Decreased IL‑37 expression in hepatocellular carcinoma tissues and liver cancer cell lines

Li,Peng; Guo,Hongsheng; Wu,Kun; Su,Liudan; Huang,Kai; Lai,Ruizhi; Deng,Ziliang; Li,Shuxian; Ouyang,Ping; Wang,Yan; Chen,Zhangquan; Zhou,Guangji; Wang,Sen

doi:10.3892/ol.2020.11393

Decreased IL‑37 expression in hepatocellular carcinoma tissues and liver cancer cell lines

Authors:
- Peng Li
- Hongsheng Guo
- Kun Wu
- Liudan Su
- Kai Huang
- Ruizhi Lai
- Ziliang Deng
- Shuxian Li
- Ping Ouyang
- Yan Wang
- Zhangquan Chen
- Guangji Zhou
- Sen Wang
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Affiliations: Department of Histology and Embryology, Basic Medical College, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China, Department of Internal Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China, Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
Published online on: February 13, 2020 https://doi.org/10.3892/ol.2020.11393
Pages: 2639-2648
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The role of IL‑37 in cancer is currently largely unknown. The present study aimed to investigate IL‑37 expression in hepatocellular carcinoma (HCC), paracancerous tissues (PT) and liver cancer cell lines, and their associations between IL‑37 and NF‑κB. A total of 65 HCC and 65 PT tissues were collected. The expression of IL‑37 and NF‑κB in tissues was detected by immunohistochemistry (IHC) and the data was analyzed using SPSS software. In the in vitro studies, IL‑37 gene was transfected into HepG2 and MHCC97H cell lines with Lipofectamine 3000, and the protein regulation of NF‑κB by IL‑37 was verified by immunofluorescence (IF) and western blotting. In HCC, the positive expression rates of IL‑37 and NF‑kB were 21.5 and 95.4%, respectively. In PT, strong positive staining of IL‑37and weak positive staining of NF‑κB were observed. The normal expression levels of IL‑37 and NF‑κB, the increased IL‑37 and decreased NF‑κB induced by IL‑37 gene transfection were observed through IF in cell lines. In terms of clinical significance, the difference in IL‑37 expression between HCC and PT was statistically significant (χ2=55.05; P<0.001). IL‑37 expression in HCC but not PT was negatively associated with serum AFP (χ2=6.522; P=0.039). IL‑37 expression in PT was associated with sex (χ2=13.12; P=0.003) and tumor size (χ2=7.996; P=0.045). NF‑κB expression in PT was associated with age, sex and BCLC stage. Notably, there was a negative correlation between IL‑37 and NF‑κB in HCC (r=‑0.277; P=0.029) but not in PT (P>0.05). IL‑37 overexpression downregulated the NF‑κB protein by 56.50% in HepG2 cells (P<0.05) and 30.52% in MHCC97H cells (P<0.05). In conclusion, the expression of IL‑37 in HCC and PT was specifically associated with serum AFP and tumor size, respectively. IL‑37 expression was negatively correlated with NF‑κB protein expression in HCC tissues and liver cancer cell lines.

