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Zhang CY, Zhang R, Zhang L, Wang ZM, Sun HZ, Cui ZG, Zheng HC. Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly. World J Gastroenterol 2023; 29:5104-5124. [PMID: 37744296 PMCID: PMC10514755 DOI: 10.3748/wjg.v29.i35.5104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells. RESULTS Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY. CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
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Affiliation(s)
- Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Rui Zhang
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, China
| | - Li Zhang
- Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Zi-Mo Wang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Zhi Sun
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Zheng-Guo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910-1193, Japan
| | - Hua-Chuan Zheng
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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Wang Y, Yan W, Lu Y, Du J, Tian X, Wu B, Peng S, Gu B, Cai W, Xiao Y. Intestinal Reg4 deficiency confers susceptibility to high-fat diet-induced liver steatosis by increasing intestinal fat absorption in mice. JHEP Rep 2023; 5:100700. [PMID: 37138677 PMCID: PMC10149362 DOI: 10.1016/j.jhepr.2023.100700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 05/05/2023] Open
Abstract
Background & Aims Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved. Methods Mice with intestinal-specific Reg4 deficiency (Reg4 ΔIEC ) and Reg4-floxed alleles (Reg4 fl/fl ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA. Results Reg4 ΔIEC mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, Reg4 ΔIEC mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis (p <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides. Conclusions Our findings directly link Reg4 deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children. Impact and Implications Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.
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Affiliation(s)
- Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Weihui Yan
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jun Du
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xinbei Tian
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Bo Wu
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shicheng Peng
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Beilin Gu
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Corresponding authors. Addresses: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University No. 1665, Kong Jiang Road, Shanghai 200092, China. Tel.: +86-21-25076441; Fax: +86-21-65791316.
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kong Jiang Road, Shanghai 200092, China. Tel.: +86-21-25076445; Fax: +86-21-65791316.
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Xiang LW, Xue H, Ha MW, Yu DY, Xiao LJ, Zheng HC. The effects of REG4 expression on chemoresistance of ovarian cancer. J OBSTET GYNAECOL 2022; 42:3149-3157. [PMID: 35929918 DOI: 10.1080/01443615.2022.2106834] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.
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Affiliation(s)
- Li-Wei Xiang
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Hang Xue
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Min-Wen Ha
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Da-Yong Yu
- Department of Cell Biology, Basic Medicine College of Chengde Medical University, Chengde, China
| | - Li-Jun Xiao
- Department of Immunology, Basic Medicine College of Chengde Medical University, Chengde, China
| | - Hua-Chuan Zheng
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
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Zheng HC, Xue H, Zhang CY. REG4 promotes the proliferation and anti-apoptosis of cancer. Front Cell Dev Biol 2022; 10:1012193. [PMID: 36172286 PMCID: PMC9511136 DOI: 10.3389/fcell.2022.1012193] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 11/27/2022] Open
Abstract
Regenerating islet-derived 4 (REG4) gene was discovered by high-throughput sequencing of ulcerative colitis cDNA libraries. REG4 is involved in infection and inflammation by enhancing macrophage polarization to M2, via activation of epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding and the killing inflammatory Escherichia coli, and closely linked to tumorigenesis. Its expression was transcriptionally activated by caudal type homeobox 2, GATA binding protein 6, GLI family zinc finger 1, SRY-box transcription factor 9, CD44 intracytoplasmic domain, activating transcription factor 2, and specificity protein 1, and translationally activated by miR-24. REG4 can interact with transmembrane CD44, G protein-coupled receptor 37, mannan and heparin on cancer cells. Its overexpression was observed in gastric, colorectal, pancreatic, gallbladder, ovarian and urothelial cancers, and is closely linked to their aggressive behaviors and a poor prognosis. Additionally, REG4 expression and recombinant REG4 aggravated such cellular phenotypes as tumorigenesis, proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, peritoneal dissemination, tumor growth, and cancer stemness via EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways. Sorted REG4-positive deep crypt secretory cells promote organoid formation of single Lgr5 (+) colon stem cells by Notch inhibition and Wnt activation. Histologically, REG4 protein is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas of the gastrointestinal tract, pancreas, ovary, and lung. It might support the histogenesis of gastric intestinal–metaplasia–globoid dysplasia–signet ring cell carcinoma. In this review, we summarized the structure, biological functions, and effects of REG4 on inflammation and cancer. We conclude that REG4 may be employed as a biomarker of tumorigenesis, subsequent progression and poor prognosis of cancer, and may be a useful target for gene therapy.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
