Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma

  • Authors:
    • Eiji Iwata
    • Takumi Hasegawa
    • Daisuke Takeda
    • Takeshi Ueha
    • Teruya Kawamoto
    • Toshihiro Akisue
    • Yoshitada Sakai
    • Takahide Komori
  • View Affiliations

  • Published online on: February 5, 2016     https://doi.org/10.3892/ijo.2016.3380
  • Pages: 1493-1498
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Abstract

Oral squamous cell carcinoma (OSCC) is the most common form of oral cancers. Recent studies have shown that the malignant transformation of various carcinomas, including OSCC, is associated with epithelial-mesenchymal transition (EMT), and that expression of the EMT factors are significantly associated with tumor invasion, tumor metastasis, and survival rates in OSCC patients. Hence, there is a possibility that EMT suppression may improve the prognosis of OSCC patients. Hypoxia inducible factor-1α (HIF-1α) is a crucial microenvironmental factor in tumor progression, which induces the expression of EMT factors. We previously reported that transcutaneous CO2 suppresses both human OSCC tumor growth and metastasis to the regional lymph nodes by improving hypoxia in treated tissue. According to this background, we hypothesized that increased EMT with HIF-1α expression may increase the progression and the metastatic potential of OSCC, and that decreased hypoxia by transcutaneous CO2 could suppress EMT. In the present study, in vitro studies showed that hypoxic conditions increased the expression of HIF-1α and EMT factors in OSCC cells. In addition, in vivo studies revealed that transcutaneous CO2 increased E-cadherin expression with the decreased expression of HIF-1α, Snail, Slug, N-cadherin, and Vimentin in tumor treatment. These results suggest that transcutaneous CO2 could suppress EMT by improving hypoxia, resulting in the reduction of metastatic potential of OSCC. The findings indicate that transcutaneous CO2 may be able to improve the prognosis of OSCC patients through the suppression of EMT.

References

1 

Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar

2 

Kume K, Haraguchi M, Hijioka H, Ishida T, Miyawaki A, Nakamura N and Ozawa M: The transcription factor Snail enhanced the degradation of E-cadherin and desmoglein 2 in oral squamous cell carcinoma cells. Biochem Biophys Res Commun. 430:889–894. 2013. View Article : Google Scholar

3 

Sasahira T, Kirita T, Yamamoto K, Ueda N, Kurihara M, Matsushima S, Bhawal UK, Bosserhoff AK and Kuniyasu H: Transport and Golgi organisation protein 1 is a novel tumour progressive factor in oral squamous cell carcinoma. Eur J Cancer. 50:2142–2151. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Savagner P: Leaving the neighborhood: Molecular mechanisms involved during epithelial-mesenchymal transition. BioEssays. 23:912–923. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Voulgari A and Pintzas A: Epithelial-mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 1796:75–90. 2009.PubMed/NCBI

7 

Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN and Larue L: The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 63:2172–2178. 2003.PubMed/NCBI

8 

Ikenouchi J, Matsuda M, Furuse M and Tsukita S: Regulation of tight junctions during the epithelium-mesenchyme transition: Direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 116:1959–1967. 2003. View Article : Google Scholar : PubMed/NCBI

9 

da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA and Kowalski LP: Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clin Exp Metastasis. 32:55–63. 2015. View Article : Google Scholar

10 

Fan CC, Wang TY, Cheng YA, Jiang SS, Cheng CW, Lee AY and Kao TY: Expression of E-cadherin, Twist, and p53 and their prognostic value in patients with oral squamous cell carcinoma. J Cancer Res Clin Oncol. 139:1735–1744. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D and Lopes CS: Prognostic value of E-cadherin immunoexpression in patients with primary ovarian carcinomas. Ann Oncol. 15:1535–1542. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Zhou YN, Xu CP, Han B, Li M, Qiao L, Fang DC and Yang JM: Expression of E-cadherin and beta-catenin in gastric carcinoma and its correlation with the clinicopatho-logical features and patient survival. World J Gastroenterol. 8:987–993. 2002. View Article : Google Scholar : PubMed/NCBI

13 

Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV and Pignatelli M: Aberrant E-cadherin and alpha-catenin expression in prostate cancer: Correlation with patient survival. Cancer Res. 57:3189–3193. 1997.PubMed/NCBI

14 

Bondi J, Bukholm G, Nesland JM, Bakka A and Bukholm IR: An increase in the number of adhesion proteins with altered expression is associated with an increased risk of cancer death for colon carcinoma patients. Int J Colorectal Dis. 21:231–237. 2006. View Article : Google Scholar

