Contrasting functions of the epithelial‑stromal interaction 1 gene, in human oral and lung squamous cell cancers

Fan,Mengmeng; Arai,Makoto; Tawada,Akinobu; Chiba,Tetsuhiro; Fukushima,Reo; Uzawa,Katsuhiro; Shiiba,Masashi; Kato,Naoya; Tanzawa,Hideki; Takiguchi,Yuichi

doi:10.3892/or.2021.8216

Contrasting functions of the epithelial‑stromal interaction 1 gene, in human oral and lung squamous cell cancers

Authors:
- Mengmeng Fan
- Makoto Arai
- Akinobu Tawada
- Tetsuhiro Chiba
- Reo Fukushima
- Katsuhiro Uzawa
- Masashi Shiiba
- Naoya Kato
- Hideki Tanzawa
- Yuichi Takiguchi
View Affiliations

Affiliations: Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan, Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan
Published online on: November 2, 2021 https://doi.org/10.3892/or.2021.8216
Article Number: 5
Copyright: © Fan 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

The epithelial‑stromal interaction 1 gene (EPSTI1) is known to play multiple roles in the malignant progression of breast cancer and also in some aspects of the immune responses to the tumor. However, the relevance of the gene in the onset/progression of oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LSCC) is not yet known. The present study was aimed at revealing the roles of EPSTI1 in conferring malignant characteristics to OSCC and LSCC, and the underlying mechanisms. Quantitative real‑time polymerase chain reaction (PCR) and western blot analyses demonstrated significant upregulation of EPSTI1 in all four OSCC cell lines (HSC2, HSC3, HSC3‑M3 and HSC4), and significant downregulation of EPST11 in all three LSCC cell lines (LK‑2, EBC‑1 and H226) used in the present study, as compared to the expression levels in the corresponding control cell lines. Both knockdown of EPST11 in OSCC and overexpression of the gene in LSCC suppressed cell proliferation, and induced cell‑cycle arrest in the G1 phase, with upregulation of p21 and downregulation of CDK2 and cyclin D1. Furthermore, these alterations of EPST11 gene expression in the OSCC and LSCC cell lines suppressed the cell migration ability and reversed the EMT phenotype of the tumor cells. Collectively, while EPSTI1 appears to have oncogenic roles in OSCC, it appears to exert tumor‑suppressive roles in LSCC. PCR array analyses revealed some genes whose expression levels were altered along with the modified EPSTI1 expression in both the OSCC and LSCC cell lines. These findings suggest that EPSTI1 may be a therapeutic target for both OSCC and LSCC.

