Differential expression of hsa_circ_0064357 and hsa_circ_0064358 between oral squamous cell carcinoma and oral lichen planus


  • Roxana Naderi Department of Biology, Faculty of Basic Sciences, East Tehran Branch (Ghiamdasht), Islamic Azad University, Tehran, Iran
  • Faranak Jamshidian Department of Biology, Faculty of Basic Sciences, East Tehran Branch (Ghiamdasht), Islamic Azad University, Tehran, Iran. *Corresponding author, Email: faranak.jamshidian@gmail.com




hsa_circ_0064357, hsa_circ_0064358, OSCC, OLP, RAF1 gene


Background/aims: Reliable biomarkers with high specificity and sensitivity and the potential to discriminate precancerous or early lesions from oral cancer improve scientific assessment and early detection. Dysregulated circRNAs play a critical role in the occurrence and progression of malignant biological behaviors of OSCC. The study of potential diagnostic roles of hsa_circ_0064357 and hsa_circ_0064358 in early diagnostic of precancerous lesions such as OLP to OSCC as the most common type of head-and-neck squamous cell carcinoma (HNSCC) was the focus of present research. Methods: The differential expression of hsa_circ_0064357, hsa_circ_0064358, and RAF1 target gene predicted using CircInteractome and Circbase databases between OSCC (n=30), OLP (n=10) tissues and their adjacent normal tissues were evaluated by qRT-PCR. The potential diagnostic value of circRNAs was identified by receiver operating characteristic (ROC) curve analysis. Results: hsa_circ_0064357 and hsa_circ_0064358 were identified to be lowly expressed, while RAF1 was upregulated in OSCC and OLP tissues more than adjacent normal tissues. Low expression of circRNAs was markedly correlated with TNM stages of OSCC patients. ROC analysis revealed AUC of 0.962 and 0.965 for hsa_circ_0064357 and hsa_circ_0064358, respectively, suggesting that circRNAs can serve as novel diagnostic biomarkers for early detection of OSCC. Conclusion: hsa_circ_0064357 and hsa_circ_0064358 might be involved in the progression and metastasis of OSCC and could be used as promising novel biomarkers for early diagnosis and the clinical monitoring of the malignant transformation of OLP into OSCC.


Ali, K. (2022). Oral cancer - the fight must go on against all odds. Evid Based Dent, 23, 4-5.

Biswas, N.K., Das, C., Das, S., Maitra, A., Nair, S., Gupta, T., D'Cruz, A.K., Sarin, R., & Majumder. P.P. (2019). Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects. Int J Cancer, 145, 2568-2579.

Biswas, N.K., Das, C., Das, S., Maitra, A., Nair, S., Gupta, T., D'Cruz, A.K., Sarin, R., & Majumder, P.P. (2019). Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects. Int J Cancer, 145, 2568-2579.

Borovski, T., Vellinga, T.T., Laoukili, J., Santo, E.E., Fatrai, S., van Schelven, S., Verheem, A., Marvin, D.L., Ubink. I., Borel Rinkes, I.H.M., & Kranenburg, O. (2017). Inhibition of RAF1 kinase activity restores apicobasal polarity and impairs tumor growth in human colorectal cancer. Gut, 66,1106–1115.

Chen, L., Zhang, S., Wu, J., Cui, J., Zhong, L., Zeng, L., & Ge, S. (2017). circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene, 36,4551-4561.

Cheng, Y., Chen, J., Shi, Y., Fang, X., & Tang, Z. (2022). MAPK Signaling Pathway in Oral Squamous Cell Carcinoma: Biological Function and Targeted Therapy. Cancers,14,4625.

Deng, W., Peng, W., Wang, T., Chen, J., Qiu, X., Fu, L., & Zhu, S. (2019). Microarray profile of circular RNAs identifies hsa_circRNA_102459 and hsa_circRNA_043621 as important regulators in oral squamous cell carcinoma. Oncol Rep,42, 2738-2749.