15 

Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C and Wang YC: SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res. 70:543–551. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Li YY, Zhou CX and Gao Y: Snail regulates the motility of oral cancer cells via RhoA/Cdc42/p-ERM pathway. Biochem Biophys Res Commun. 452:490–496. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Wushou A, Pan HY, Liu W, Tian Z, Wang LZ, Shali S and Zhang ZY: Correlation of increased twist with lymph node metastasis in patients with oral squamous cell carcinoma. J Oral Maxillofac Surg. 70:1473–1479. 2012. View Article : Google Scholar

18 

Zhao D, Tang XF, Yang K, Liu JY and Ma XR: Over-expression of integrin-linked kinase correlates with aberrant expression of Snail, E-cadherin and N-cadherin in oral squamous cell carcinoma: Implications in tumor progression and metastasis. Clin Exp Metastasis. 29:957–969. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Zhou J, Tao D, Xu Q, Gao Z and Tang D: Expression of E-cadherin and vimentin in oral squamous cell carcinoma. Int J Clin Exp Pathol. 8:3150–3154. 2015.PubMed/NCBI

20 

Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U and Vaupel P: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56:4509–4515. 1996.PubMed/NCBI

21 

Jing SW, Wang YD, Chen LQ, Sang MX, Zheng MM, Sun GG, Liu Q, Cheng YJ and Yang CR: Hypoxia suppresses E-cadherin and enhances matrix metalloproteinase-2 expression favoring esophageal carcinoma migration and invasion via hypoxia inducible factor-1 alpha activation. Dis Esophagus. 26:75–83. 2013. View Article : Google Scholar

22 

Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH and Semenza GL: Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66:2725–2731. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, et al: Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63:1138–1143. 2003.PubMed/NCBI

24 

Lv L, Yuan J, Huang T, Zhang C, Zhu Z, Wang L, Jiang G and Zeng F: Stabilization of Snail by HIF-1α and TNF-α is required for hypoxia-induced invasion in prostate cancer PC3 cells. Mol Biol Rep. 41:4573–4582. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Wang F, Chang M, Shi Y, Jiang L, Zhao J, Hai L, Sharen G and Du H: Down-regulation of hypoxia-inducible factor-1 suppresses malignant biological behavior of triple-negative breast cancer cells. Int J Clin Exp Med. 7:3933–3940. 2014.

26 

Wang N, Dong CR, Jiang R, Tang C, Yang L, Jiang QF, Chen GG and Liu ZM: Overexpression of HIF-1α, metallothionein and SLUG is associated with high TNM stage and lymph node metastasis in papillary thyroid carcinoma. Int J Clin Exp Pathol. 7:322–330. 2013.

27 

Takeda D, Hasegawa T, Ueha T, Imai Y, Sakakibara A, Minoda M, Kawamoto T, Minamikawa T, Shibuya Y, Akisue T, et al: Transcutaneous carbon dioxide induces mitochondrial apoptosis and suppresses metastasis of oral squamous cell carcinoma in vivo. PLoS One. 9:e1005302014. View Article : Google Scholar : PubMed/NCBI

28 

Matsui T, Ota T, Ueda Y, Tanino M and Odashima S: Isolation of a highly metastatic cell line to lymph node in human oral squamous cell carcinoma by orthotopic implantation in nude mice. Oral Oncol. 34:253–256. 1998. View Article : Google Scholar : PubMed/NCBI

29 

Okada Y, Akisue T, Hara H, Kishimoto K, Kawamoto T, Imabori M, Kishimoto S, Fukase N, Onishi Y and Kurosaka M: The effect of bevacizumab on tumour growth of malignant fibrous histiocytoma in an animal model. Anticancer Res. 30:3391–3395. 2010.PubMed/NCBI

30 

Jordan RC and Daley T: Oral squamous cell carcinoma: new in sights. J Can Dent Assoc. 63:517–518. 521–525. 1997.

31 

Christiansen JJ and Rajasekaran AK: Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 66:8319–8326. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Smith A, Teknos TN and Pan Q: Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol. 49:287–292. 2013. View Article : Google Scholar :

33 

Acloque H, Adams MS, Fishwick K, Bronner-Fraser M and Nieto MA: Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease. J Clin Invest. 119:1438–1449. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Huber MA, Kraut N and Beug H: Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 17:548–558. 2005. View Article : Google Scholar : PubMed/NCBI

36 

Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y and Johnson KR: Cadherin switching. J Cell Sci. 121:727–735. 2008. View Article : Google Scholar : PubMed/NCBI

37 

Peinado H, Olmeda D and Cano A: Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI

38 

Peinado H, Portillo F and Cano A: Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol. 48:365–375. 2004. View Article : Google Scholar : PubMed/NCBI

39 

Mattijssen V, Peters HM, Schalkwijk L, Manni JJ, van ‘t Hof-Grootenboer B, de Mulder PH and Ruiter DJ: E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. Int J Cancer. 55:580–585. 1993. View Article : Google Scholar : PubMed/NCBI

