IRF2‑induced Claudin‑7 suppresses cell proliferation, invasion and migration of oral squamous cell carcinoma

Li,Xin; Yang,Weidong

doi:10.3892/etm.2021.10929

IRF2‑induced Claudin‑7 suppresses cell proliferation, invasion and migration of oral squamous cell carcinoma

Authors:
- Xin Li
- Weidong Yang
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Affiliations: Department of Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210018, P.R. China
Published online on: October 27, 2021 https://doi.org/10.3892/etm.2021.10929
Article Number: 7
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Oral squamous cell carcinoma (OSCC) is a common type of malignant tumor worldwide. Claudin‑7 (CLDN7) has been reported to exhibit low expression in tissues of patients with OSCC; however, the underlying mechanisms of CLDN7 remain to be elucidated. The present study aimed to investigate the effects of CLDN7 on the progression of OSCC and identify its potential regulatory mechanisms. CLDN7 and interferon regulatory factor‑2 (IRF2) expression in several OSCC cell lines were detected using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. Following CLDN7 overexpression, cell proliferation, invasion and migration were determined using a Cell Counting Kit‑8, colony formation, Transwell and wound healing assays, respectively. The potential binding sites of IRF2 on the CLDN7 promoter were analyzed using the PROMO and JASPAR databases, which were verified via chromatin immunoprecipitation and RT‑qPCR assays. The effects of IRF2 and CLDN7 on the biological functions of OSCC cells were examined by transfection with short hairpin RNA (shRNA) against CLDN7 (sh‑CLDN7), or IRF2 and CLDN7 overexpression plasmids. The results revealed that CLDN7 and IRF2 expression were significantly downregulated in OSCC cell lines, and CLDN7 overexpression reduced the proliferation, invasion and migration of OSCC cells. Additionally, IRF2 was confirmed to combine with the CLDN7 promoter. CLDN7 silencing reversed the inhibitory effects of IRF2 overexpression on the proliferation, invasion and migration of OSCC cells. Taken together, these findings demonstrated that IRF2‑induced CLDN7 upregulation suppressed the proliferation, invasion and migration of OSCC cells, suggesting the possibility of CLDN7 and IRF2 as novel targets for the treatment of OSCC.

