Downregulated Tim‑3 expression is responsible for the incidence and development of colorectal cancer

Zhang,Ping; Wang,Yan; Liu,Xue‑Rong; Hong,Shi‑Ru; Yao,Jian

doi:10.3892/ol.2018.8697

Downregulated Tim‑3 expression is responsible for the incidence and development of colorectal cancer

Authors:
- Ping Zhang
- Yan Wang
- Xue‑Rong Liu
- Shi‑Ru Hong
- Jian Yao
View Affiliations

Affiliations: Department of Integrated Traditional Chinese Medicine and Western Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Respiratory Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: May 11, 2018 https://doi.org/10.3892/ol.2018.8697
Pages: 1059-1066

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the role of T cell immunoglobulin domain and mucin‑3 (Tim‑3) in its gene and protein forms in colorectal cancer (CRC), and to verify the significance of Tim‑3 expression in patients with CRC. A prospective analysis of 258 patients with CRC and 246 normal controls was conducted between December 2012 and June 2015. Intestinal samples were collected, including of CRC tissues, paracancerous tissues and normal colon mucosa tissues. Peripheral venous blood samples were also collected. Polymerase chain reaction (PCR) amplification, reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis was performed for the detection and evaluation of Tim‑3 gene and protein in various tissues. PCR analysis indicated that the T and G alleles of ‑882C/T and 4259T/G are associated with a significantly increased risk of CRC. Following the confirmation of Tim‑3 expression in CRC tissues, RT‑qPCR detection and western blot analysis revealed clear downregulation of Tim‑3 mRNA and protein expression in the blood and tissue samples obtained from patients with CRC, as compared with in the corresponding control samples. Similar trends of decreased Tim‑3 mRNA levels and protein expression were observed in CRC tissues compared with in the paracancerous and the normal colon mucosa tissues. In addition, the mRNA and protein expression levels in the paracancerous tissues were lower than those in the normal colon mucosa tissues. Furthermore, significantly lower Tim‑3 mRNA levels were observed in patients with a tumor size >5 cm, a poor differentiation degree, higher tumor‑node‑metastasis stage (stage III‑IV), and lymph node and distant metastasis. Collectively, genetic changes to Tim‑3, expressed as polymorphisms in Tim‑3, and decreased mRNA/protein expression may be partially responsible for the incidence and development of CRC.