- *Correspondence: Hua-Chuan Zheng,
| | - Hang Xue
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Bishnupuri KS, Sainathan SK, Ciorba MA, Houchen CW, Dieckgraefe BK. Reg4 Interacts with CD44 to Regulate Proliferation and Stemness of Colorectal and Pancreatic Cancer Cells. Mol Cancer Res 2022; 20:387-399. [PMID: 34753802 DOI: 10.1158/1541-7786.mcr-21-0224] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/08/2021] [Accepted: 11/01/2021] [Indexed: 11/16/2022]
Abstract
Regenerating Gene 4 (Reg4) is highly upregulated in gastrointestinal (GI) malignancies including colorectal and pancreatic cancers. Numerous studies demonstrated an association between higher Reg4 expression and tumor aggressiveness, intrinsic resistance to apoptotic death, and poor outcomes from GI malignancies. However, the precise receptor and underlying signaling mechanism have remained unknown. Although we previously reported a Reg4-mediated induction of EGFR activity in colorectal cancer cells, a direct interaction between Reg4 and EGFR was not observed. This study is focused on identifying the cell surface binding partner of Reg4 and dissecting its role in colorectal cancer and pancreatic cancer growth and stem cell survival. In vitro models of human colorectal cancer and pancreatic cancer were used to evaluate the results. Results of this study find: (i) Reg4 interacts with CD44, a transmembrane protein expressed by a population of colorectal cancer and pancreatic cancer cells; (ii) Reg4 activates regulated intramembrane proteolysis of CD44 resulting in γ-secretase-mediated cleavage and release of the CD44 intracytoplasmic domain (CD44ICD) that functions as a transcriptional activator of D-type cyclins involved in the regulation of cancer cell proliferation and Klf4 and Sox2 expression involved in regulating pluripotency of cancer stem cells; and (iii) Reg4 significantly increases colorectal cancer and pancreatic cancer cell proliferation and their clonogenic potential in stem cell assays. IMPLICATIONS These results suggest that pro-proliferative and pro-stemness effects of Reg4 are mediated through γ-secretase-mediated CD44/CD44ICD signaling, hence strategies to disrupt Reg4-CD44-γ-secretase-CD44ICD signaling axis may increase cancer cell susceptibility to chemo- and radiotherapeutics.
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Affiliation(s)
- Kumar S Bishnupuri
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
- Veteran Affair St Louis Health Care System, St Louis, Missouri
| | - Satheesh K Sainathan
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
| | - Matthew A Ciorba
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
| | - Courtney W Houchen
- Section of Digestive Disease and Nutrition, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Brian K Dieckgraefe
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
- Veteran Affair St Louis Health Care System, St Louis, Missouri
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Chai D, Du H, Li K, Zhang X, Li X, Zhao X, Lian X, Xu Y. CDX2 and Reg IV expression and correlation in gastric cancer. BMC Gastroenterol 2021; 21:92. [PMID: 33639844 PMCID: PMC7913228 DOI: 10.1186/s12876-021-01678-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/15/2021] [Indexed: 01/10/2023] Open
Abstract
Background Ectopic expression of CDX2 is associated with the development and progression of gastric cancer. Previous studies showed that CDX2 may be an upstream regulator of Reg IV expression in gastric cancer, and our previous report showed that Reg IV upregulated SOX9 expression and enhanced cell migration and invasion in gastric cancer cells. However, the regulatory roles of CDX2 have not been clarified in gastric cancer, and the correlation between CDX2 and Reg IV requires further study. Methods CDX2 and Reg IV were examined in gastric cancer specimens and paired adjacent tissues via real-time PCR and immunohistochemistry (IHC). The association between CDX2 and Reg IV was assessed using the χ2-test and Spearman’s rank correlation. To verify their relationship, knockdown and exogenous expression of CDX2 or Reg IV were performed in AGS and MKN-45 gastric cancer cells, and their expression was subsequently analyzed via a real-time PCR and western blotting. Wound-healing and Transwell assays were used to examine migration and invasion in AGS and MKN-45 cells following CDX2 silencing or overexpression. Results A positive correlation was observed between CDX2 and Reg IV expression at the mRNA and protein levels in gastric cancer tissues. CDX2 silencing significantly downregulated Reg IV expression, and CDX2 overexpression significantly upregulated Reg IV expression in AGS and MKN-45 cells. Neither Reg IV silencing nor overexpression had any effect on CDX2 protein expression in AGS or MKN-45 cells, even though both affected the expression of CDX2 mRNA. Functionally, CDX2 silencing significantly inhibited cell migration and invasion, and CDX2 overexpression significantly promoted cell migration and invasion in AGS and MKN-45 cells. Conclusions Our findings demonstrate that CDX2 expression was positively correlated with that of Reg IV in gastric cancer, and CDX2 promoted cell migration and invasion through upregulation of Reg IV expression in AGS and MKN-45 cells.