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1	Sasahira T and Kirita T: Hallmarks of cancer-related newly prognostic factors of oral squamous cell carcinoma. Int J Mol Sci. 19(2413)2018.PubMed/NCBI View Article : Google Scholar
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018.PubMed/NCBI View Article : Google Scholar
3	Sequeira I, Neves JF, Carrero D, Peng Q, Palasz N, Liakath-Ali K, Lord GM, Morgan PR, Lombardi G and Watt FM: Immunomodulatory role of Keratin 76 in oral and gastric cancer. Nat Commun. 9(3437)2018.PubMed/NCBI View Article : Google Scholar
4	Li YY, Tao YW, Gao S, Li P, Zheng JM, Zhang SE, Liang J and Zhang Y: Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. EBioMedicine. 36:209–220. 2018.PubMed/NCBI View Article : Google Scholar
5	Gao D, Xu T, Qi X, Ning W, Ren S, Ru Z, Ji K, Ma Y, Yu T, Li Y, et al: CLAUDIN7 modulates trophectoderm barrier function to maintain blastocyst development in pigs. Theriogenology. 158:346–357. 2020.PubMed/NCBI View Article : Google Scholar
6	Wang K, Li T, Xu C, Ding Y, Li W and Ding L: Claudin-7 downregulation induces metastasis and invasion in colorectal cancer via the promotion of epithelial-mesenchymal transition. Biochem Biophys Res Commun. 508:797–804. 2019.PubMed/NCBI View Article : Google Scholar
7	Poon CE, Madawala RJ, Day ML and Murphy CR: Claudin 7 is reduced in uterine epithelial cells during early pregnancy in the rat. Histochem Cell Biol. 139:583–593. 2013.PubMed/NCBI View Article : Google Scholar
8	Romani C, Zizioli V, Silvestri M, Ardighieri L, Bugatti M, Corsini M, Todeschini P, Marchini S, D'Incalci M, Zanotti L, et al: Low expression of Claudin-7 as potential predictor of distant metastases in high-grade serous ovarian carcinoma patients. Front Oncol. 10(1287)2020.PubMed/NCBI View Article : Google Scholar
9	Ji H, Ding X, Zhang W, Zheng Y, Du H, Zheng Y, Song H, Li M, Jiang Y, Xie J, et al: Claudin-7 inhibits proliferation and metastasis in salivary adenoid cystic carcinoma through Wnt/β-catenin signaling. Cell Transplant. 29(963689720943583)2020.PubMed/NCBI View Article : Google Scholar
10	Yoshizawa K, Nozaki S, Kato A, Hirai M, Yanase M, Yoshimoto T, Kimura I, Sugiura S, Okamune A, Kitahara H, et al: Loss of claudin-7 is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma. Oncol Rep. 29:445–450. 2013.PubMed/NCBI View Article : Google Scholar
11	Wang Y, Liu DP, Chen PP, Koeffler HP, Tong XJ and Xie D: Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Cancer Res. 67:2535–2543. 2007.PubMed/NCBI View Article : Google Scholar
12	Cui L, Deng Y, Rong Y, Lou W, Mao Z, Feng Y, Xie D and Jin D: IRF-2 is over-expressed in pancreatic cancer and promotes the growth of pancreatic cancer cells. Tumour Biol. 33:247–255. 2012.PubMed/NCBI View Article : Google Scholar
13	Kneitz B, Krebs M, Kalogirou C, Schubert M, Joniau S, van Poppel H, Lerut E, Kneitz S, Scholz CJ, Ströbel P, et al: Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3. Cancer Res. 74:2591–2603. 2014.PubMed/NCBI View Article : Google Scholar
14	Pettersson S, Kelleher M, Pion E, Wallace M and Ball KL: Role of Mdm2 acid domain interactions in recognition and ubiquitination of the transcription factor IRF-2. Biochem J. 418:575–585. 2009.PubMed/NCBI View Article : Google Scholar
15	Chen YJ, Liang L, Li J, Wu H, Dong L, Liu TT and Shen XZ: IRF-2 inhibits gastric cancer invasion and migration by down-regulating MMP-1. Dig Dis Sci. 65:168–177. 2020.PubMed/NCBI View Article : Google Scholar
16	Tian JB, Cao L and Dong GL: Long noncoding RNA DDX11-AS1 induced by YY1 accelerates colorectal cancer progression through targeting miR-873/CLDN7 axis. Eur Rev Med Pharmacol Sci. 23:5714–5729. 2019.PubMed/NCBI View Article : Google Scholar
17	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.PubMed/NCBI View Article : Google Scholar
18	Binmadi NO and Basile JR: Perineural invasion in oral squamous cell carcinoma: A discussion of significance and review of the literature. Oral Oncol. 47:1005–1010. 2011.PubMed/NCBI View Article : Google Scholar
19	Takahara T, Kasamatsu A, Yamatoji M, Iyoda M, Kasama H, Saito T, Takeuchi S, Endo-Sakamoto Y, Shiiba M, Tanzawa H and Uzawa K: SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7. Exp Cell Res. 352:357–363. 2017.PubMed/NCBI View Article : Google Scholar
20	Suren D, Yildirim M, Kaya V, Elal R, Selcuk OT, Osma U, Yildiz M, Gunduz S and Sezer C: Expression patterns of claudins 1, 4, and 7 and their prognostic significance in nasopharyngeal carcinoma. J BUON. 20:212–217. 2015.PubMed/NCBI
21	Usami Y, Chiba H, Nakayama F, Ueda J, Matsuda Y, Sawada N, Komori T, Ito A and Yokozaki H: Reduced expression of claudin-7 correlates with invasion and metastasis in squamous cell carcinoma of the esophagus. Hum Pathol. 37:569–577. 2006.PubMed/NCBI View Article : Google Scholar
22	Lioni M, Brafford P, Andl C, Rustgi A, El-Deiry W, Herlyn M and Smalley KS: Dysregulation of claudin-7 leads to loss of E-cadherin expression and the increased invasion of esophageal squamous cell carcinoma cells. Am J Pathol. 170:709–721. 2007.PubMed/NCBI View Article : Google Scholar
23	Zhang B, Lin Y, Bao QF, Zheng YT and Lan L: MiR-1193 inhibits the malignancy of cervical cancer cells by targeting claudin 7 (CLDN7). OncoTargets Ther. 13:4349–4358. 2020.PubMed/NCBI View Article : Google Scholar
24	Wu Z, Shi J, Song Y, Zhao J, Sun J, Chen X, Gao P and Wang Z: Claudin-7 (CLDN7) is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, invasion and maintains mesenchymal state. Neoplasma. 65:349–359. 2018.PubMed/NCBI View Article : Google Scholar
25	Lourenço SV, Coutinho-Camillo CM, Buim ME, de Carvalho AC, Lessa RC, Pereira CM, Vettore AL, Carvalho AL, Fregnani JH, Kowalski LP and Soares FA: Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma. Histopathology. 57:689–698. 2010.PubMed/NCBI View Article : Google Scholar
26	Tamura T, Yanai H, Savitsky D and Taniguchi T: The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 26:535–584. 2008.PubMed/NCBI View Article : Google Scholar
27	Sun L, Jiang Z, Acosta-Rodriguez VA, Berger M, Du X, Choi JH, Wang J, Wang KW, Kilaru GK, Mohawk JA, et al: HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections. J Exp Med. 214:3263–3277. 2017.PubMed/NCBI View Article : Google Scholar
28	Zhao GN, Jiang DS and Li H: Interferon regulatory factors: At the crossroads of immunity, metabolism, and disease. Biochim Biophys Acta. 1852:365–378. 2015.PubMed/NCBI View Article : Google Scholar
29	Sakai T, Mashima H, Yamada Y, Goto T, Sato W, Dohmen T, Kamada K, Yoshioka M, Uchinami H, Yamamoto Y and Ohnishi H: The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer. Pancreas. 43:909–916. 2014.PubMed/NCBI View Article : Google Scholar
30	Li X, Zhou C, Zhang C, Xie X, Zhou Z, Zhou M, Chen L and Ding Z: MicroRNA-664 functions as an oncogene in cutaneous squamous cell carcinomas (cSCC) via suppressing interferon regulatory factor 2. J Dermatol Sci. 94:330–338. 2019.PubMed/NCBI View Article : Google Scholar
31	Lu C, Peng K, Guo H, Ren X, Hu S, Cai Y, Han Y, Ma L and Xu P: miR-18a-5p promotes cell invasion and migration of osteosarcoma by directly targeting IRF2. Oncol Lett. 16:3150–3156. 2018.PubMed/NCBI View Article : Google Scholar
32	Zhang F, Zhu J, Li J, Zhu F and Zhang P: IRF2-INPP4B axis participates in the development of acute myeloid leukemia by regulating cell growth and survival. Gene. 627:9–14. 2017.PubMed/NCBI View Article : Google Scholar