View Figures

View References

1	Richter J, Rudeck S, Kretz AL, Kramer K, Just S, Henne-Bruns D, Hillenbrand A, Leithauser F, Lemke J and Knippschild U: Decreased CK1δ expression predicts prolonged survival in colorectal cancer patients. Tumour Biol. 27:8731–8739. 2016. View Article : Google Scholar
2	Day LW and Velayos F: Colorectal cancer of the elderly. Curr Treat Options Gastroenterol. 12:269–282. 2014. View Article : Google Scholar : PubMed/NCBI
3	Burada F, Nicoli ER, Ciurea ME, Uscatu DC, Ioana M and Gheonea DI: Autophagy in colorectal cancer: An important switch from physiology to pathology. World J Gastrointest Oncol. 7:271–284. 2015. View Article : Google Scholar : PubMed/NCBI
4	Pibiri F, Kittles RA, Sandler RS, Keku TO, Kupfer SS, Xicola RM, Llor X and Ellis NA: Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control. 25:561–570. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kumar K, Brim H, Giardiello F, Smoot DT, Nouraie M, Lee EL and Ashktorab H: Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans. Clin Cancer Res. 15:1155–1161. 2009. View Article : Google Scholar : PubMed/NCBI
6	Sun K, Deng HJ, Lei ST, Dong JQ and Li GX: miRNA-338-3p suppresses cell growth of human colorectal carcinoma by targeting smoothened. World J Gastroenterol. 19:2197–2207. 2013. View Article : Google Scholar : PubMed/NCBI
7	Sun K, Wang W, Zeng JJ, Wu CT, Lei ST and Li GX: MicroRNA-221 inhibits CDKN1C/p57 expression in human colorectal carcinoma. Acta Pharmacol Sin. 32:375–384. 2011. View Article : Google Scholar : PubMed/NCBI
8	Triantafillidis JK, Vagianos C and Malgarinos G: Colonoscopy in colorectal cancer screening: Current aspects. Indian J Surg Oncol. 6:237–250. 2015. View Article : Google Scholar : PubMed/NCBI
9	Malkomes P, Lunger I, Luetticke A, Oppermann E, Haetscher N, Serve H, Holzer K, Bechstein WO and Rieger MA: Selective AKT inhibition by MK-2206 represses colorectal cancer-initiating stem cells. Ann Surg Oncol. 23:2849–2857. 2016. View Article : Google Scholar : PubMed/NCBI
10	Nedrebø BS, Søreide K, Eriksen MT, Kvaløy JT, Søreide JA and Kørner H: Excess mortality after curative surgery for colorectal cancer changes over time and differs for patients with colon versus rectal cancer. Acta Oncol. 52:933–940. 2013. View Article : Google Scholar : PubMed/NCBI
11	van Gestel YR, de Hingh IH, van Herk-Sukel MP, van Erning FN, Beerepoot LV, Wijsman JH, Slooter GD, Rutten HJ, Creemers GJ and Lemmens VE: Patterns of metachronous metastases after curative treatment of colorectal cancer. Cancer Epidemiol. 38:448–454. 2014. View Article : Google Scholar : PubMed/NCBI
12	Matsumoto T, Hasegawa S, Matsumoto S, Horimatsu T, Okoshi K, Yamada M, Kawada K and Sakai Y: Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. Dis Colon Rectum. 57:679–686. 2014. View Article : Google Scholar : PubMed/NCBI
13	Vissers PA, Thong MS, Pouwer F, den Oudsten BL, Nieuwenhuijzen GA and van de Poll-Franse LV: The individual and combined effect of colorectal cancer and diabetes on health-related quality of life and sexual functioning: Results from the PROFILES registry. Support Care Cancer. 22:3071–3079. 2014. View Article : Google Scholar : PubMed/NCBI
14	Jeon JY and Meyerhardt JA: Can we change the past for colorectal cancer patients and how do we move forward? Cancer. 120:1450–1452. 2014. View Article : Google Scholar : PubMed/NCBI
15	Kontou N, Psaltopoulou T, Soupos N, Polychronopoulos E, Xinopoulos D, Linos A and Panagiotakos DB: Metabolic syndrome and colorectal cancer: The protective role of Mediterranean diet-a case-control study. Angiology. 63:390–396. 2012. View Article : Google Scholar : PubMed/NCBI
16	Okugawa Y, Grady WM and Goel A: Epigenetic alterations in colorectal cancer: Emerging Biomarkers. Gastroenterology. 149:1204–1225.e12. 2015. View Article : Google Scholar : PubMed/NCBI
17	Mundade R, Imperiale TF, Prabhu L, Loehrer PJ and Lu T: Genetic pathways, prevention, and treatment of sporadic colorectal cancer. Oncoscience. 1:400–406. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zoratto F, Rossi L, Verrico M, Papa A, Basso E, Zullo A, Tomao L, Romiti A, Lo Russo G and Tomao S: Focus on genetic and epigenetic events of colorectal cancer pathogenesis: Implications for molecular diagnosis. Tumour Biol. 35:6195–6206. 2014. View Article : Google Scholar : PubMed/NCBI