View Figures

View References

1	Dotto GP and Rustgi AK: Squamous cell cancers: A unified perspective on biology and genetics. Cancer Cell. 29:622–637. 2016. View Article : Google Scholar : PubMed/NCBI
2	Chi AC, Day TA and Neville BW: Oral cavity and oropharyngeal squamous cell carcinoma-an update. CA Cancer J Clin. 65:401–421. 2015. View Article : Google Scholar : PubMed/NCBI
3	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
4	Silverman S Jr: Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge. J Am Dent Assoc. 132 (Suppl):S7–S11. 2001. View Article : Google Scholar
5	Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F and Soerjomataram I: The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin. 67:51–64. 2017. View Article : Google Scholar : PubMed/NCBI
6	Li Y, Gu J, Xu F, Zhu Q, Ge D and Lu C: Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data. Sci Rep. 8:158342018. View Article : Google Scholar : PubMed/NCBI
7	Sharma B and Kanwar SS: Phosphatidylserine: A cancer cell targeting biomarker. Semin Cancer Biol. 52:17–25. 2018. View Article : Google Scholar : PubMed/NCBI
8	Loong HH, Kwan SS, Mok TS and Lau YM: Therapeutic strategies in EGFR mutant non-small cell lung cancer. Curr Treat Options Oncol. 19:582018. View Article : Google Scholar : PubMed/NCBI
9	Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New Engl J Med. 354:567–578. 2006. View Article : Google Scholar : PubMed/NCBI
10	Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359:1116–1127. 2008. View Article : Google Scholar : PubMed/NCBI
11	Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol. 16:763–774. 2015. View Article : Google Scholar : PubMed/NCBI
12	Nielsen HL, Ronnov-Jessen L, Villadsen R and Petersen OW: Identification of EPSTI1, a novel gene induced by epithelial-stromal interaction in human breast cancer. Genomics. 79:703–710. 2002. View Article : Google Scholar : PubMed/NCBI
13	Tran-Thanh D and Done SJ: The role of stromal factors in breast tumorigenicity. Am J Pathol. 176:1072–1074. 2010. View Article : Google Scholar : PubMed/NCBI
14	de Neergaard M, Kim J, Villadsen R, Fridriksdottir AJ, Rank F, Timmermans-Wielenga V, Langerød A, Børresen-Dale AL and Petersen OW: Epithelial-stromal interaction 1 (EPSTI1) substitutes for peritumoral fibroblasts in the tumor microenvironment. Am J Pathol. 176:1229–1240. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kim YH, Lee JR and Hahn MJ: Regulation of inflammatory gene expression in macrophages by epithelial-stromal interaction 1 (Epsti1). Biochem Biophys Res Commun. 496:778–783. 2018. View Article : Google Scholar : PubMed/NCBI
16	Kim SC, Hong CW, Jang SG, Kim YA, Yoo BC, Shin YK, Jeong SY, Ku JL and Park JG: Establishment and characterization of paired primary and peritoneal seeding human colorectal cancer cell lines: Identification of genes that mediate metastatic potential. Transl Oncol. 11:1232–1243. 2018. View Article : Google Scholar : PubMed/NCBI
17	Hastie E, Cataldi M, Moerdyk-Schauwecker MJ, Felt SA, Steuerwald N and Grdzelishvili VZ: Novel biomarkers of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus. Oncotarget. 7:61601–61618. 2016. View Article : Google Scholar : PubMed/NCBI
18	Li T, Lu H, Shen C, Lahiri SK, Wason MS, Mukherjee D, Yu L and Zhao J: Identification of epithelial stromal interaction 1 as a novel effector downstream of Kruppel-like factor 8 in breast cancer invasion and metastasis. Oncogene. 33:4746–4755. 2014. View Article : Google Scholar : PubMed/NCBI
19	Capdevila-Busquets E, Badiola N, Arroyo R, Alcalde V, Soler-Lopez M and Aloy P: Breast cancer genes PSMC3IP and EPSTI1 play a role in apoptosis regulation. PLoS One. 10:e01153522015. View Article : Google Scholar : PubMed/NCBI
20	Fijak M and Meinhardt A: The testis in immune privilege. Immunol Rev. 213:66–81. 2006. View Article : Google Scholar : PubMed/NCBI
21	Kosova G, Scott NM, Niederberger C, Prins GS and Ober C: Genome-wide association study identifies candidate genes for male fertility traits in humans. Am J Human Genet. 90:950–961. 2012. View Article : Google Scholar : PubMed/NCBI
