Expression of inositol‑requiring enzyme 1β is downregulated in azoxymethane/dextran sulfate sodium‑induced mouse colonic tumors

Dai,Faliang; Dong,Shizhen; Rong,Zhenhua; Xuan,Qingxia; Chen,Pan; Chen,Menglu; Fan,Yonggang; Gao,Qiang

doi:10.3892/etm.2019.7317

Expression of inositol‑requiring enzyme 1β is downregulated in azoxymethane/dextran sulfate sodium‑induced mouse colonic tumors

Authors:
- Faliang Dai
- Shizhen Dong
- Zhenhua Rong
- Qingxia Xuan
- Pan Chen
- Menglu Chen
- Yonggang Fan
- Qiang Gao
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Affiliations: Department of Gastroenterology and Hepatology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, P.R. China, Department of Clinical Laboratory Diagnosis, The First Affiliated Hospital and Clinical Medical College, Henan University of Science and Technology, Luoyang, Henan 471023, P.R. China, Department of Minimally Invasive Interventional Oncology, Caoxian People's Hospital, Heze, Shandong 274400, P.R. China, Department of Gastroenterology and Hepatology, The First Affiliated Hospital and Clinical Medical College, Henan University of Science and Technology, Luoyang, Henan 471023, P.R. China, Department of Surgery, The First Affiliated Hospital and Clinical Medical College, Henan University of Science and Technology, Luoyang, Henan 471023, P.R. China
Published online on: February 26, 2019 https://doi.org/10.3892/etm.2019.7317
Pages: 3181-3188

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Abstract

Inflammatory bowel disease (IBD) is a risk factor in colon cancer. Endoplasmic reticulum (ER) stress is associated with IBD and cancer. In the current study an azoxymethane (AOM) and dextran sulfate sodium (DSS)‑induced mouse colonic tumor model was established to analyze the expression of ER stress chaperone molecules. Female C57BL/6 mice were intraperitoneally injected with 12 mg/kg AOM. On the 7th day following AOM injection, mice were treated with 1% DSS supplemented to the drinking water for 7 days, then followed by 14 days of normal drinking water. The cycle of 7 days DSS plus 14 days normal water was repeated twice and colonic tumors were evaluated for their number and size. Mice in the control group were injected with saline and received normal drinking water for the course of the experiment. mRNA levels of cytokines, inositol‑requiring enzyme (IRE)1α and 1β, their downstream targets X‑box binding protein (XBP)1u, XBP1s and mucin (MUC) 2 and interleukin (IL)‑6, IL‑8 and tumor necrosis factor (TNF)‑α were detected by reverse transcription‑quantitative polymerase chain reaction. IRE1α, IRE1β and MUC2 protein expression was evaluated by immunohistochemistry, and IRE1α and IRE1β levels were further assessed by western blot analysis. It was observed that tumors developed in the distal colon of mice treated with AOM/DSS. IL‑6, IL‑8 and TNF‑α mRNA levels were significantly increased in mice of the tumor group compared with mice of the control group. There were no significant differences in IRE1α mRNA and protein expression between the two groups and XBP1s mRNA levels were increased in the tumor compared with the control group. IRE1β and MUC2 mRNA levels were significantly decreased in the tumor compared with the control group (decreased by 42 and 30%, respectively). IRE1β and MUC2 proteins were predominately expressed in colonic epithelial cells and expression was decreased in the tumor compared with the control group. In conclusion, the downregulation of IRE1β and MUC2 may reduce the ability of colon tissues to resist inflammation, thus promoting the occurrence and development of colonic tumors.