19	Hu T, Wu Z, Vervelde L, Rothwell L, Hume DA and Kaiser P: Functional annotation of the T-cell immunoglobulin mucin family in birds. Immunology. 148:287–303. 2016. View Article : Google Scholar : PubMed/NCBI
20	Xu G, Zheng K, Lu X and Wang J, Chai Y and Wang J: Association between polymorphisms in the promoter region of T cell immunoglobulin and mucin domain-3 and myasthenia gravis-associated thymoma. Oncol Lett. 9:1470–1474. 2015. View Article : Google Scholar : PubMed/NCBI
21	Angiari S and Constantin G: Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein. Trends Mol Med. 20:675–684. 2014. View Article : Google Scholar : PubMed/NCBI
22	Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W, et al: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol. 52:322–329. 2010. View Article : Google Scholar : PubMed/NCBI
23	Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, Chalasani G, Sayegh MH, Najafian N and Rothstein DM: Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 121:3645–3656. 2011. View Article : Google Scholar : PubMed/NCBI
24	Xiao S, Brooks CR, Sobel RA and Kuchroo VK: Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol. 194:1602–1608. 2015. View Article : Google Scholar : PubMed/NCBI
25	Xu J, Jiang P and Liu J: Pooled-analysis of the association between TIM-1 5383_5397 insertion/deletion polymorphism and asthma susceptibility. Mol Biol Rep. 41:7825–7831. 2014. View Article : Google Scholar : PubMed/NCBI
26	Li M, Ablan SD, Miao C, Zheng YM, Fuller MS, Rennert PD, Maury W, Johnson MC, Freed EO and Liu SL: TIM-family proteins inhibit HIV-1 release. Proc Natl Acad Sci USA. 111:E3699–E3707. 2014. View Article : Google Scholar : PubMed/NCBI
27	Chou FC, Kuo CC, Chen HY, Chen HH and Sytwu HK: DNA demethylation of the TIM-3 promoter is critical for its stable expression on T cells. Genes Immun. 17:179–186. 2016. View Article : Google Scholar : PubMed/NCBI
28	Cai XZ, Huang WY, Qiao Y, Chen Y, Du SY, Chen D, Yu S, Liu N, Dou LY and Jiang Y: Downregulation of TIM-3 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Braz J Med Biol Res. 48:77–82. 2015. View Article : Google Scholar : PubMed/NCBI
29	Shan NN, Hu Y, Hou M, Gao J, Wang X, Liu X and Li Y: Decreased Tim-3 and its correlation with Th1 cells in patients with immune thrombocytopenia. Thromb Res. 133:52–56. 2014. View Article : Google Scholar : PubMed/NCBI
30	Lee MJ, Woo MY, Heo YM, Kim JS, Kwon MH, Kim K and Park S: The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine. Biochem Biophys Res Commun. 402:88–93. 2010. View Article : Google Scholar : PubMed/NCBI
31	Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ, et al: Tim-3/galectin-9 pathway: Regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol. 185:1383–1392. 2010. View Article : Google Scholar : PubMed/NCBI
32	Roth CG, Garner K, Eyck ST, Boyiadzis M, Kane LP and Craig FE: TIM3 expression by leukemic and non-leukemic myeloblasts. Cytometry B Clin Cytom. 84:167–172. 2013. View Article : Google Scholar : PubMed/NCBI
33	Moller-Hackbarth K, Dewitz C, Schweigert O, Trad A, Garbers C, Rose-John S and Scheller J: A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J Biol Chem. 288:34529–34544. 2013. View Article : Google Scholar : PubMed/NCBI
34	Zhao D, Hou N, Cui M, Liu Y, Liang X, Zhuang X, Zhang Y, Zhang L, Yin D, Gao L, et al: Increased T cell immunoglobulin and mucin domain 3 positively correlate with systemic IL-17 and TNF-α level in the acute phase of ischemic stroke. J Clin Immunol. 31:719–727. 2011. View Article : Google Scholar : PubMed/NCBI
35	M PN: World medical association publishes the revised declaration of Helsinki. Natl Med J India. 27:562014.PubMed/NCBI
36	Ali R, Toh HC and Chia WK: ASCOLT Trial Investigators: The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer-the ASCOLT study: Study protocol for a randomized controlled trial. Trials. 12:2612011. View Article : Google Scholar : PubMed/NCBI
37	Hu H, Krasinskas A and Willis J: Perspectives on current tumor-node-metastasis (TNM) staging of cancers of the colon and rectum. Semin Oncol. 38:500–510. 2011. View Article : Google Scholar : PubMed/NCBI