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Affiliation(s)
- Dandan Chai
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Huifen Du
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Kesheng Li
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China.
| | - Xueliang Zhang
- Department of Internal Medicine, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaoqin Li
- Department of Pathology, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaoning Zhao
- Department of Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaowen Lian
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Yang Xu
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
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Zhang J, Zhu Z, Miao Z, Huang X, Sun Z, Xu H, Wang Z. The Clinical Significance and Mechanisms of REG4 in Human Cancers. Front Oncol 2021; 10:559230. [PMID: 33489872 PMCID: PMC7819868 DOI: 10.3389/fonc.2020.559230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/23/2020] [Indexed: 11/13/2022] Open
Abstract
Regenerating islet-derived type 4 (REG4), a member of the calcium-dependent lectin gene superfamily, is abnormally expressed in various cancers, such as colorectal, gastric, gallbladder, pancreatic, ovarian, prostate, and lung cancer. REG4 is associated with a relatively unfavorable prognosis and clinicopathologic features in cancers, including advanced tumor and nodal stage, histological differentiation, and liver and peritoneal metastasis. Moreover, REG4-positive cancer cells show more frequent resistance to chemoradiotherapy, especially 5-FU-based chemotherapy. REG4 participates in many aspects of carcinogenesis, including cell proliferation, apoptosis, cell cycle, invasion, metastasis, and drug resistance. The underlying mechanisms are complex and involve a series of signaling mediators and multiple pathways. Thus, REG4 may be a potential diagnostic and prognostic biomarker as well as a candidate therapeutic target in cancer patients. In this review, we systematically summarize the advances about the clinical significance, biological functions, and mechanisms underlying REG4 in cancer to provide new directions for future cancer research.
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Affiliation(s)
- Junyan Zhang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhi Zhu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhifeng Miao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhe Sun
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huimian Xu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Chen S, Gou WF, Zhao S, Niu ZF, Zhao Y, Takano Y, Zheng HC. The role of the REG4 gene and its encoding product in ovarian epithelial carcinoma. BMC Cancer 2015; 15:471. [PMID: 26077911 PMCID: PMC4469329 DOI: 10.1186/s12885-015-1435-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 05/13/2015] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Although its biological function remains poorly understood, REG4 is reported to be a potent activator of the EGFR/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis. METHODS SKOV3 cells were transfected with a REG4-expressing plasmid or treated with recombinant REG4. We then analyzed proliferation, cell cycle, apoptosis, invasion and metastasis or expression of related molecules. REG4 expression was examined in normal ovarian tissue, benign and borderline tumors, and cancers by immunohistochemistry or real-time PCR. RESULTS REG4 overexpression and the recombinant protein inhibited cell apoptosis, enhanced G2/S progression, proliferation, migration and invasion. Furthermore, expression of Wnt5a, p70s6k, survivin and VEGF expression was increased, while Bax expression was decreased at both the mRNA and protein levels compared to control or mock cells (P<0.05). REG4 mRNA levels were higher in benign tumors and primary cancer compared to those in normal ovarian tissue (P<0.05) while, REG4 protein expression was higher in all three tumor types than that in normal ovarian tissue (P<0.05). Higher REG4 mRNA expression was observed in mucinous carcinomas than serous carcinomas (P<0.05), and in well- and moderately-differentiated carcinomas than poorly-differentiated carcinomas (P<0.05). Survival analysis revealed an inverse relationship between REG4 expression and cumulative or relapse-free survival rates of the patients with ovarian cancer as an independent factor (P<0.05). CONCLUSIONS Our findings indicate that aberrant REG4 expression plays an essential role in early ovarian carcinogenesis and is closely linked to mucinous ovarian tumors, differentiation and adverse prognosis of ovarian cancer by modulating proliferation, apoptosis, migration and invasion.
