The Contribution of Reg Family Proteins to Cell Growth and Survival in Pancreatic Islets

Xiong, Xinhong; Liu, Jun Li

doi:10.1007/978-94-007-6884-0_47-2

Cited by 3 publications

(3 citation statements)

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“…Reg proteins are known to be secreted into the circulation under certain conditions [19, 20]. We performed a whole panel of Reg proteins ELISA on the sera of PDAC patients and matching healthy subjects, as well as chronic pancreatitis patients.…”

Section: Resultsmentioning

confidence: 99%

Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

Wang

Zogopoulos

et al. 2016

Oncotarget

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These results were further validated by the quantification of Reg 1A and 1B mRNA levels in the microdissected tissues (22- and 6-fold increases vs. non-tumor tissues). Interestingly, patients with higher levels of Reg1A and 1B exhibited improved survival rate than those with lower levels. Furthermore, tissue expressions of Reg1A, Reg1B, and Reg4 could differentiate metastatic PDAC in the liver from intrahepatic cholangiocarcinoma with 92% sensitivity and 95% specificity. Overall, our results demonstrate the upregulation of Reg proteins during PDAC development. If validated in larger scale, Reg1A and Reg1B could become clinical markers for detecting early stages of PDAC, monitoring therapeutic response, and/or predicting patient's prognosis.

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Section: Resultsmentioning

confidence: 99%

Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

Wang

Zogopoulos

et al. 2016

Oncotarget

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“…In humans, REG gene family members have been reported and some of them have been associated with regeneration and neogenesis of β-cells 4 . The REG gene expression in the pancreas is induced during morphogenesis of islets or by damage to β-cells 5,6 . It rejuvenates the β-cell population and improves experimentally induced diabetes 7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…Reg I the first member of the family is produced by exocrine pancreas acinar cells and resides in β-cells secretory granules along with insulin 5 . REG Iα is encoded by an approximately 2.7 kb gene, comprising six exons and five intervening sequences located on chromosome 2p12.…”

Section: Introductionmentioning

confidence: 99%

“Regenerating” Iα Gene Variants g. -385T>C and g. -243T>G in Type 2 Diabetes

2022

PJMD

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Background: Restoration of the body’s ability to produce insulin by regeneration of β-cells is an essential step toward the management of diabetes. REG Iα is released from damaged β-cell and facilitates their renewal. However, genetic variants of REG Iα and their clinical associations are overlooked areas. This study was designed to identify polymorphisms of REG Iα gene exon 1 and its association with type 2 diabetes. Methods: This was a case-control study conducted on individuals n=51 both diabetics (n=36) (aged, 52±9 years; males 25, females 11) (group II) and age-related controls (n=15) (aged, 50±3 years; males 9, female 6) (group I) recruited from PNS Shifa Hospital, Karachi. The samples were amplified, and the gene was sequenced to identify polymorphisms. Chi-square (γ2) test was used to determine whether each polymorphism obeys Hardy-Weinberg equilibrium (HWE). Odds ratios, 95% confidence interval along with corresponding p values were calculated through logistic regression analysis. p < 0.05 was considered statistically significant. Results: A set of two single nucleotide polymorphisms (SNPs) were detected in the REG Iα gene exon1 in the subjects under study. SNPs studied were: g.-243T>G [rs 283890], and g.-385T>C [rs10165462]). Both variants g-243T>G, and g-385T>C showed significant association (γ2=12.8, p=0.0003, γ2=13.8, p=0.0002) with smoking. The allele G showed an eight-fold increased risk of disease in smokers while allele C had less chance of the disease in smokers as compared to non-smokers. Conclusion: Among the SNPs detected in exon 1 of the gene for REG Iα, the g. -385T>C and g. -243T>G variants showed an association with smoking in type 2 diabetes and the SNP -243G (rs 283890) was found to increase the risk of disease in smokers. Keywords: REG Iα gene; Polymorphisms; Type 2 Diabetes; β-cells Regeneration.

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REG3β Plays a Key Role in IL17RA Protumoral Effect—Letter

Li¹,

Liu²,

Gao³

2016

Cancer Research

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We have read with great interest the recent report by Loncle and colleagues (1) investigating the role of REG3b in mediating protumoral effects of IL17. We agree in principal with their conclusion that Reg3b is involved in the initiation of pancreatic ductal adenocarcinoma (PDAC) and its progression. We also found Reg gene expression in duct-like structures in tumor-adjacent areas of pancreatic cancer in our study (article submitted to Modern Pathology, MP-2015MP- -1066, which is an indicator of acinar-to-ductal metaplasia as described in this article. However, we would like to clarify two potential controversies. First, the results of Fig. 5B showing Reg3b expression in human peritumor and well-differentiated PDAC lesions are questionable because Reg3b (transcript ID NM_011036) is only expressed in rodents; its human ortholog is Reg3A (NM_002580.2; ref. 2). They share the name of pancreatitis-associated protein and are both expressed after pancreatitis and in normal intestine (3). The result obtained on human tissues by using mouse Reg3b antibody (Dynabio S.A.) is very different from what we have seen using human Reg3A antibody (sc-134854, against residues 107-175). In short, we have never seen significant staining of Reg3A in either well-or poorly differentiated cancer cells. Instead, it is highly expressed in stromal cells surrounding the cancer epithelium, which was not described in the article.Second, the authors used a gp130 antibody to block the action of Reg3b. However, the designation of Reg3b receptor gp130 (glycoprotein 130) has not been reported. There has never been a consensus on a cell surface receptor activated by either mouse Reg3b or human Reg3A, nor a peer-reviewed evidence showing receptor binding, competitive, or functional blockage. Only a review article has predicted that Reg3b expression might be stimulated by ciliary neurotrophic factor-related cytokines through the leukemia inhibitory factor (LIF) receptor complex, including gp130 and LIF receptor b (4). Thus, the use of gp130 antibody does not support the involvement of Reg3b in STAT3 phosphorylation and cell proliferation. This claim would mislead the readers. For all Reg proteins (7 in rodents and 5 in human), only a receptor for Reg1 (exostosin-like 3, EXTL3) has been reported and confirmed (5). Related to this potential defect, we do not believe that the proposed gp130-JAK2-STAT3 signaling pathway has been well established.Despite these disagreements, we still feel that this is an excellent article that opens up a new prospect on the treatment and prevention of pancreatic cancer. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.Received October 23, 2015; revised December 19, 2015; accepted December 29, 2015; published OnlineFirst March 18, 2016. 3. Itoh T, Teraoka H. Cloning and tissue-specific expression of cDNAs for the human and mouse homologues of rat pancreatitis-associated protein (PAP).

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The Contribution of Reg Family Proteins to Cell Growth and Survival in Pancreatic Islets

Cited by 3 publications

References 198 publications

Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

“Regenerating” Iα Gene Variants g. -385T>C and g. -243T>G in Type 2 Diabetes

REG3β Plays a Key Role in IL17RA Protumoral Effect—Letter

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