Dou, Z., Gao, L., Ren, W., Zhang, H., Wang, X., Li, S., Zheng, J., Kong, X., Chi, P., & Zhi, K. (2020). CiRS-7 functions as a ceRNA of RAF-1/PIK3CD to promote metastatic progression of oral squamous cell carcinoma via MAPK/AKT signaling pathways. Exp Cell Res,396,112290.

Ferlini, A., Scotton, C., & Novelli, G. (2013). Biomarkers in rare diseases. Public Health Genom,16, 313-21.

Garlapati, P., Ling, J., Chiao P.J., & Fu, J. (2021). Circular RNAs regulate cancer-related signaling pathways and serve as potential diagnostic biomarkers for human cancers. Cancer Cell Int, 21,317.

Gollob, J.A., Wilhelm, S., Carter, C., & Kelley, S.L. (2006). Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33, 392-406.

Guo, Y.J., Pan, W.W., Liu, S.B., Shen, Z.F., Xu, Y., & Hu, L.L. (2020). ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med, 19, 1997-2007.

Huang, L., Pei, T., Wu, G., Liu, J., Pan, W., & Pan, X. (2022). Circular RNAs as a Diagnostic Biomarker in Oral Squamous Cell Carcinoma: A Meta-Analysis. J Oral Maxillofac Surg, 80, 756-766.

Jahangiri, F., Farahani, S., & Jamshidian, F. (2022). Diagnostic and Prognostic Value of miR-4789-5p, miR-3941, circ_0045638 and circ_0045639 in Malignant Transformation of Oral Lichen Planus and OSCC. Egypt. Acad. J. Biol. Sci. C, Physi. Mol. Biol, 14,451-463.

Kordi-Tamandani, D.M., Saberi, E., Jamali, S., & Ladiz, M.A. (2014). ERK and RAF1 genes: analysis of methylation and expression profiles in patients with oral squamous cell carcinoma. Br J Biomed Sci,71,100-3.

Kristensen, L.S., Jakobsen, T., Hager, H., & Kjems, J. (2022). The emerging roles of circRNAs in cancer and oncology. Nat Rev Clin Oncol,19,188-206.

Li, B., Wang, F., Li, X., Sun, S., Shen, Y., & Yang, H. (2018). Hsa_circ_0008309 May Be a Potential Biomarker for Oral Squamous Cell Carcinoma. Dis Markers,23,7496890.

Li, Y., Pan, M., Lu, T., Dan, Y., Chuan, L., Zhihai, W., & Guohua, H. (2022). RAF1 promotes lymphatic metastasis of hypopharyngeal carcinoma via regulating LAGE1: experimental research. J Transl Med,255,1-23.

Lin, N.C., Hsien, S.I., Hsu, J.T., & Chen, M.Y.C. (2021). Impact on patients with oral squamous cell carcinoma in different anatomical subsites: a single-center study in Taiwan. Sci Rep, 11, 15446.

Livak, K.J., & Schmittgen, T.D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25,402-8.

Loud, J.T., & Murphy, J. (2017). Cancer Screening and Early Detection in the 21st Century. Semin Oncol Nurs, 33, 121-128.

Meng, S., Zhou, H., Feng, Z., Xu, Z., Tang, Y., Li, P., & Wu. M. (2017). CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer,16,94.

Pindborg, J.J., Reichart, P.A., Smith, C.J., & Van der Waal, I. (1997). World Health Organization: Histological Typing of Cancer and Precancer of the Oral Mucosa. 2ndED., Springer-Verlag, Berlin, Heidelberg, New York, pp. 75

Ren, G., Liu, X., Mao, X., Zhang, Y., Stankiewicz, E., Hylands, L., Song, R., Berney, D.M., Clark, J., Cooper, C., & Lu, Y.J. (2012). Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. Genes Chromosomes Cancer,51,1014–1023.

Slattery, M.L., Lundgreen, A., & Wolff, R.K. (2012). MAP kinase genes and colon and rectal cancer. Carcinogenesis,33,2398–2408.

Su, W., Sun, S., Wang, F., Shen, Y., & Yang, H. (2019). Circular RNA hsa_circ_0055538 regulates the malignant biological behavior of oral squamous cell carcinoma through the p53/Bcl-2/caspase signaling pathway. J Transl Med, 17, 76.

