Abstract
Oral squamous cell carcinoma (OSCC) is one of the common types of cancer. Its progression follows a transition from oral potentially malignant disorders (OPMDs) such as oral submucous fibrosis (OSMF). Epigenetic modifiers, especially microRNAs (miRNAs), have an appreciable role in the regulation of various carcinogenic pathways which are being used as biomarkers. miRNAs may also be helpful in the differentiation of oral submucous fibrosis from oral squamous cell carcinoma. Three miRNAs, miR-221-3p, miR133a-3p, and miR-9-5p, were found differentially expressed in many cancers in the literature search supported by our preliminary database search-based screening. The literature and our functional enrichment analysis in an earlier study have reported these miRNAs to regulate carcinogenesis at various steps. In the present study, the expression of these miRNAs was examined in 34 histopathologically confirmed OSCC, 30 OSMF, and 29 control (healthy volunteers) human samples. There was a significant downregulation of miRNA-133a-3p in OSCC compared to OSMF and controls, whereas there was up-regulation in oral submucous fibrosis compared to controls. There was no significant difference in the expression of miR-221-3p between OSCC and OSMF, but an upregulation in OSCC compared to controls. miR-9-5p was also found upregulated in both OSCC and OSMF. Further, miR-133a-3p expression was negatively correlated with age, smoking, drinking status, and AJCC staging, whereas miR-9-5p expression was only positively associated with tobacco/ areca nut chewing. The ROC plots, logistic regression model generated, and the correlation between the expression of miR-9-5p and miR-133a-3p in blood and tissue suggests that these could be used as risk stratification biomarkers.
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References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
El-Sakka H, Kujan O, Farah CS. Assessing miRNAs profile expression as a risk stratification biomarker in oral potentially malignant disorders: a systematic review. Oral Oncol. 2018;77:57–82.
Warnakulasuriya S, Kujan O, Aguirre-Urizar JM, Bagan JV, González-Moles M, Kerr AR, et al. Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer. Oral Dis. 2020.
Dionne KR, Warnakulasuriya S, Zain RB, Cheong SC. Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory. Int J Cancer. 2015;136(3):503–15.
Shih Y-H, Wang T-H, Shieh T-M, Tseng Y-H. Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy. Int J Mol Sci [Internet]. 2019 Jun 16 [cited 2020 Jul 22];20(12). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627879/.
Hashibe M. Risk Factors for Cancer of the Mouth: Tobacco, Betel Quid, and Alcohol. In: Warnakulasuriya S, Greenspan JS, editors. Textbook of Oral Cancer: Prevention, Diagnosis and Management [Internet]. Cham: Springer International Publishing; 2020 [cited 2020 Jul 22]. p. 23–30. (Textbooks in Contemporary Dentistry). Available from: https://doi.org/10.1007/978-3-030-32316-5_3.
Saravanan K, Kodanda Ram M, Ganesh R. Molecular biology of oral sub mucous fibrosis. J Cancer Res Ther. 2013;9(2):179–80.
Garad A, Joshi SB, Naik CS, Ansari A, Mhatre B. ORAL SUB-MUCOUS FIBROSIS. A REVIEW [Internet]. 2018 [cited 2020 Jul 22].
Speight PM, Khurram SA, Kujan O. Oral potentially malignant disorders: risk of progression to malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):612–27.
Seven M, Karatas OF, Duz MB, Ozen M. The role of miRNAs in cancer: from pathogenesis to therapeutic implications. Future Oncol Lond Engl. 2014;10(6):1027–48.
Balatti V, Croce CM. MicroRNA dysregulation and multi-targeted therapy for cancer treatment. Adv Biol Regul. 2020;1:75:100669.
Lajer CB, Nielsen FC, Friis-Hansen L, Norrild B, Borup R, Garnæs E, et al. Different miRNA signatures of oral and pharyngeal squamous cell carcinomas: a prospective translational study. Br J Cancer. 2011;104(5):830–40.
Fukumoto I, Hanazawa T, Kinoshita T, Kikkawa N, Koshizuka K, Goto Y, et al. MicroRNA expression signature of oral squamous cell carcinoma: functional role of microRNA-26a/b in the modulation of novel cancer pathways. Br J Cancer. 2015;112(5):891–900.
Gai C, Camussi F, Broccoletti R, Gambino A, Cabras M, Molinaro L, et al. Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma. BMC Cancer. 2018;18(1):439. https://doi.org/10.1186/s12885-018-4364-z.
Schneider A, Victoria B, Lopez YN, Suchorska W, Barczak W, Sobecka A, et al. Tissue and serum microRNA profile of oral squamous cell carcinoma patients. Sci Rep. 2018;8(1):675.
Scapoli L, Palmieri A, Muzio LL, Pezzetti F, Rubini C, Girardi A, et al. MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. Int J Immunopathol Pharmacol. 2010;23(4):1229–34.
Harrandah AM, Fitzpatrick SG, Smith MH, Wang D, Cohen DM, Chan EKL. MicroRNA-375 as a biomarker for malignant transformation in oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Dec;122(6):743–52.e1.
Kim H, Yang JM, Ahn S-H, Jeong W-J, Chung J-H, Paik JH. Potential oncogenic role and prognostic implication of microRNA-155-5p in oral squamous cell carcinoma. Anticancer Res. 2018;38(9):5193–200.
B L, J C, X J. [Changes of miRNA after oral submucous fibrosis co-cultured with Salvia and low-dose prednisolone]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2014;39(5):471–6.
Cervigne NK, Reis PP, Machado J, Sadikovic B, Bradley G, Galloni NN, et al. Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma. Hum Mol Genet. 2009;18(24):4818–29.