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1	Wong MC, Jiang JY, Goggins WB, Liang M, Fang Y, Fung FD, Leung C, Wang HH, Wong GL, Wong VW and Chan HL: International incidence and mortality trends of liver cancer: A global profile. Sci Rep. 7:458462017. View Article : Google Scholar : PubMed/NCBI
2	Cheuk-Fung Yip T, Wai-Sun Wong V, Lik-Yuen Chan H, Tse YK, Pik-Shan Kong A, Long-Yan Lam K, Chung-Yan Lui G and Lai-Hung Wong G: Effects of diabetes and glycemic control on risk of hepatocellular carcinoma after seroclearance of hepatitis B surface antigen. Clin Gastroenterol Hepatol. 16:765–773. 2018. View Article : Google Scholar : PubMed/NCBI
3	Saha Turna N and Wu F: Risk assessment of aflatoxin-related liver cancer in Bangladesh. Food Additi Contam Part A Chem Anal Control Expo Risk Assess. 36:320–326. 2019. View Article : Google Scholar
4	Kawamura Y, Arase Y, Ikeda K, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Inao M, Mochida S and Kumada H: Effects of alcohol consumption on hepatocarcinogenesis in Japanese patients with fatty liver disease. Clin Gastroenterol Hepatol. 14:597–605. 2016. View Article : Google Scholar : PubMed/NCBI
5	Taniguchi K and Karin M: NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol. 18:309–324. 2018. View Article : Google Scholar : PubMed/NCBI
6	Banchereau J, Pascual V and O'garra A: From IL-2 to IL-37: The expanding spectrum of anti-inflammatory cytokines. Nat Immunol. 13:925–931. 2012. View Article : Google Scholar : PubMed/NCBI
7	Wang WQ, Dong K, Zhou L, Jiao GH, Zhu CZ, Li WW, Yu G, Wu WT, Chen S, Sun ZN, et al: IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice. Acta Pharm Sin. 36:1377–1387. 2015. View Article : Google Scholar
8	Wang L, Wang Y, Xia L, Shen H and Lu J: Elevated frequency of IL-37-and IL-18Rα-positive T cells in the peripheral blood of rheumatoid arthritis patients. Cytokine. 110:291–297. 2018. View Article : Google Scholar : PubMed/NCBI
9	Wang J, Shen Y, Li C, Liu C, Wang ZH, Li YS, Ke X and Hu GH: IL-37 attenuates allergic process via STAT6/STAT3 pathways in murine allergic rhinitis. Int Immunopharmacol. 69:27–33. 2019. View Article : Google Scholar : PubMed/NCBI
10	de Sousa JR, Prudente RL, Dias Junior LB, Oliveira Carneiro FR, Sotto MN and Simoes Quaresma JA: IL-37 and leprosy: A novel cytokine involved in the host response to mycobacterium leprae infection. Cytokine. 106:89–94. 2018. View Article : Google Scholar : PubMed/NCBI
11	Ye L, Ji L, Wen Z, Zhou Y, Hu D, Li Y, Yu T, Chen B, Zhang J, Ding L, Du J, Huang Z, et al: IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: Its correlation with disease activity. J Transl Med. 12:692014. View Article : Google Scholar : PubMed/NCBI
12	Yang Y, Zhang ZX, Lian D, Haig A, Bhattacharjee RN and Jevnikar AM: IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia-reperfusion injury. Kidney Int. 87:396–408. 2015. View Article : Google Scholar : PubMed/NCBI
13	Bulau AM, Fink M, Maucksch C, Kappler R, Mayr D, Wagner K and Bufler P: In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. ScientificWorldJournal. 11:2480–2490. 2011. View Article : Google Scholar : PubMed/NCBI
14	Feng XX, Chi G, Wang H, Gao Y, Chen Q, Ru YX, Luo ZL, Yan W, Li PY, Liu M, et al: IL-37 suppresses the sustained hepatic IFN-γ/TNF-α production and T cell-dependent liver injury. Int Immunopharmacol. 69:184–193. 2019. View Article : Google Scholar : PubMed/NCBI
15	Wang S, An W, Yao Y, Chen R, Zheng X, Yang W, Zhao Y, Hu X, Jiang E, Bie Y, et al: Interleukin 37 expression inhibits STAT3 to suppress the proliferation and invasion of human cervical cancer cells. J Cancer. 6:962–969. 2015. View Article : Google Scholar : PubMed/NCBI
16	Ouyang P, An W, Chen R, Zhang H, Chen D, Jiang E, Zhu W, Li P, Guo H, Chen Z and Wang S: IL-37 promotes cell apoptosis in cervical cancer involving bim upregulation. OncoTargets Ther. 12:2703–2712. 2019. View Article : Google Scholar
17	Jiang M, Wang Y, Zhang H, Ji Y, Zhao P, Sun R and Zhang C: IL-37 inhibits invasion and metastasis in nonsmall cell lung cancer by suppressing the IL-6/STAT3 signaling pathway. Thoracic Cancer. 9:621–629. 2018. View Article : Google Scholar : PubMed/NCBI
18	Wu T, Xu B, Zhao G, Luo J and Luo C: IL-37 suppresses migration and invasion of gallbladder cancer cells through inhibition of HIF-1α induced epithelial-mesenchymal transition. Eur Rev Med Pharm Sci. 22:8179–8185. 2018.
19	Zhu B, Zhang P, Liu M, Jiang C, Liu H and Fu J: Prognostic significance of CSN2, CD8, and MMR status-associated nomograms in patients with colorectal cancer. Transl Oncol. 11:1202–1212. 2018. View Article : Google Scholar : PubMed/NCBI
20	Zhao JJ, Pan QZ, Pan K, Weng DS, Wang QJ, Li JJ, Lv L, Wang DD, Zheng HX, Jiang SS, et al: Interleukin-37 mediates the antitumor activity in hepatocellular carcinoma: Role for CD57+ NK cells. Sci Rep. 4:51772014. View Article : Google Scholar : PubMed/NCBI
21	Li P, Guo H, Zhou G, Shi H, Li Z, Guan X, Deng Z, Li S, Zhou S, Wang Y and Wang S: Increased ZNF84 expression in cervical cancer. Arch Gynecol Obstet. 297:1525–1532. 2018. View Article : Google Scholar : PubMed/NCBI
22	Chan AW, Kumada T, Toyoda H, Tada T, Chong CC, Mo FK, Yeo W, Johnson PJ, Lai PB, Chan AT, et al: Integration of albumin-bilirubin (ALBI) score into barcelona clinic liver cancer (BCLC) system for hepatocellular carcinoma. J Gastroenterol Hepatol. 31:1300–1306. 2016. View Article : Google Scholar : PubMed/NCBI
23	Yoneda M, Hyun J, Jakubski S, Saito S, Nakajima A, Schiff ER and Thomas E: Hepatitis B virus and DNA stimulation trigger a rapid innate immune response through NF-κB. J Immunol. 197:630–643. 2016. View Article : Google Scholar : PubMed/NCBI
24	Yan X, Zhao J and Zhang R: Interleukin-37 mediates the antitumor activity in colon cancer through β-catenin suppression. Oncotarget. 8:490642017.PubMed/NCBI
25	Ge G, Wang A, Yang J, Chen Y, Yang J, Li Y and Xue Y: Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer. J Exp Clin Cancer Res. 35:132016. View Article : Google Scholar : PubMed/NCBI
26	Ma H, Sun X, Chen L, Cheng W, Han XX, Zhao B and He C: Multiplex immunochips for high-accuracy detection of AFP-L3% based on surface-enhanced raman scattering: Implications for early liver cancer diagnosis. Anal Chem. 89:8877–8883. 2017. View Article : Google Scholar : PubMed/NCBI
27	Yang JY, Li X, Gao L, Teng ZH and Liu WC: Co-transfection of dendritic cells with AFP and IL-2 genes enhances the induction of tumor antigen-specific antitumor immunity. Exp Ther Med. 4:655–660. 2012. View Article : Google Scholar : PubMed/NCBI
28	Xia Y, Shen S and Verma IM: NF-κB, an active player in human cancers. Cancer Immunol Res. 2:823–830. 2014. View Article : Google Scholar : PubMed/NCBI