IL‑33/ST2 promotes the malignant progression of gastric cancer via the MAPK pathway

Huang,Ning; Cui,Xing; Li,Wen; Zhang,Chunlai; Liu,Liqing; Li,Jinxing

doi:10.3892/mmr.2021.12000

IL‑33/ST2 promotes the malignant progression of gastric cancer via the MAPK pathway

Authors:
- Ning Huang
- Xing Cui
- Wen Li
- Chunlai Zhang
- Liqing Liu
- Jinxing Li
View Affiliations

Affiliations: Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China, Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, P.R. China
Published online on: March 16, 2021 https://doi.org/10.3892/mmr.2021.12000
Article Number: 361
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Gastric cancer (GC) remains one of the commonest malignant tumors and the second leading cause of cancer‑related deaths worldwide. IL‑33 is highly expressed in tumor tissues and serum of patients with GC. However, the function of the IL‑33 and IL‑33 receptor ST2 in the malignant progression of GC is yet to be elucidated. The present study aimed to explore the effect of the IL‑33/ST2 axis on the biological functions of GC cells. The expression of ST2 in GC tissues was measured by immunohistochemistry. GC cell lines (AGS and MKN45) were treated with IL‑33, and the expression of ST2 was downregulated by using specific siRNA. The effects of the IL‑33/ST2 axis on cell proliferation, migration, invasion, cell cycle and apoptosis was detected by CCK8, Transwell, wound healing, flow cytometry and western blotting assays. The present study found that ST2 was highly expressed in GC tissues compared with normal tissues. IL‑33 promoted the proliferation and cell cycle progression of GC cells, and upregulated the expression levels of CDK4, CDK6 and cyclin D1. Furthermore, IL‑33 inhibited the apoptosis of GC cells and regulated the expression of apoptosis‑associated proteins. In addition, IL‑33 stimulated the invasion and migration of GC cells. However, the transfection of ST2 small interfering (si)RNA attenuated the effects of IL‑33. Finally, IL‑33 stimulation increased the phosphorylation levels of ERK1/2, JNK and p38. The transfection of ST2 siRNA could significantly inhibit the IL‑33‑induced ERK1/2, JNK and p38 activation. In conclusion, it was found that ST2 was highly expressed in GC tissues. IL‑33/ST2 promoted the malignant progression of GC cells by inducing the activation of ERK1/2, JNK and p38.

