Prognostic value of SOX2 in Head and Neck Squamous Cell Carcinomas: Systematic Review




Squamous cell carcinoma; Prognosis; SOX Transcription Factors.


Introduction: head and neck squamous cell carcinoma (HNSCC) is a type of malignant tumor quite common in the world and has worrying survival rates. Therefore, establishing biomarkers, such as SOX2, which is associated with the proliferation of cancer stem cells (CTCs), is important for early detection of the disease, as well as determining the prognosis, which assists in the treatment. Purpose: analyze the performance of SOX2 as a prognostic predictor for HNSCC. Materials and Methods: this is an systematic literature review realized in BVS, PUBMED, Web of Science and SCOPUS databases, based on the strategy “SOX2 AND (oral squamous cell carcinoma OR head and neck squamous cell carcinoma) AND (prognosis OR aggressiveness)”. The final sample consisted of 19 articles. Results: survival data showed divergence between the studies: 10 studies concluded that the greater expression of SOX2 is associated with a good prognosis, while 8 concluded the opposite. 1 article did not show a relationship between the two factors. Data on the occurrence of metastases, mesenchymal epithelial transition, tumor proliferation and invasion were analyzed, resulting in radiotherapy, grade, differentiation and size of the tumor, with divergent notes between studies. Conclusion: the clinical findings point to relationships between SOX2 and the CECP, however, not conclusively. Thus, the literature does not support the use of SOX2 as a prognostic predictor, reinforcing the need to elucidate mechanisms and molecular pathways through which SOX2 influences the progression of cancer.


Al-Hajj, M. & Clarke, M. F. (2004). Self-renewal and solid tumor stem cells. Oncogene, 23, 7274-82.

Attramadal, C., Halstensen, T., Dhakal, H., Ulekleiv, C., Boysen, M., Nesland, J. and Bryne, M. (2014). High nuclear SOX2 expression is associated with radiotherapy response in small (T1/T2) oral squamous cell carcinoma. Journal of Oral Pathology & Medicine, 44(7), pp.515-522.

Avincsal, M., Jimbo, N., Fujikura, K., Shinomiya, H., Otsuki, N., & Morimoto, K. et al. (2018). Epigenetic down-regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers. Histopathology, 72(5), pp.826-837.

Bass, A. J. and Wang, T. C. (2013) An inflammatory situation: SOX2 and Stat3 cooperate in squamous cell carcinoma initiation. Cell Stem Cell, 12(3), pp.266-268.

Baumeister, P., Hollmann, A., Kitz, J., Afthonidou, A., Simon, F., Shakhtour, J., Mack, B., Kranz, Z., Libl, D., Leu, M., Schirmer, M. A., Canis, M., Belka, C., Zitzelsberger, H., Ganswindt, U., Hess, J., Jakob, M., Unger, K., Gires, O. (2018). High Expression of EpCAM and Sox2 is a Positive Prognosticator of Clinical Outcome for Head and Neck Carcinoma. Science Reports, 8(1), 14582.

Bayo, P., Jou, A., Stenzinger, A., Shao, C., Gross, M., Jensen, A., Grabe, N., Mende, C. H., Rados, P. V., Debus, J., Weichert, W., Plinkert, P. K., Lichter, P., Freier, K., Hess, J. (2015). Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma. Molecular Oncology, 9(8), pp.1704-1719.

Bora-Singhal, N., Perumal, D., Nguyen, J. and Chellappan, S. (2015). Gli1-mediated regulation of Sox2 facilitates self-renewal of stem-like cells and confers resistance to egfr inhibitors in non-small cell lung cancer. Neoplasia, 17, pp.538-551

Bochen, F., Adisurya, H., Wemmert, S., Lerner, C., Greiner, M., Zimmermann, R., Hasenfus, A., Wagner, M., Smola, S., Pfuhl, T., Bozzato, A., Al Kadah, B., Schick, B., & Linxweiler, M. (2017). Effect of 3q oncogenes SEC62 and SOX2 on lymphatic metastasis and clinical outcome of head and neck squamous cell carcinomas. Oncotarget, 8(3), pp.4922–4934.