Chattopadhyay E, Singh R, Ray A, Roy R, De Sarkar N, Paul RR, et al. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer. Sci Rep. 2016 Sep;6(1):32735. 6(.
De Sarkar N, Roy R, Mitra JK, Ghose S, Chakraborty A, Paul RR, et al. A quest for miRNA bio-marker: a track back approach from gingivo buccal cancer to two different types of precancers. PLoS ONE. 2014;9(8):e104839.
Yang C-J, Shen WG, Liu C-J, Chen Y-W, Lu H-H, Tsai M-M, et al. miR-221 and miR-222 expression increased the growth and tumorigenesis of oral carcinoma cells: miR-221 and miR-222 in OSCC. J Oral Pathol Med. 2011;40(7):560–6.
Khafaei M, Rezaie E, Mohammadi A, Shahnazi Gerdehsang P, Ghavidel S, Kadkhoda S, et al. miR-9: From function to therapeutic potential in cancer. J Cell Physiol. 2019.
Kim BG, Gao M-Q, Kang S, Choi YP, Lee JH, Kim JE, et al. Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation. Cell Death Dis. 2017;8(3):e2646–e2646.
Tong F, Mao X, Zhang S, **e H, Yan B, Wang B, et al. HPV + HNSCC-derived exosomal miR-9 induces macrophage M1 polarization and increases tumor radiosensitivity. Cancer Lett. 2020;28:34–44.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif. 2001;25(4):402–8.
Khanna JN, Andrade NN. Oral submucous fibrosis: a new concept in surgical management. Report of 100 cases. Int J Oral Maxillofac Surg. 1995 Dec;24(6):433–9.
Chang C-C, Yang Y-J, Li Y-J, Chen S-T, Lin B-R, Wu T-S, et al. MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol. 2013;49(9):923–31.
Acharya S, Singh S, Bhatia S. Role of MicroRNA profiling in oral submucous fibrosis pathogenesis and anticarcinogenic action of curcumin in microRNA dysregulation in oral carcinogenesis: a literature update. Indian J Dental Sci. 2019;11:175–9.
Brito JAR, Gomes CC, Guimarães ALS, Campos K, Gomez RS. Relationship between microRNA expression levels and histopathological features of dysplasia in oral leukoplakia. J Oral Pathol Med. 2014;43(3):211–6.
Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary MicroRNAs for detection of oral cancer. J Dent Res. 2014;93(7_suppl):86S-93S.
Harrandah AM, Fitzpatrick SG, Smith MH, Wang D, Cohen DM, Chan EKL. MicroRNA-375 as a biomarker for malignant transformation in oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(6):743-52.e1.
Mazumder S, Datta S, Ray JG, Chaudhuri K, Chatterjee R. Liquid biopsy: miRNA as a potential biomarker in oral cancer. Cancer Epidemiol. 2019;58:137–45.
Yoon AJ, Wang S, Shen J, Robine N, Philipone E, Oster MW, et al. Prognostic value of miR-375 and miR-214-3p in early-stage oral squamous cell carcinoma. Am J Transl Res. 2014;11(5):580–92
Liu X, Zhang A, **ang J, Lv Y, Zhang X. miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. Oncol Rep. 2016;36(3):1385–92.
Uchida A, Seki N, Mizuno K, Yamada Y, Misono S, Sanada H, et al. Regulation of KIF2A by antitumor miR-451a inhibits cancer cell aggressiveness features in lung squamous cell carcinoma. Cancers. 2019;11(2):258.
Koshizuka K, Hanazawa T, Fukumoto I, Kikkawa N, Matsushita R, Mataki H, et al. Dual-receptor (EGFR and c-MET) inhibition by tumor-suppressive miR-1 and miR-206 in head and neck squamous cell carcinoma. J Hum Genet. 2017;62(1):113–21.
Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, et al. miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127(12):2804–14.
Nohata N, Hanazawa T, Enokida H, Seki N. microRNA-1/133a and microRNA-206/133b clusters: dysregulation and functional roles in human cancers. Oncotarget. 2012;3(1):9–21.
Yang J, Wang H, Xu W, Chen Z. Inhibition of miR-133b indicates poor prognosis and promotes progression of OSCC via SOX4.:10.
Arakeri G, Rai KK, Hunasgi S, Merkx M, a. W, Gao S, Brennan PA. Oral submucous fibrosis: An update on current theories of pathogenesis. J Oral Pathol Med. 2017;46(6):406–12.
Jung JE, Lee JY, Park HR, Kang JW, Kim YH, Lee JH. MicroRNA-133 targets phosphodiesterase 1C in drosophila and human oral cancer cells to regulate epithelial-mesenchymal transition. J Cancer. 2021;12(17):5296–309.
Sharma M, Fonseca FP, Hunter KD, Radhakrishnan R. Loss of oral mucosal stem cell markers in oral submucous fibrosis and their reactivation in malignant transformation. Int J Oral Sci. 2020;12(1):1–10.
He J, **g Y, Li W, Qian X, Xu Q, Li F-S, et al. Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. PLoS ONE. 2013;20(2):e56647.
Ye H, Wang A, Lee B-S, Yu T, Sheng S, Peng T, et al. Proteomic based identification of manganese superoxide dismutase 2 (SOD2) as a metastasis marker for oral squamous cell carcinoma. Cancer Genomics Proteomics. 2008;5(2):85–93.
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Ukey, S., Jain, A., Dwivedi, S. et al. Study of MicroRNA (miR-221-3p, miR-133a-3p, and miR-9-5p) Expressions in Oral Submucous Fibrosis and Squamous Cell Carcinoma. Ind J Clin Biochem 38, 73–82 (2023). https://doi.org/10.1007/s12291-022-01035-x
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DOI: https://doi.org/10.1007/s12291-022-01035-x