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1	Rabeneck L, Horton S, Zauber AG and Earle C: Colorectal cancer. JAMA J Am Med Assoc. 270:23022015.
2	Arvelo F, Sojo F and Cotte C: Biology of colorectal cancer. Ecancermedicalscience. 9:5202015. View Article : Google Scholar : PubMed/NCBI
3	Raskov H, Pommergaard HC, Burcharth J and Rosenberg J: Colorectal carcinogenesis-update and perspectives. World J Gastroenterol. 20:18151–18164. 2014. View Article : Google Scholar : PubMed/NCBI
4	Grivennikov SI: Inflammation and colorectal cancer: Colitis-associated neoplasia. Semin Immunopathol. 35:229–244. 2013. View Article : Google Scholar : PubMed/NCBI
5	Terzic J, Grivennikov S, Karin E and Karin M: Inflammation and colon cancer. Gastroenterology. 138:2101–2114.e5. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bye WA, Nguyen TM, Parker CE, Jairath V and East JE: Strategies for detecting colon cancer in patients with inflammatory bowel disease. Cochrane Database Syst Rev. 9:CD0002792017.PubMed/NCBI
7	Neufert C, Becker C and Neurath MF: An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc. 2:1998–2004. 2007. View Article : Google Scholar : PubMed/NCBI
8	Kanneganti M, Mino-Kenudson M and Mizoguchi E: Animal models of colitis-associated carcinogenesis. J Biomed Biotechnol. 2011:3426372011. View Article : Google Scholar : PubMed/NCBI
9	Luo K and Cao SS: Endoplasmic reticulum stress in intestinal epithelial cell function and inflammatory bowel disease. Gastroenterol Res Pract. 2015:3287912015. View Article : Google Scholar : PubMed/NCBI
10	Dicks N, Gutierrez K, Michalak M, Bordignon V and Agellon LB: Endoplasmic reticulum stress, genome damage, and cancer. Front Oncol. 5:112015. View Article : Google Scholar : PubMed/NCBI
11	Cao SS, Luo KL and Shi L: Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol. 231:288–294. 2016. View Article : Google Scholar : PubMed/NCBI
12	Parmar VM and Schröder M: Sensing endoplasmic reticulum stress. Adv Exp Med Biol. 738:153–168. 2012. View Article : Google Scholar : PubMed/NCBI
13	Gardner BM, Pincus D, Gotthardt K, Gallagher CM and Walter P: Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol. 5:a0131692013. View Article : Google Scholar : PubMed/NCBI
14	McMillan DR, Gething MJ and Sambrook J: The cellular response to unfolded proteins: Intercompartmental signaling. Curr Opin Biotechnol. 5:540–545. 1994. View Article : Google Scholar : PubMed/NCBI
15	Cox JS, Shamu CE and Walter P: Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 73:1197–1206. 1993. View Article : Google Scholar : PubMed/NCBI
16	Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho JH, West AB and Ron D: Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest. 107:585–593. 2001. View Article : Google Scholar : PubMed/NCBI
17	Manie SN, Lebeau J and Chevet E: Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 3. Orchestrating the unfolded protein response in oncogenesis: An update. Am J Physiol Cell Physiol. 307:C901–C907. 2014. View Article : Google Scholar : PubMed/NCBI
18	Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M and Koong AC: Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood. 117:1311–1314. 2011. View Article : Google Scholar : PubMed/NCBI
19	Yoshida H, Matsui T, Yamamoto A, Okada T and Mori K: XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 107:881–891. 2001. View Article : Google Scholar : PubMed/NCBI
20	Koong AC, Chauhan V and Romero-Ramirez L: Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol Ther. 5:756–759. 2006. View Article : Google Scholar : PubMed/NCBI
21	Welihinda AA, Tirasophon W and Kaufman RJ: The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expr. 7:293–300. 1999.PubMed/NCBI
22	Martino MB, Jones L, Brighton B, Ehre C, Abdulah L, Davis CW, Ron D, O'Neal WK and Ribeiro CM: The ER stress transducer IRE1beta is required for airway epithelial mucin production. Mucosal Immunol. 6:639–654. 2013. View Article : Google Scholar : PubMed/NCBI
23	Chen Ya and Brandizzi F: IRE1: ER stress sensor and cell fate executor. Trends Cell Biol. 23:547–555. 2013. View Article : Google Scholar : PubMed/NCBI
24	Zhang HS, Chen Y, Fan L, Xi QL, Wu GH, Li XX, Yuan TL, He SQ, Yu Y, Shao ML, et al: The endoplasmic reticulum stress sensor IRE1α in intestinal epithelial cells is essential for protecting against colitis. J Biol Chem. 290:15327–15336. 2015. View Article : Google Scholar : PubMed/NCBI
25	Oikawa D, Kitamura A, Kinjo M and Iwawaki T: Direct association of unfolded proteins with mammalian ER stress sensor, IRE1β. PLoS One. 7:e512902012. View Article : Google Scholar : PubMed/NCBI
26	Nakamura D, Tsuru A, Ikegami K, Imagawa Y, Fujimoto N and Kohno K: Mammalian ER stress sensor IRE1β specifically down-regulates the synthesis of secretory pathway proteins. FEBS Lett. 585:133–138. 2011. View Article : Google Scholar : PubMed/NCBI
27	Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, Tsuru A and Kohno K: Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol. 3:158–164. 2001. View Article : Google Scholar : PubMed/NCBI
28	Tsuru A, Fujimoto N, Takahashi S, Saito M, Nakamura D, Iwano M, Iwawaki T, Kadokura H, Ron D and Kohno K: Negative feedback by IRE1β optimizes mucin production in goblet cells. Proc Natl Acad Sci USA. 110:2864–2869. 2013. View Article : Google Scholar : PubMed/NCBI