22	Ishii T, Onda H, Tanigawa A, Ohshima S, Fujiwara H, Mima T, Katada Y, Deguchi H, Suemura M, Miyake T, et al: Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients. DNA Res. 12:429–439. 2005. View Article : Google Scholar : PubMed/NCBI
23	Sun JL, Zhang HZ, Liu SY, Lian CF, Chen ZL, Shao TH, Zhang S, Zhao LL, He CM, Wang M, et al: Elevated EPSTI1 promote B cell hyperactivation through NF-kappaB signalling in patients with primary Sjogren's syndrome. Ann Rheum Dis. 79:518–524. 2020. View Article : Google Scholar : PubMed/NCBI
24	Meng X, Yang D, Yu R and Zhu H: EPSTI1 is involved in IL-28A-mediated inhibition of HCV infection. Mediators Inflamm. 2015:7163152015. View Article : Google Scholar : PubMed/NCBI
25	Yamano Y, Uzawa K, Shinozuka K, Fushimi K, Ishigami T, Nomura H, Ogawara K, Shiiba M, Yokoe H and Tanzawa H: Hyaluronan-mediated motility: A target in oral squamous cell carcinoma. Int J Oncol. 32:1001–1009. 2008.PubMed/NCBI
26	Peng CH, Liao CT, Peng SC, Chen YJ, Cheng AJ, Juang JL, Tsai CY, Chen TC, Chuang YJ, Tang CY, et al: A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One. 6:e234522011. View Article : Google Scholar : PubMed/NCBI
27	Hou J, Aerts J, den Hamer B, van Ijcken W, den Bakker M, Riegman P, van der Leest C, van der Spek P, Foekens JA, Hoogsteden HC, et al: Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One. 5:e103122010. View Article : Google Scholar : PubMed/NCBI
28	Douglas NC and Papaioannou VE: The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 18:143–147. 2013. View Article : Google Scholar : PubMed/NCBI
29	Du WL, Fang Q, Chen Y, Teng JW, Xiao YS, Xie P, Jin B and Wang JQ: Effect of silencing the TBox transcription factor TBX2 in prostate cancer PC3 and LNCaP cells. Mol Med Rep. 16:6050–6058. 2017. View Article : Google Scholar : PubMed/NCBI
30	Khalil AA, Sivakumar S, Lucas FAS, McDowell T, Lang W, Tabata K, Fujimoto J, Yatabe Y, Spira A, Scheet P, et al: TBX2 subfamily suppression in lung cancer pathogenesis: A high-potential marker for early detection. Oncotarget. 8:68230–68241. 2017. View Article : Google Scholar : PubMed/NCBI
31	Ohtaki Y, Shimizu K, Kawabata-Iwakawa R, Gombodorj N, Altan B, Rokudai S, Yamane A, Kaira K, Yokobori T, Nagashima T, et al: Carbonic anhydrase 9 expression is associated with poor prognosis, tumor proliferation, and radiosensitivity of thymic carcinomas. Oncotarget. 10:1306–1319. 2019. View Article : Google Scholar : PubMed/NCBI
32	Ding M, He SJ and Yang J: MCP-1/CCL2 mediated by autocrine loop of PDGF-BB promotes invasion of lung cancer cell by recruitment of macrophages via CCL2-CCR2 axis. J Interferon Cytokine Res. 39:224–232. 2019. View Article : Google Scholar : PubMed/NCBI
33	De la Fuente Lopez M, Landskron G, Parada D, Dubois-Camacho K, Simian D, Martinez M, Romero D, Roa JC, Chahuán I, Gutiérrez R, et al: The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol. 40:10104283188100592018. View Article : Google Scholar : PubMed/NCBI
34	Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J and Pollard JW: CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 212:1043–1059. 2015. View Article : Google Scholar : PubMed/NCBI
35	Ling Z, Yang X, Chen X, Xia J, Cheng B and Tao X: CCL2 promotes cell migration by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma. J Oral Pathol Med. 48:477–482. 2019. View Article : Google Scholar : PubMed/NCBI
36	Liu Y, Liu WB, Liu KJ, Ao L, Cao J, Zhong JL and Liu JY: Overexpression of miR-26b-5p regulates the cell cycle by targeting CCND2 in GC-2 cells under exposure to extremely low frequency electromagnetic fields. Cell Cycle. 15:357–367. 2016. View Article : Google Scholar : PubMed/NCBI
37	Lee JY, Tokumoto M, Hwang GW, Lee MY and Satoh M: Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity. Sci Rep. 7:172872017. View Article : Google Scholar : PubMed/NCBI
38	Watanabe J, Takiyama Y, Honjyo J, Makino Y, Fujita Y, Tateno M and Haneda M: Role of IGFBP7 in diabetic nephropathy: TGF-β1 induces IGFBP7 via Smad2/4 in human renal proximal tubular epithelial cells. PLoS One. 11:e01508972016. View Article : Google Scholar : PubMed/NCBI