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Affiliation(s)
- Shuo Chen
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Wen-Feng Gou
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Shuang Zhao
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Zhe-Feng Niu
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
| | - Yang Zhao
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Yasuo Takano
- Clinical Cancer Institute, Kanagawa Cancer Center, Yokohama, 241-0815, Japan.
| | - Hua-Chuan Zheng
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110001, China.
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Duan Y, Hu L, Liu B, Yu B, Li J, Yan M, Yu Y, Li C, Su L, Zhu Z, Xiang M, Liu B, Yang Q. Tumor suppressor miR-24 restrains gastric cancer progression by downregulating RegIV. Mol Cancer 2014; 41:373-85. [PMID: 24886316 DOI: 10.1007/s11033-013-2871-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 11/06/2013] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND microRNAs are small noncoding RNAs that modulate a variety of cellular processes by regulating multiple targets, which can promote or inhibit the development of malignant behaviors. Accumulating evidence suggests miR-24 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive. This study examined the role of miR-24 in gastric cancer (GC). METHODS The expression of miR-24 in GC tissues compared with matched non-tumor tissues and GC cells was detected by qRT-PCR. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vectors were used to regulate miR-24 expression in GC cells to investigate its function in vitro and in vivo. RESULTS miR-24 was significantly downregulated in GC tissues compared with matched non-tumor tissues and was associated with tumor differentiation. Ectopic expression of miR-24 in SGC-7901 GC cells suppressed cell proliferation, migration and invasion in vitro as well as tumorigenicity in vivo by inducing cell cycle arrest in G0/G1 phase and promoting cell apoptosis. Furthermore, we identified RegIV as a target of miR-24 and demonstrated that miR-24 regulated RegIV expression via binding its 3' untranslated region. CONCLUSIONS miR-24 functions as a novel tumor suppressor in GC and the anti-oncogenic activity may involve its inhibition of the target gene RegIV. These findings suggest the possibility for miR-24 as a therapeutic target in GC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No 197 Ruijin er Road, Shanghai 200025, People's Republic of China.
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Duan Y, Hu L, Liu B, Yu B, Li J, Yan M, Yu Y, Li C, Su L, Zhu Z, Xiang M, Liu B, Yang Q. Tumor suppressor miR-24 restrains gastric cancer progression by downregulating RegIV. Mol Cancer 2014; 13:127. [PMID: 24886316 PMCID: PMC4041902 DOI: 10.1186/1476-4598-13-127] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND microRNAs are small noncoding RNAs that modulate a variety of cellular processes by regulating multiple targets, which can promote or inhibit the development of malignant behaviors. Accumulating evidence suggests miR-24 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive. This study examined the role of miR-24 in gastric cancer (GC). METHODS The expression of miR-24 in GC tissues compared with matched non-tumor tissues and GC cells was detected by qRT-PCR. Synthetic short single or double stranded RNA oligonucleotides and lentiviral vectors were used to regulate miR-24 expression in GC cells to investigate its function in vitro and in vivo. RESULTS miR-24 was significantly downregulated in GC tissues compared with matched non-tumor tissues and was associated with tumor differentiation. Ectopic expression of miR-24 in SGC-7901 GC cells suppressed cell proliferation, migration and invasion in vitro as well as tumorigenicity in vivo by inducing cell cycle arrest in G0/G1 phase and promoting cell apoptosis. Furthermore, we identified RegIV as a target of miR-24 and demonstrated that miR-24 regulated RegIV expression via binding its 3' untranslated region. CONCLUSIONS miR-24 functions as a novel tumor suppressor in GC and the anti-oncogenic activity may involve its inhibition of the target gene RegIV. These findings suggest the possibility for miR-24 as a therapeutic target in GC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No 197 Ruijin er Road, Shanghai 200025, People's Republic of China.
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11
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Abstract
The regenerating gene (Reg) family is a group of small molecules that includes four members found in various species, although only three are found in human tissues. Their expression is stimulated by certain growth factors or cytokines. The Reg family plays different roles in proliferation, migration, and anti-apoptosis through activating different signaling pathways. Their dysexpression is closely associated with a number of human conditions and diseases such as inflammation and cancer, especially in the human digestive system. Clinically, upregulation of Reg proteins is usually demonstrated in histological sections and sera from cancer patients. Therefore, Reg proteins can predict the progression and prognosis of cancers, especially those of the digestive tract, and can also act as diagnostic markers and therapeutic targets.