38	Ma B, Qu P, Zhang XM, Zhang YF, Hu PZ, Ge W, Si SY, Huang Y, Li X and Sui YF: Culturing dendritic cells from the peripheral blood with successive adherence method and observing the utralmicrostructure of cells. J Mod Oncol. 2007.
39	Forlenza M, Kaiser T, Savelkoul HF and Wiegertjes GF: The use of real-time quantitative PCR for the analysis of cytokine mRNA levels. Methods Mol Biol. 820:7–23. 2012. View Article : Google Scholar : PubMed/NCBI
40	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
41	Sun Y, Shen S, Liu X, Tang H, Wang Z, Yu Z, Li X and Wu M: MiR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. Mol Cell Biochem. 390:19–30. 2014. View Article : Google Scholar : PubMed/NCBI
42	Jayachandran R and Pieters J: Regulation of immune cell homeostasis and function by coronin 1. Int Immunopharmacol. 28:825–828. 2015. View Article : Google Scholar : PubMed/NCBI
43	Sharma R, Kapila R, Dass G and Kapila S: Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice. Age (Dordr). 36:96862014. View Article : Google Scholar : PubMed/NCBI
44	Freeman GJ, Casasnovas JM, Umetsu DT and DeKruyff RH: TIM genes: A family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 235:172–189. 2010. View Article : Google Scholar : PubMed/NCBI
45	Zhang L, Ai Y and Tsung A: Clinical application: Restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis. Exp Ther Med. 11:1159–1167. 2016. View Article : Google Scholar : PubMed/NCBI
46	Rossi M and Bot A: The Th17 cell population and the immune homeostasis of the gastrointestinal tract. Int Rev Immunol. 32:471–474. 2013. View Article : Google Scholar : PubMed/NCBI
47	Takeuchi Y and Nishikawa H: Roles of regulatory T cells in cancer immunity. Int Immunol. 28:401–409. 2016. View Article : Google Scholar : PubMed/NCBI
48	Cabrera R, Ararat M, Xu Y, Brusko T, Wasserfall C, Atkinson MA, Chang LJ, Liu C and Nelson DR: Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 62:737–746. 2013. View Article : Google Scholar : PubMed/NCBI
49	Liu Y, Gao LF, Liang XH and Ma CH: Role of Tim-3 in hepatitis B virus infection: An overview. World J Gastroenterol. 22:2294–2303. 2016. View Article : Google Scholar : PubMed/NCBI
50	Wang L, Zhao C, Peng Q, Shi J and Gu G: Expression levels of CD28, CTLA-4, PD-1 and Tim-3 as novel indicators of T-cell immune function in patients with chronic hepatitis B virus infection. Biomed Rep. 2:270–274. 2014. View Article : Google Scholar : PubMed/NCBI
51	Cai C, Xu YF, Wu ZJ, Dong Q, Li MY, Olson JC, Rabinowitz YM, Wang LH and Sun Y: Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma. World J Urol. 34:561–567. 2016. View Article : Google Scholar : PubMed/NCBI
52	da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I and Bhardwaj N: Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res. 2:410–422. 2014. View Article : Google Scholar : PubMed/NCBI
53	Cheng YQ, Ren JP, Zhao J, Wang JM, Zhou Y, Li GY, Moorman JP and Yao ZQ: MicroRNA-155 regulates interferon-gamma production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection. Immunology. 145:485–497. 2015. View Article : Google Scholar : PubMed/NCBI
54	Fu X, Wu B, Huang B, Zheng H, Huang S, Gan Y, Shen J, Lun ZR and Lu F: The correlation of Tim-3 and IFN-γ expressions in mice infected with Toxoplasma gondii during gestation. Parasitol Res. 114:125–132. 2015. View Article : Google Scholar : PubMed/NCBI
55	Charwat V, Rothbauer M, Tedde SF, Hayden O, Bosch JJ, Muellner P, Hainberger R and Ertl P: Monitoring dynamic interactions of tumor cells with tissue and immune cells in a lab-on-a-chip. Anal Chem. 85:11471–11478. 2013. View Article : Google Scholar : PubMed/NCBI
56	Bose T and Trimper S: Noise-assisted interactions of tumor and immune cells. Phys Rev E Stat Nonlin Soft Matter Phys. 84:0219272011. View Article : Google Scholar : PubMed/NCBI
57	Mazer B: Is there a place for B cells as regulators of immune tolerance in allergic diseases? Clin Exp Allergy. 44:469–471. 2014. View Article : Google Scholar : PubMed/NCBI
58	Gao X, Yang J, He Y and Zhang J: Quantitative assessment of TIM-3 polymorphisms and cancer risk in Chinese Han population. Oncotarget. 7:35768–35775. 2016.PubMed/NCBI