29	Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L and Hansson GC: The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA. 105:15064–15069. 2008. View Article : Google Scholar : PubMed/NCBI
30	Kawashima H: Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer. Biol Pharm Bull. 35:1637–1641. 2012. View Article : Google Scholar : PubMed/NCBI
31	Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Büller HA, Dekker J, Van Seuningen I, Renes IB and Einerhand AW: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 131:117–129. 2006. View Article : Google Scholar : PubMed/NCBI
32	Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K and Augenlicht L: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 295:1726–1729. 2002. View Article : Google Scholar : PubMed/NCBI
33	Jackson LN, Zhou Y, Qiu S, Wang Q and Evers BM: Alternative medicine products as a novel treatment strategy for inflammatory bowel disease. Am J Chin Med. 36:953–965. 2008. View Article : Google Scholar : PubMed/NCBI
34	Esworthy RS, Kim BW, Larson GP, Yip ML, Smith DD, Li M and Chu FF: Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2. Inflamm Bowel Dis. 17:1373–1386. 2011. View Article : Google Scholar : PubMed/NCBI
35	Li H, Zhou Y, Zheng Y, Guo H, Gao L, Chen P, Feng D, Wu L, Yang M, Qi Y, et al: The gastric mucosa from patients infected with CagA+ or VacA+ Helicobacter pylori has a lower level of dual oxidase-2 expression than uninfected or infected with CagA-/VacA-H. pylori. Dig Dis Sci. 61:2328–2337. 2016. View Article : Google Scholar : PubMed/NCBI
36	Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M and Rozen SG: Primer3-new capabilities and interfaces. Nucleic Acids Res. 40:e1152012. View Article : Google Scholar : PubMed/NCBI
37	Wong ML and Medrano JF: Real-time PCR for mRNA quantitation. Biotechniques. 39:75–85. 2005. View Article : Google Scholar : PubMed/NCBI
38	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
39	Thaker AI, Shaker A, Rao MS and Ciorba MA: Modeling colitis-associated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS). J Vis Exp:. (pii): 41002012.PubMed/NCBI
40	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
41	Chen C and Zhang X: IRE1alpha-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling. J Transl Med. 15:422017. View Article : Google Scholar : PubMed/NCBI
42	Fujimoto T, Onda M, Nagai H, Nagahata T, Ogawa K and Emi M: Upregulation and overexpression of human X-box binding protein 1 (hXBP-1) gene in primary breast cancers. Breast Cancer. 10:301–306. 2003. View Article : Google Scholar : PubMed/NCBI
43	Fujimoto T, Yoshimatsu K, Watanabe K, Yokomizo H, Otani T, Matsumoto A, Osawa G, Onda M and Ogawa K: Overexpression of human X-box binding protein 1 (XBP-1) in colorectal adenomas and adenocarcinomas. Anticancer Res. 27:127–131. 2007.PubMed/NCBI
44	Jiang Y, Zhou Y, Zheng Y, Guo H, Gao L, Chen P, Feng D, Qi R, Li X, Chang Y, et al: Expression of inositol-requiring enzyme 1β is downregulated in colorectal cancer. Oncol Lett. 13:1109–1118. 2017. View Article : Google Scholar : PubMed/NCBI
45	Hetz C, Martinon F, Rodriguez D and Glimcher LH: The unfolded protein response: Integrating stress signals through the stress sensor IRE1α. Physiol Rev. 91:1219–1243. 2011. View Article : Google Scholar : PubMed/NCBI
46	Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM and Walter P: IRE1 signaling affects cell fate during the unfolded protein response. Science. 318:944–949. 2007. View Article : Google Scholar : PubMed/NCBI
47	Lencer WI, DeLuca H, Grey MJ and Cho JA: Innate immunity at mucosal surfaces: The IRE1-RIDD-RIG-I pathway. Trends Immunol. 36:401–409. 2015. View Article : Google Scholar : PubMed/NCBI
48	Kaser A, Adolph TE and Blumberg RS: The unfolded protein response and gastrointestinal disease. Semin Immunopathol. 35:307–319. 2013. View Article : Google Scholar : PubMed/NCBI
49	Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH and Blumberg RS: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 134:743–756. 2008. View Article : Google Scholar : PubMed/NCBI
50	Romero-Ramirez L, Cao H, Regalado MP, Kambham N, Siemann D, Kim JJ, Le QT and Koong AC: X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Transl Oncol. 2:31–38. 2009. View Article : Google Scholar : PubMed/NCBI
51	Yadav RK, Chae SW, Kim HR and Chae HJ: Endoplasmic reticulum stress and cancer. J Cancer Prev. 19:75–88. 2014. View Article : Google Scholar : PubMed/NCBI
52	Coelho DS and Domingos PM: Physiological roles of regulated Ire1 dependent decay. Front Genet. 5:762014. View Article : Google Scholar : PubMed/NCBI
53	Moradi Marjaneh R, Hassanian SM, Ghobadi N, Ferns GA, Karimi A, Jazayeri MH, Nasiri M, Avan A and Khazaei M: Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. J Cell Physiol. 233:6538–6549. 2018. View Article : Google Scholar : PubMed/NCBI
54	Iqbal J, Dai K, Seimon T, Jungreis R, Oyadomari M, Kuriakose G, Ron D, Tabas I and Hussain MM: IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab. 7:445–455. 2008. View Article : Google Scholar : PubMed/NCBI
55	Dai K, Khatun I and Hussain MM: NR2F1 and IRE1beta suppress microsomal triglyceride transfer protein expression and lipoprotein assembly in undifferentiated intestinal epithelial cells. Arterioscler Thromb Vasc Biol. 30:568–574. 2010. View Article : Google Scholar : PubMed/NCBI