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12
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Zhao Y, Zhang T, Wang Q. S100 calcium-binding protein A4 is a novel independent prognostic factor for the poor prognosis of gastric carcinomas. Oncol Rep 2013; 30:111-8. [PMID: 23612849 DOI: 10.3892/or.2013.2419] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 03/05/2013] [Indexed: 12/26/2022] Open
Abstract
Overexpression of the S100 calcium-binding protein A4 (S100A4) is involved in epithelial-to-mesenchymal transition, oncogenic transformation, angiogenesis, cytoskeletal integrity and cancer metastasis. Here, we elucidated the role of S100A4 in tumorigenesis and progression of gastric carcinomas. S100A4 expression in gastric carcinomas, adenomas and adjacent non-neoplastic mucosa was analyzed by immunohistochemical, real-time reverse transcriptase (RT)-polymerase chain reaction (PCR) and western blot analyses, and was correlated with various clinicopathological parameters. S100A4 protein expression was increased gradually in the following order: gastritis (19.2%), intestinal metaplasia (IM; 23.3%), dysplasia (34.9%) and carcinoma (55.2%; P<0.001). S100A4 was positively correlated with tumor size, depth of invasion, lymphatic invasion, lymph node metastasis and tumor-node-metastasis (TNM) staging (P<0.05), but not with the age and gender of the carcinoma patients (P>0.05). Intestinal-type (IT) carcinomas showed a higher S100A4 expression than diffuse-type (DT) carcinomas (P<0.001). S100A4 mRNA expression also increased in the following order: gastritis < IM < dysplasia < carcinoma (P<0.05). S100A4 overexpression was observed in gastric carcinomas with a larger diameter, deeper invasion, lymph node metastasis and in IT carcinoma (P<0.05). Univariate analysis using the Kaplan-Meier method indicated a lower cumulative survival rate for patients with weak or moderate S100A4 expression compared with patients not expressing S100A4 (P<0.001). Multivariate analysis using Cox's proportional hazard model demonstrated that depth of invasion, lymphatic or venous invasion, lymph node metastasis, TNM staging and S100A4 expression were independent factors for poor patient prognosis (P<0.05). In conclusion, S100A4 upregulation is positively associated with the pathogenesis, growth, invasion, metastasis and differentiation of gastric carcinomas. S100A4 may be a promising marker indicative of the aggressive behavior and prognosis of gastric carcinomas.
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Affiliation(s)
- Ying Zhao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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13
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Zhao Y, Zhang TB, Wang Q. Clinical significance of altered S100A2 expression in gastric cancer. Oncol Rep 2013; 29:1556-62. [PMID: 23337980 DOI: 10.3892/or.2013.2236] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 12/18/2012] [Indexed: 11/06/2022] Open
Abstract
The S100A2 gene has been reported to be a putative tumor‑suppressor gene. Nevertheless, overexpression of S100A2 has been found in certain types of cancer. This study investigated S100A2 expression in tissue specimens of gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer to determine its association with clinical features. A serial of tissue samples (gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer samples) were used for quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical analyses of S100A2 expression. The data revealed that there was a gradual loss of S100A2 expression from gastritis, intestinal metaplasia and dysplasia to cancer tissue specimens (p<0.001). In gastric cancer samples, loss of S100A2 expression was associated with increased tumor size, depth of invasion, lymph node metastasis and a poor prognosis (p<0.001). However, the intestinal type of gastric cancer expressed more S100A2 protein than the diffuse type (p<0.001). In conclusion, data from the present study demonstrated that loss of S100A2 expression contributes to gastric cancer development and progression; therefore, the determination of S100A2 expression levels may help to predict the carcinogenesis and aggressiveness of gastric cancer as well as patient survival.