Charafe-Jauffret, E., Ginestier, C., Iovino, F., Tarpin, C., Diebel, M., Esterni, B., Houvenaeghel, G., Extra, J. M., Bertucci, F., Jacquemier, J., Xerri, L., Dontu, G., Stassi, G., Xiao, Y., Barsky, S. H., Birnbaum, D., Viens, P., & Wicha, M. S. (2010). Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 16(1), pp.45–55.

Chiou, S. H., Yu, C. C., Huang, C. Y., Lin, S. C., Liu, C. J., Tsai, T. H., Chou, S. H., Chien, C. S., Ku, H. H., & Lo, J. F. (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research, 14(13), pp.4085–4095.

Chuang, W. Y., Chang, Y. S., Chao, Y. K., Yeh, C. J., Liu, Y. H., Tseng, C. K., Chang, H. K., Wan, Y. L., & Hsueh, C. (2015). High sex determining region Y-box 2 (SOX2) expression correlates with absence of nodal metastasis in esophageal squamous cell carcinoma. International journal of clinical and experimental pathology, 8(8), pp.9248–9255.

Chung, J. H., Jung, H. R., Jung, A. R., Lee, Y. C., Kong, M., Lee, J. S., & Eun, Y. G. (2018). SOX2 activation predicts prognosis in patients with head and neck squamous cell carcinoma. Scientific reports, 8(1), pp.1677.

Corominas-Faja, B., Cufí, S., Oliveras-Ferraros, C., Cuyàs, E., López-Bonet, E., Lupu, R., Alarcón, T., Vellon, L., Iglesias, J. M., Leis, O., Martín, Á. G., Vazquez-Martin, A., & Menendez, J. A. (2013). Nuclear reprogramming of luminal-like breast cancer cells generates Sox2-overexpressing cancer stem-like cellular states harboring transcriptional activation of the mTOR pathway. Cell cycle (Georgetown, Tex.), 12(18), pp.3109–3124.

Costea, D., Tsinkalovsky, O., Vintermyr, O., Johannessen, A. and Mackenzie, I. (2006). Cancer stem cells – new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Diseases, 12, pp.443-454.

Dogan, S., Xu, B., Middha, S., Vanderbilt, C.M., Bowman, A.S., Migliacci, J., Morris, L.G., Seshan, V.E. and Ganly, I. (2019), Identification of prognostic molecular biomarkers in 157 HPV‐positive and HPV‐negative squamous cell carcinomas of the oropharynx. Int. J. Cancer, 145: 3152-3162.

Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., Bray, F. (2015). Incidência e mortalidade por câncer em todo o mundo: fontes, métodos e padrões principais no GLOBOCAN. 2012. Internacional Journal of Cancer. 136: E359-386.

Fu, T. Y., Hsieh, I. C., Cheng, J. T., Tsai, M. H., Hou, Y. Y., Lee, J. H., Liou, H. H., Huang, S. F., Chen, H. C., Yen, L. M., Tseng, H. H., & Ger, L. P. (2016). Association of OCT4, SOX2, and NANOG expression with oral squamous cell carcinoma progression. Journal of oral pathology & medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology, 45(2), pp.89–95.

Galvão, T. F., Pansani, T. S. A., Harrad, D. (2015). Principais itens para relatar Revisões sistemáticas e Meta-análises: A recomendação PRISMA. Epidemiologia e Serviços de Saúde, 24(2), pp.335-342.

Gen, Y., Yasui, K., Nishikawa, T., Yoshikawa, T. (2013). SoX2 promotes tumor growth of esophageal squamous cell carcinoma through the aKt/mammalian target of rapamycin complex 1 signaling pathway. Cancer Sci, 104: pp.810-816.

Agência Internacional de Pesquisa sobre Câncer. Organização Mundial de Saúde. Globocan 2012. Incidência, mortalidade e prevalência estimadas de câncer em todo o mundo em 2012.