View Figures

View References

1	Nagini S: Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 4:156–169. 2012. View Article : Google Scholar : PubMed/NCBI
2	Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, Malvezzi M and La Vecchia C: Recent patterns in gastric cancer: A global overview. Int J Cancer. 125:666–673. 2009. View Article : Google Scholar : PubMed/NCBI
3	Bergis D, Kassis V and Radeke HH: High plasma sST2 levels in gastric cancer and their association with metastatic disease. Cancer Biomark. 16:117–125. 2016. View Article : Google Scholar : PubMed/NCBI
4	Ye XL, Zhao YR, Weng GB, Chen YC, Wei XN, Shao JP and Ji H: IL-33-induced JNK pathway activation confers gastric cancer chemotherapy resistance. Oncol Rep. 33:2746–2752. 2015. View Article : Google Scholar : PubMed/NCBI
5	Yu XX, Hu Z, Shen X, Dong LY, Zhou WZ and Hu WH: IL-33 promotes gastric cancer cell invasion and migration via ST2-ERK1/2 pathway. Dig Dis Sci. 60:1265–1272. 2015. View Article : Google Scholar : PubMed/NCBI
6	Ikeguchi M, Hatada T, Yamamoto M, Miyake T, Matsunaga T, Fukumoto Y, Yamada Y, Fukuda K, Saito H and Tatebe S: Serum interleukin-6 and −10 levels in patients with gastric cancer. Gastric Cancer. 12:95–100. 2009. View Article : Google Scholar : PubMed/NCBI
7	Kang JS, Bae SY, Kim HR, Kim YS, Kim DJ, Cho BJ, Yang HK, Hwang YI, Kim KJ, Park HS, et al: Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44. Carcinogenesis. 30:1987–1996. 2009. View Article : Google Scholar : PubMed/NCBI
8	Haghshenas MR, Hosseini SV, Mahmoudi M, Saberi-Firozi M, Farjadian S and Ghaderi A: IL-18 serum level and IL-18 promoter gene polymorphism in Iranian patients with gastrointestinal cancers. J Gastroenterol Hepatol. 24:1119–1122. 2009. View Article : Google Scholar : PubMed/NCBI
9	Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, et al: IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 23:479–490. 2005. View Article : Google Scholar : PubMed/NCBI
10	Mirchandani AS, Salmond RJ and Liew FY: Interleukin-33 and the function of innate lymphoid cells. Trends Immunol. 33:389–396. 2012. View Article : Google Scholar : PubMed/NCBI
11	Liu J, Shen JX, Hu JL, Huang WH and Zhang GJ: Significance of interleukin-33 and its related cytokines in patients with breast cancers. Front Immunol. 5:1412014. View Article : Google Scholar : PubMed/NCBI
12	Mohran ZY, Ali-Eldin FA and Abdel Aal HA: Serum interleukin-18: Does it have a role in the diagnosis of hepatitis C virus related hepatocellular carcinoma? Arab J Gastroenterol. 12:29–33. 2011. View Article : Google Scholar : PubMed/NCBI
13	Musolino C, Allegra A, Profita M, Alonci A, Saitta S, Russo S, Bonanno A, Innao V and Gangemi S: Reduced IL-33 plasma levels in multiple myeloma patients are associated with more advanced stage of disease. Br J Haematol. 160:709–710. 2013. View Article : Google Scholar : PubMed/NCBI
14	Sun P, Ben Q, Tu S, Dong W, Qi X and Wu Y: Serum interleukin-33 levels in patients with gastric cancer. Dig Dis Sci. 56:3596–3601. 2011. View Article : Google Scholar : PubMed/NCBI
15	Hu W and Wu C, Li X, Zheng Z, Xie Q, Deng X, Jiang J and Wu C: Serum IL-33 level is a predictor of progression-free survival after chemotherapy. Oncotarget. 8:35116–35123. 2017. View Article : Google Scholar : PubMed/NCBI
16	Hu W, Li X, Li Q, Tan Y, Xu B, Xie Q, Deng X, Lu B, Jiang J and Wu C: Interleukin-33 expression does not correlate with survival of gastric cancer patients. Pathol Oncol Res. 23:615–619. 2017. View Article : Google Scholar : PubMed/NCBI
17	Livak JK 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
18	Santulli P, Even M, Chouzenoux S, Millischer AE, Borghese B, de Ziegler D, Batteux F and Chapron C: Profibrotic interleukin-33 is correlated with uterine leiomyoma tumour burden. Hum Reprod. 28:2126–2133. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhang P, Liu XK, Chu Z, Ye JC, Li KL, Zhuang WL, Yang DJ and Jiang YF: Detection of interleukin-33 in serum and carcinoma tissue from patients with hepatocellular carcinoma and its clinical implications. J Int Med Res. 40:1654–1661. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bai F, Ba F, You Y, Feng Y, Tao W, Wu C, Jiu M and Nie Y: Decreased ST2 expression is associated with gastric cancer progression and pathogenesis. Oncol Lett. 17:5761–5767. 2019.PubMed/NCBI
21	Trajkovic V, Sweet MJ and Xu D: T1/ST2-an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 15:87–95. 2004. View Article : Google Scholar : PubMed/NCBI
22	Zhao Y, Wu K, Cai K, Zhai R, Tao K, Wang G and Wang J: Increased numbers of gastric-infiltrating mast cells and regulatory T cells are associated with tumor stage in gastric adenocarcinoma patients. Oncol Lett. 4:755–758. 2012. View Article : Google Scholar : PubMed/NCBI
23	Eissmann MF, Dijkstra C, Jarnicki A, Phesse T, Brunnberg J, Poh AR, Etemadi N, Tsantikos E, Thiem S, Huntington ND, et al: IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun. 10:27352019. View Article : Google Scholar : PubMed/NCBI
24	Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S and Kastelein RA: IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol. 179:2551–2555. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wu Y, Wang F, Fan L, Zhang W, Wang T, Du Y and Bai X: Baicalin alleviates atherosclerosis by relieving oxidative stress and inflammatory responses via inactivating the NF-κB and p38 MAPK signaling pathways. Biomed Pharmacother. 97:1673–1679. 2018. View Article : Google Scholar : PubMed/NCBI
26	Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN and Lukic ML: IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunology. 1:229–231. 2012. View Article : Google Scholar : PubMed/NCBI
27	Sui X, Kong N, Ye L, Han W, Zhou J, Zhang Q, He C and Pan H: p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. 344:174–179. 2014. View Article : Google Scholar : PubMed/NCBI