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Affiliation(s)
- Ying Zhao
- Department of General Surgery, Shengjing Hospital of China Medical University, and Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, Liaoning 110004, PR China
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14
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Lu H, Sun HZ, Li H, Cong M. The Clinicopathological Significance of Bmi-1 Expression in Pathogenesis and Progression of Gastric Carcinomas. Asian Pac J Cancer Prev 2012; 13:3437-41. [DOI: 10.7314/apjcp.2012.13.7.3437] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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15
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Wang Q, Deng J, Yuan J, Wang L, Zhao Z, He S, Zhang Y, Tu Y. Oncogenic reg IV is a novel prognostic marker for glioma patient survival. Diagn Pathol 2012; 7:69. [PMID: 22713481 PMCID: PMC3465175 DOI: 10.1186/1746-1596-7-69] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 06/19/2012] [Indexed: 12/22/2022] Open
Abstract
Aim The aberrant expression of regenerating islet-derived family member, 4 (Reg IV) has been found in various human cancers. However, the roles of Reg IV gene and its encoding product in human glioma have not been clearly understood. Therefore, the aim of this study was to investigate the clinicopathological significance of Reg IV expression in glioma. Methods Reg IV mRNA and protein expression in human gliomas and non-neoplastic brain tissues were respectively detected by real-time quantitative RT-PCR assay, Western blot, and immunohistochemistry. The association of Reg IV immunostaining with clinicopathological factors and prognosis of glioma patients was also statistically analyzed. Results Reg IV mRNA and protein expression levels in glioma tissues were both significantly higher than those in the corresponding non-neoplastic brain tissues (both P < 0.001). Additionally, the increased Reg IV immunostaining in glioma tissues was significantly associated with advanced pathological grade (P = 0.008). Reg IV protein up-regulation was also significantly correlated with low Karnofsky performance score (KPS) (P = 0.02). Moreover, the overall survival of patients with high Reg IV protein expression was dramatically shorter than those with low Reg IV protein expression (P < 0.001). Multivariate Cox regression analysis further confirmed that Reg IV expression was an independent prognostic factor for patients with gliomas (P = 0.008). Conclusions These convinced evidences suggest for the first time that Reg IV might accelerate disease progression and act as a candidate prognostic marker for gliomas. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2145344361720706
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Affiliation(s)
- Qi Wang
- Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710032, China
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16
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Yang X, Takano Y, Zheng HC. The pathobiological features of gastrointestinal cancers (Review). Oncol Lett 2012; 3:961-969. [PMID: 22783373 DOI: 10.3892/ol.2012.628] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 12/16/2011] [Indexed: 01/05/2023] Open
Abstract
Gastrointestinal adenocarcinoma (GIA) is a common malignant disease worldwide. Its tumorigenesis and progression is a multistage process with the involvement of a multifactorial etiology. Knowledge regarding altered expression of these genes during carcinogenesis may not only provide information about the molecular events during the initiation and progression of cancer, but may also result in the discovery of biological markers for the evaluation of cancer diagnosis and prognosis. In this review, we assessed molecular markers of pathogenesis, invasion, metastasis and prognosis, such as tumor suppressor and metastasis suppressor genes, and angiogenesis, cell adhesion, cell mobility, ER stress, mucin production, threonine protein kinase and REG family protein expression, by the establishment of tissue microarray (TMA) of GIA and immunohistochemistry (IHC) by intermittent microwave irradiation and in situ hybridization (ISH). Finally, we characterized the pathobiological features of Lauren's and WHO subtypes. It was found that the aberrant and cell-specific expression of these molecules is important in the malignant transformation of gastrointestinal epithelium and subsequent progression. These molecules also underlie the histogenic mechanisms of gastric carcinoma according to Lauren's and WHO classification. The combination of TMA, IHC and ISH may be widely applied to screen for molecular markers in GIA.
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Affiliation(s)
- Xue Yang
- Department of Biochemistry and Molecular Biology and Institute of Pathology and Pathophysiology, College of Basic Medicine, China Medical University, Shenyang, P.R. China
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17
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Parikh A, Stephan AF, Tzanakakis ES. Regenerating proteins and their expression, regulation and signaling. Biomol Concepts 2011; 3:57-70. [PMID: 22582090 DOI: 10.1515/bmc.2011.055] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The regenerating (Reg) protein family comprises C-type lectin-like proteins discovered independently during pancreatitis and pancreatic islet regeneration. However, an increasing number of studies provide evidence of participation of Reg proteins in the proliferation and differentiation of diverse cell types. Moreover, Reg family members are associated with various pathologies, including diabetes and forms of gastrointestinal cancer. These findings have led to the emergence of key roles for Reg proteins as anti-inflammatory, antiapoptotic and mitogenic agents in multiple physiologic and disease contexts. Yet, there are significant gaps in our knowledge regarding the regulation of expression of different Reg genes. In addition, the pathways relaying Reg-triggered signals, their targets and potential cross-talk with other cascades are still largely unknown. In this review, the expression patterns of different Reg members in the pancreas and extrapancreatic tissues are described. Moreover, factors known to modulate Reg levels in different cell types are discussed. Several signaling pathways, which have been implicated in conferring the effects of Reg ligands to date, are also delineated. Further efforts are necessary for elucidating the biological processes underlying the action of Reg proteins and their involvement in various maladies. Better understanding of the function of Reg genes and proteins will be beneficial in the design and development of therapies utilizing or targeting this protein group.