Hayashi, H., Higashi, T., Yokoyama, N., Kaida, T., Sakamoto, K., Fukushima, Y., Ishimoto, T., Kuroki, H. Nitta, H., Hashimoto, D., Chikamoto, A., Oki, E., Beppu, O., Baba, H. (2015). An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem Cell-like behaviors contributing to disease progression. Cancer Research. 75:4985–97.

Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M., Bruns, C. J., & Heeschen, C. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell stem cell, 1(3), pp.313–323.

Hussein, A.A., Forouzanfar, T., Bloemena, E., de Vischerr, J. G. A. M., Brakenhoff, R. H., Leemans, C. R., Helder, M. N. (2018) A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma. British Journal of Cancer, 119, pp.724–736.

Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. The Journal of clinical investigation, 119(6), pp.1420–1428.

Kamachi, Y., Uchikawa, M., Kondoh, H. (2000). Emparelhamento SOX off: com parceiros na regulação do desenvolvimento embrionário. Trends Genet, 16, pp.182-187.

Lawson, D. A., Bhakta, N. R., Kessenbrock, K., Prummel, K. D., Yu, Y., Takai, K., Zhou, A., Eyob, H., Balakrishnan, S., Wang, C. Y., Yaswen, P., Goga, A., & Werb, Z. (2015). Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature, 526(7571), pp.131–135.

Li, C., & Wang, J. (2015). Quantifying the Landscape for Development and Cancer from a Core Cancer Stem Cell Circuit. Cancer research, 75(13), pp.2607–2618.

Li, Y., Rogoff, H. A., Keates, S., Gao, Y., Murikipudi, S., Mikule, K., Leggett, D., Li, W., Pardee, A. B., & Li, C. J. (2015). Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proceedings of the National Academy of Sciences of the United States of America, 112(6), pp.1839–1844.

Li, J., Li, Z., Wu, Y., Wang, Y., Wang, D., Zhang, W., Yuan, H., Ye, J., Song, X., Yang, J., Jiang, H., Cheng, J. (2019). The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma. Cell Death Dis, 10, 603.

Li, X., Xu, Y., Chen, Y., Chen, S., Jia, X., Sun, T., Liu, Y., Li, X., Xiang, R., & Li, N. (2013). SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/β-catenin signal network. Cancer letters, 336(2), pp.379–389.

Lim, Y. C., Kang, H. J., Kim, Y. S., Choi, E. C. (2012) All-trans-retinoic acid inhibits growth of head and neck cancer stem cells by suppression of Wnt/β-catenin pathway. European Journal of Cancer, 48, pp.3310-3318.

Liu, X., Qiao, B., Zhao, T., Hu, F., Lam, A. K., & Tao, Q. (2018). Sox2 promotes tumor aggressiveness and epithelial mesenchymal transition in tongue squamous cell carcinoma. International journal of molecular medicine, 42(3), pp.1418–1426.

Lu W., Liu C., Tu H., Chung Y., Yang C., Kao S., Chang K., Lin S. miR-31 targets ARID1A and enhances the oncogenicity and stemness of head and neck squamous cell carcinoma. Oncotarget. 2016; 7: pp.57254-57267.

Lytle, N.K., Barber, A. & Reya, T. (2018). Stem cell fate in cancer growth, progression and therapy resistance. Nature Reviews Cancer, 18, pp. 669–680.

Magnano, M., Bongioannini, G., Lerda, W., Canale, G., Tondolo, E., Bona, M., Viora, L., Gabini, A., & Gabriele, P. (1999). Lymphnode metastasis in head and neck squamous cells carcinoma: multivariate analysis of prognostic variables. Journal of experimental & clinical cancer research : CR, 18(1), 79–83.

Mendes, K. D. S., Silveira, R. C. C. P., Galvão, C. M. (2008). Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto e contexto Enfermagem. 17(4), 758-764.