Tampa, M., Caruntu, C., Mitran, M., Mitran, C., Sarbu, I., Rusu, L.C., Matei, C., Constantin, C., Neagu, M., & Georgescu S.R. (2018). Markers of Oral Lichen Planus Malignant Transformation. Dis Markers, 2018,1959506.

Tian, H., Yin, L., Ding, K., Xia, Y.Y., Wang, X.H., Wu, J.Z., & He, X. (2018). Raf1 is a prognostic factor for progression in patients with non small cell lung cancer after radiotherapy. Oncol Rep, 39, 1966-1974.

Tsushima, F., Sakurai, J., Uesugi, A., Oikawa, Y., Ohsako, T., Mochizuki, Y., Hirai, H., Kayamori, K., & Harada, H. (2021). Malignant transformation of oral lichen planus: a retrospective study of 565 Japanese patients. BMC Oral Health,21,298.

Wang, F., Jiang, C., Sun, Q., Yan, F., Wang, L., Fu, Z., Liu, T., & Hu, F. (2015). miR-195 is a key regulator of Raf1 in thyroid cancer. Onco Targets Ther,8,3021-3028.

Wang, L., Wei, Y., Yan, Y., Wang, H., Yang, J., Zheng, Z., Zha, J., Bo, P., Tang, Y., Guo, X., Chen, W., Zhu, X., & Ge, L. (2018). CircDOCK1 suppresses cell apoptosis via inhibition of miR 196a 5p by targeting BIRC3 in OSCC. Oncol Rep,39,951-966.

Wang, M., Zhang, L., Ren, W., Li, S., Zhi, K., Zheng, J., & Gao, L. (2021). Diagnostic Value of CircRNAs as Potential Biomarkers in Oral Squamous Cell Carcinoma: a Meta-Analysis. Front Oncol,11,693284.

Wang, Y.F., Li, B.W., Sun, S., Li, X., Su, W., Wang, Z.H., Wang, F., Zhang, W., & Yang, H.Y. (2018). Circular RNA Expression in Oral Squamous Cell Carcinoma. Front Oncol, 8,398.

Xu, Y., Jiang, E., Shao, Z., & Shang, Z. (2021). Long Noncoding RNAs in the Metastasis of Oral Squamous Cell Carcinoma. Front Oncol, 10, 616717.

Xue, C., Li, G., Lu, J., & Lanjuan, L. (2021). Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Sig Transduct. Target. Ther,6,400.

Yardimci, G., Kutlubay, Z., Engin, B., & Tuzun, Y. (2014). Precancerous lesions of oral mucosa. World J Clin Cases, 2, 866-872.

Zendehdel, K. (2021). Cancer Statistics in I.R. Iran in 2020. Basic Clin Cancer Res, 12, 159-165.

Zhang, B., Li, F., Zhu, Z., Ding, A., & Luo, J. (2020). CircRNA CDR1as/miR-1287/Raf1 Axis Modulates Hepatocellular Carcinoma Progression Through MEK/ERK Pathway. Cancer Manag Res,12,8951-8964.

Zhang, H., Shen, Y., Zhang, B., Qian, M., Zhang, Y., & Yang, H. (2020). Hsa_circ_0003829 serves as a potential diagnostic predictor for oral squamous cell carcinoma. J Int Med Res,48,300060520936880.

Zhou, P., Xie, W., Huang, H.L., Huang, R.Q., Tian, C., Zhu, H.B., Dai, Y.H., & Li, Z.Y. (2020). circRNA_100859 functions as an oncogene in colon cancer by sponging the miR-217-HIF-1α pathway. Aging,12,13338–13353.

Zhu, X., Shao, P., Tang, Y., Shu, M., Hu, W.W., & Zhang, Y. (2019). hsa_circRNA_100533 regulates GNAS by sponging hsa_miR_933 to prevent oral squamous cell carcinoma. J Cell Biochem,120,19159-19171.






Research article