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Affiliation(s)
- Abhirath Parikh
- Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, NY 14260
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18
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Suh YS, Lee HJ, Jung EJ, Kim MA, Nam KT, Goldenring JR, Yang HK, Kim WH. The combined expression of metaplasia biomarkers predicts the prognosis of gastric cancer. Ann Surg Oncol 2011; 19:1240-9. [PMID: 22048633 DOI: 10.1245/s10434-011-2125-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer. METHODS The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers. RESULTS MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis. CONCLUSIONS The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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19
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Zheng HC, Sugawara A, Okamoto H, Takasawa S, Takahashi H, Masuda S, Takano Y. Expression profile of the REG gene family in colorectal carcinoma. J Histochem Cytochem 2011; 59:106-15. [PMID: 21339177 DOI: 10.1369/jhc.2010.956961] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Regenerating (REG) gene family belongs to the calcium-dependent lectin gene superfamily and encodes small multifunctional secretory proteins, which might be involved in cell proliferation, differentiation, and carcinogenesis. To clarify REG expression profile in colorectal carcinoma (CRC), the authors examined the expression of REG Iα, Iβ, III, HIP/PAP, and REG IV by immunohistochemistry on tissue microarray. The expression of REG Iα, III, and HIP/PAP was more frequently observed in the CRCs than adjacent non-neoplastic mucosa (p < 0.001), whereas it was the converse for REG Iβ and IV (p < 0.001). The expression of REG Iα, Iβ, III, and HIP/PAP was negatively correlated with the depth of invasion of CRCs (p < 0.05). The REG Iβ and HIP/PAP were less expressed in CRCs with than without venous invasion (p < 0.05). The positive rates of REG Iα and HIP/PAP were significantly higher in CRCs without than with lymph node metastasis (p < 0.05). Mucinous carcinoma more frequently expressed REG IV protein than well- and moderately differentiated ones (p < 0.05). There was a positive relationship between REG Iα, Iβ, III, and HIP/PAP expression (p < 0.05). Survival analysis indicated the REG Iβ or HIP/PAP expression was positively linked to favorable prognosis of carcinoma patients (p < 0.05). This study indicated that aberrant REG expression might be closely linked to the pathogenesis, invasion, or lymph node metastasis of CRCs. REG Iβ and HIP/PAP could be considered reliable markers of favorable prognosis of CRC patients.
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Affiliation(s)
- Hua-chuan Zheng
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, China.
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20
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Tao HQ, He XJ, Ma YY, Wang HJ, Xia YJ, Ye ZY, Zhao ZS. Evaluation of REG4 for early diagnosis and prognosis of gastric cancer. Hum Pathol 2011; 42:1401-9. [PMID: 21419474 DOI: 10.1016/j.humpath.2010.08.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Revised: 07/30/2010] [Accepted: 08/03/2010] [Indexed: 12/14/2022]
Abstract
We explored the correlation between the development of gastric cancer and the concentration of REG4 and hence the suitability of REG4 as an indicator of the prognosis of patients with GC. Real-time polymerase chain reaction was conducted to detect REG4 messenger RNA expression. The amount of the REG4 protein was measured by immunohistochemistry staining of tissue and enzyme-linked immunosorbent assay of serum. Serum carcinoembryonic antigen and carbohydrate antigen 19-9 concentrations were measured using a commercial automated immunoassay. Real-time polymerase chain reaction results confirmed that REG4 was significantly up-regulated in gastric cancer compared with paired normal mucosa (P < .001). Immunohistochemistry staining revealed that high expression of REG4 correlated with diffuse type, poor differentiation, lymph node metastasis, distant metastasis, and TNM stage III or IV. The mean survival time for patients in the REG4-positive group was significantly less than that in the REG4-negative group (P = .013). The percentage of serum samples that were REG4 positive was 44.0%, which was higher than that for serum carcinoembryonic antigen (P = .039) or carbohydrate antigen 19-9 (P = .012) in TNM stage I and was significantly higher (P = .031) than that in TNM stage II. Thus, REG4 may be not only a prognostic indicator but also a better serum marker than carcinoembryonic antigen and carbohydrate antigen 19-9 for early diagnosis of gastric cancer.