40 

Thomas PA, Kirschmann DA, Cerhan JR, Folberg R, Seftor EA, Sellers TA and Hendrix MJ: Association between keratin and vimentin expression, malignant phenotype, and survival in postmenopausal breast cancer patients. Clin Cancer Res. 5:2698–2703. 1999.PubMed/NCBI

41 

Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R and Nagayama M: Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol. 37:65–71. 2001. View Article : Google Scholar

42 

Tang CH and Tsai CC: CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/ MEK/ERK/NF-κB signaling pathway. Biochem Pharmacol. 83:335–344. 2012. View Article : Google Scholar

43 

Barrallo-Gimeno A and Nieto MA: Evolutionary history of the Snail/Scratch superfamily. Trends Genet. 25:248–252. 2009. View Article : Google Scholar : PubMed/NCBI

44 

Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 3:155–166. 2002. View Article : Google Scholar : PubMed/NCBI

45 

Parent AE, Newkirk KM and Kusewitt DF: Slug (Snai2) expression during skin and hair follicle development. J Invest Dermatol. 130:1737–1739. 2010. View Article : Google Scholar : PubMed/NCBI

46 

Murray SA, Oram KF and Gridley T: Multiple functions of Snail family genes during palate development in mice. Development. 134:1789–1797. 2007. View Article : Google Scholar : PubMed/NCBI

47 

Li G, Satyamoorthy K and Herlyn M: N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 61:3819–3825. 2001.PubMed/NCBI

48 

Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, Tiron C, Lorens JB and Ivaska J: Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 30:1436–1448. 2011. View Article : Google Scholar

49 

Hashimoto T, Soeno Y, Maeda G, Taya Y, Aoba T, Nasu M, Kawashiri S and Imai K: Progression of oral squamous cell carcinoma accompanied with reduced E-cadherin expression but not cadherin switch. PLoS One. 7:e478992012. View Article : Google Scholar : PubMed/NCBI

50 

Mandal M, Myers JN, Lippman SM, Johnson FM, Williams MD, Rayala S, Ohshiro K, Rosenthal DI, Weber RS, Gallick GE, et al: Epithelial to mesenchymal transition in head and neck squamous carcinoma: Association of Src activation with E-cadherin down-regulation, vimentin expression, and aggressive tumor features. Cancer. 112:2088–2100. 2008. View Article : Google Scholar : PubMed/NCBI

51 

Zhang S, Zhou X, Wang B, Zhang K, Liu S, Yue K, Zhang L and Wang X: Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol. 50:809–817. 2014. View Article : Google Scholar : PubMed/NCBI

52 

Teppo S, Sundquist E, Vered M, Holappa H, Parkkisenniemi J, Rinaldi T, Lehenkari P, Grenman R, Dayan D, Risteli J, et al: The hypoxic tumor microenvironment regulates invasion of aggressive oral carcinoma cells. Exp Cell Res. 319:376–389. 2013. View Article : Google Scholar

53 

Wu XY, Fu ZX and Wang XH: Effect of hypoxia-inducible factor 1-α on Survivin in colorectal cancer. Mol Med Rep. 3:409–415. 2010.

54 

Zhang Q, Zhang ZF, Rao JY, Sato JD, Brown J, Messadi DV and Le AD: Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas. Int J Cancer. 111:849–857. 2004. View Article : Google Scholar : PubMed/NCBI

55 

Sakai Y, Miwa M, Oe K, Ueha T, Koh A, Niikura T, Iwakura T, Lee SY, Tanaka M and Kurosaka M: A novel system for transcutaneous application of carbon dioxide causing an ‘artificial Bohr effect’ in the human body. PLoS One. 6:e241372011. View Article : Google Scholar

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April 2016
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Copy and paste a formatted citation
APA
Iwata, E., Hasegawa, T., Takeda, D., Ueha, T., Kawamoto, T., Akisue, T. ... Komori, T. (2016). Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma. International Journal of Oncology, 48, 1493-1498. https://doi.org/10.3892/ijo.2016.3380
MLA
Iwata, E., Hasegawa, T., Takeda, D., Ueha, T., Kawamoto, T., Akisue, T., Sakai, Y., Komori, T."Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma". International Journal of Oncology 48.4 (2016): 1493-1498.
Chicago
Iwata, E., Hasegawa, T., Takeda, D., Ueha, T., Kawamoto, T., Akisue, T., Sakai, Y., Komori, T."Transcutaneous carbon dioxide suppresses epithelial-mesenchymal transition in oral squamous cell carcinoma". International Journal of Oncology 48, no. 4 (2016): 1493-1498. https://doi.org/10.3892/ijo.2016.3380