Michifuri, Y., Hirohashi, Y., Torigoe, T., Miyazaki, A., Kobayashi, J., Sasaki, T., Fujino, J., Asanuma, H., Tamura, Y., Nakamori, K., Hasegawa, T., Hiratsuka, H. and Sato, N. (2012), High expression of ALDH1 and SOX2 diffuse staining pattern of oral squamous cell carcinomas correlates to lymph node metastasis. Pathology International, 62: pp. 684-689.

Muraki, Y., Hasegawa, T., Takeda, D., Ueha, T., Iwata, E., Saito, I., Amano, R., Sakakibara, A., Akashi, M., & Komori, T. (2019). Induced Pluripotent Stem Cell-related Genes Correlate With Poor Prognoses of Oral Squamous Cell Carcinoma. Anticancer research, 39(3), pp.1205–1216.

Muraki, Y., Hasegawa, T., Takeda, D., Ueha, T., Iwata, E., Saito, I., Amano, R., Sakakibara, A., Akashi, M., & Komori, T. (2019). Induced Pluripotent Stem Cell-related Genes Correlate With Poor Prognoses of Oral Squamous Cell Carcinoma. Anticancer research, 39(3), pp. 1205–1216.

Park, I. H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H., Ince, T. A., Lerou, P. H., Lensch, M. W., & Daley, G. Q. (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature, 451(7175), pp.141–146.

Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005). Global cancer statistics, 2002. CA: a cancer journal for clinicians, 55(2), 74–108.

Pedregal-Mallo, D., Hermida-Prado, F., Granda-Díaz, R., Montoro-Jiménez, I., Allonca, E., Pozo-Agundo, E., Álvarez-Fernández, M., Álvarez-Marcos, C., García-Pedrero, J. M., & Rodrigo, J. P. (2020). Prognostic Significance of the Pluripotency Factors NANOG, SOX2, and OCT4 in Head and Neck Squamous Cell Carcinomas. Cancers, 12(7), pp.1794.

Peng, F., Wang, J. H., Fan, W. J., Meng, Y. T., Li, M. M., Li, T. T., Cui, B., Wang, H. F., Zhao, Y., An, F., Guo, T., Liu, X. F., Zhang, L., Lv, L., Lv, D. K., Xu, L. Z., Xie, J. J., Lin, W. X., Lam, E. W., Xu, J., … Liu, Q. (2018). Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene, 37(8), pp.1062–1074.

Pradhan, Sonali, Guddattu, Vasudeva, & Solomon, Monica Charlotte. (2019). Association of the co-expression of SOX2 and Podoplanin in the progression of oral squamous cell carcinomas - an immunohistochemical study. Journal of Applied Oral Science, 27, e20180348.

Rivera C. (2015). Essentials of oral cancer. International journal of clinical and experimental pathology, 8(9), pp. 11884–11894.

Samanta, D., Park, Y., Andrabi, S. A., Shelton, L. M., Gilkes, D. M., Semenza, G. L. (2016). PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis. Cancer Research. 76: 4430–2. 10.1158 / 0008-5472.CAN-16-0530.

Singh, S., Trevino, J., Bora-Singhal, N., Coppola, D., Haura, E., Altiok, S., & Chellappan, S. P. (2012). EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Molecular cancer, 11, 73.

Yao, Z., Du, L., Xu, M., Li, K., Guo, H., Ye, G., Zhang, D., Coppes, R. P., & Zhang, H. (2019). MTA3-SOX2 Module Regulates Cancer Stemness and Contributes to Clinical Outcomes of Tongue Carcinoma. Frontiers in oncology, 9, 816.

de Sousa E Melo, F., Colak, S., Buikhuisen, J., Koster, J., Cameron, K., de Jong, J. H., Tuynman, J. B., Prasetyanti, P. R., Fessler, E., van den Bergh, S. P., Rodermond, H., Dekker, E., van der Loos, C. M., Pals, S. T., van de Vijver, M. J., Versteeg, R., Richel, D. J., Vermeulen, L., & Medema, J. P. (2011). Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell stem cell, 9(5), pp.476–485.

Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), pp. 861–872.

