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

Mitani, Yoshitsugu; Oue, Naohide; Matsumura, Shunji; Yoshida, Kazuhiro; Noguchi, Tsuyoshi; Ito, Masanori; Tanaka, Shinji; Kuniyasu, Hiroki; Kamata, Nobuyuki; Yasui, Wataru

doi:10.1038/sj.onc.1210215

Cited by 112 publications

(135 citation statements)

References 24 publications

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“…Recently, REG4 has been reported as a novel serum marker in several malignancies. 16,17,30 Therefore, REG4 may be a promising marker to indicate the need for surgery for IPMN limited to the branch ducts.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of REG4 in tumor cells was defined as positive when 10% or more tumor cells were stained (scores 2 þ and 3 þ ) and negative when less than 10% of cancer cells were stained (score 0 and 1 þ ), as described previously. 17 For CDX2, only nuclear staining was considered positive, as previously demonstrated. 24 Positive MUC2 staining was determined, as described previously.…”

Section: Evaluation Of Immunohistochemical Stainingmentioning

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: Discussionmentioning

confidence: 99%

Section: Evaluation Of Immunohistochemical Stainingmentioning

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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“…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.…”

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confidence: 99%

“…11,19 In addition, Reg IV upregulation has been implicated in drug resistance. 13,15,17,21 In vivo models have shown that Reg IV overexpression mediates increased tumor size, survival and metastases. 22 Functional studies with Reg IV have demonstrated an impact on cell growth in pancreatic and colorectal cell lines, and an antibody directed against Reg IV inhibited pancreatic cancer cell line growth.…”

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

Vanderlaag¹,

Wang²,

Fayadat‐Dilman³

et al. 2011

Intl Journal of Cancer

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Regenerating islet‐derived family member, 4 (Reg IV) is a secreted protein and member of the C‐type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin‐like growth factor receptor as well as their downstream effectors, mitogen‐activated protein kinase and phosphatidylinositol‐3‐kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage‐dependent and anchorage‐independent (both soft‐agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl‐2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl‐2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA‐mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl‐2 and multiple RTKs.

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Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

Gao,

Han,

Chen

et al. 2023

Cancer Medicine

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BackgroundBetter predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil‐based adjuvant chemotherapy benefits.MethodsCDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193).ResultsIn the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2‐negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2‐negative and CDX2‐positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5‐year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery‐only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts.ConclusionsNegative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

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

Cited by 112 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

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

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

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