.5 ng/mL) was significantly higher than that in healthy individuals (n = 76, 16.6 ± 1.6 ng/mL). In patients with stage I GC, the sensitivity of serum olfactomedin 4 (25%) and Reg IV (35%) was superior to that of CA19‐9 (5%) or CEA (3%). Furthermore, in patients with stage I GC, the combination of olfactomedin 4 and Reg IV elevated the diagnostic sensitivity to 52%. These results suggest that serum olfactomedin 4 is a useful marker for GC and its measurement alone or in combination with Reg IV has utility in the early detection of GC. © 2009 UICC

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Expression and localization of Reg IV in human neoplastic and non‐neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma

Cited by 118 publications

References 24 publications

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

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

Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy

Serum olfactomedin 4 (GW112, hGC‐1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

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