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Affiliation(s)
- Hou-Quan Tao
- Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, China.
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21
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Jin CX, Hayakawa T, Ko SBH, Ishiguro H, Kitagawa M. Pancreatic stone protein/regenerating protein family in pancreatic and gastrointestinal diseases. Intern Med 2011; 50:1507-16. [PMID: 21804274 DOI: 10.2169/internalmedicine.50.5362] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Pancreatic stone protein (PSP; reported in 1979), pancreatitis-associated protein (PAP; 1984) and regenerating protein (Reg I; 1988) were discovered independently in the fields of the exocrine (pancreatitis) and endocrine (diabetes) pancreas. Subsequent analysis revealed that PSP and Reg I are identical and PAP belongs to the same protein family. PSP/Reg I and PAP share a selective and specific trypsin cleavage site and result in insoluble fibrils (PTP, PATP). Search for a functional role of PSP had led to the idea that it might serve as an inhibitor in pancreatic stone formation and PSP was renamed lithostathine. Inhibitory effects of lithostathine in stone formation have been questioned. Evidence so far obtained can support a lithogenic role rather than a lithostatic role of PSP. PAP and its isoforms have been investigated mainly regarding responses to inflammation and stress. Reg I and its isoforms have been examined on regeneration, growth and mitogenesis in gastrointestinal neoplastic diseases as well as diabetes. Evidence obtained can be applied in the prediction of prognosis and therapy for inflammatory and neoplastic diseases.
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Affiliation(s)
- Chun Xiang Jin
- The First Clinical College of Norman Bethune Medical Division, Jilin University, China
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Li FY, Ren XB, Xu EP, Huang Q, Sheng HQ, Lv BJ, Lai MD. RegIV expression showing specificity to gastrointestinal tract and its potential role in diagnosing digestive tract neuroendocrine tumor. J Zhejiang Univ Sci B 2010; 11:258-66. [PMID: 20349522 DOI: 10.1631/jzus.b0900383] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Regenerating gene IV (RegIV), a member of the regenerating gene family discovered in 2001, has been found to be involved in malignancy in several different organs including the stomach, colorectum, pancreas and prostate, but the overall expression profile of RegIV has not been reported. To learn more about RegIV, we evaluated its distribution by immunohistochemistry (IHC) in a total of 360 samples including 24 types of normal tissue, 40 benign and malignant lesions, and 18 neuroendocrine tumors. We found that in normal tissues, in addition to its relative specificity for the gastrointestinal tract, RegIV was detected in the adrenal gland and mammary gland. Among all the malignancies of various histological types under evaluation, RegIV was found mostly in adenocarcinomas. Studies on additional sets of colorectal tumor samples showed that RegIV expression was predominant in colorectal adenoma (87.5%) and peritumoral tissue (100%) but not in cancer tissue (30.8%). Among neuroendocrine tumors, RegIV had a relatively restricted expression to those of digestive system.
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Affiliation(s)
- Feng-ying Li
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China
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Yashima K, Sasaki S, Koda M, Kawaguchi K, Harada K, Murawaki Y. Premalignant lesions in gastric cancer. Clin J Gastroenterol 2009; 3:6-12. [PMID: 26189899 DOI: 10.1007/s12328-009-0130-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 11/18/2009] [Indexed: 12/27/2022]
Abstract
Despite a plateau in incidence, gastric cancer is one of the most common cancers worldwide and causes considerable morbidity and mortality. Premalignant gastric lesions are well known risk factors for the development of intestinal-type gastric adenocarcinomas. In this multistep model of gastric carcinogenesis, Helicobacter pylori causes chronic active inflammation of the gastric mucosa, which slowly progresses through the premalignant stages of atrophic gastritis, intestinal metaplasia, and adenoma/dysplasia to gastric carcinoma. This progression is paralleled by a stepwise accumulation of multiple genetic and epigenetic abnormalities. Detection, treatment, and molecular analyses of premalignant lesions may thus provide a basis for gastric cancer prevention. This review describes an overview of current knowledge on premalignant gastric lesions. It also reviews the issue of surveillance of patients with premalignant lesions in order to improve the survival of patients with gastric cancer.
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Affiliation(s)
- Kazuo Yashima
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan.
| | - Shuji Sasaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Masaharu Koda
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
| | - Yoshikazu Murawaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori, 683-8504, Japan
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