Vaiphei, K., Sinha, S. K., & Kochhar, R. (2014). Comparative analysis of Oct4 in different histological subtypes of esophageal squamous cell carcinomas in different clinical conditions. Asian Pacific journal of cancer prevention: APJCP, 15(8), 3519–3524.

de Vicente, J. C., Donate-Pérez Del Molino, P., Rodrigo, J. P., Allonca, E., Hermida-Prado, F., Granda-Díaz, R., Rodríguez Santamarta, T., & García-Pedrero, J. M. (2019). SOX2 Expression Is an Independent Predictor of Oral Cancer Progression. Journal of clinical medicine, 8(10), 1744.

Wang, H., Zhang, H., Tang, L., Chen, H., Wu, C., Zhao, M., Yang, Y., Chen, X., & Liu, G. (2013). Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis. Toxicology, 303, pp.139–146.

Wilbertz, T., Wagner, P., Petersen, K., Stiedl, A. C., Scheble, V. J., Maier, S., Reischl, M., Mikut, R., Altorki, N. K., Moch, H., Fend, F., Staebler, A., Bass, A. J., Meyerson, M., Rubin, M. A., Soltermann, A., Lengerke, C., & Perner, S. (2011). SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 24(7), pp.944–953.

Wolf, G. T., Winter, W., Bellile, E., Nguyen, A., Donnelly, C. R., McHugh, J. B., Thomas, D., Amlani, L., Rozek, L., Lei, Y. L., & Head and Neck SPORE Program (2018). Histologic pattern of invasion and epithelial-mesenchymal phenotype predict prognosis in squamous carcinoma of the head and neck. Oral oncology, 87, pp.29–35.

Yang, N., Hui, L., Wang, Y., Yang, H., & Jiang, X. (2014). Overexpression of SOX2 promotes migration, invasion, and epithelial-mesenchymal transition through the Wnt/β-catenin pathway in laryngeal cancer Hep-2 cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 35(8), pp.7965–7973.

Yao, Z., Du, L., Xu, M., Li, K., Guo, H., Ye, G., Zhang, D., Coppes, R. P., & Zhang, H. (2019). MTA3-SOX2 Module Regulates Cancer Stemness and Contributes to Clinical Outcomes of Tongue Carcinoma. Frontiers in oncology, 9, 816.

Ye, X., Wu, F., Wu, C., Wang, P., Jung, K., Gopal, K., Ma, Y., Li, L., Lai, R. (2014). β-catenin, a Sox2 binding partner, regulates the dna binding and transcriptional activity of Sox2 in breast cancer cells. Cellular Signalling, 26: pp.492-501.

Yoshihama, R., Yamaguchi, K., Imajyo, I., Mine, M., Hiyake, N., Akimoto, N., Kobayashi, Y., Chigita, S., Kumamaru, W., Kiyoshima, T., Mori, Y., & Sugiura, T. (2016). Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma. Oncology letters, 11(2), pp.1435–1446.

Zheng, H., Pomyen, Y., Hernandez, M. O., Li, C., Livak, F., Tang, W., Dang, H., Greten, T. F., Davis, J. L., Zhao, Y., Mehta, M., Levin, Y., Shetty, J., Tran, B., Budhu, A., & Wang, X. W. (2018). Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology (Baltimore, Md.), 68(1), pp.127–140.

Züllig, L., Roessle, M., Weber, C., Graf, N., Haerle, S. K., Jochum, W., Stoeckli, S. J., Moch, H., Huber, G. F. (2013). High sex determining region Y-box 2 expression is a negative predictor of occult lymph node metastasis in early squamous cell carcinomas of the oral cavity. European Journal of Cancer, 49 : pp.1915-1922.



How to Cite

Oliveira, F. J. D. de, Costa, L. L., Sousa, L. C. de, Amancio, A. de M., Silva, G. G. da, Pinheiro, J. C., Silva Filho, P. S. F. da, Brasil, G. M. L. C. ., Jales, J. M. R. ., Oliveira, D. J. D. de, & Paiva, D. F. F. (2020). Prognostic value of SOX2 in Head and Neck Squamous Cell Carcinomas: Systematic Review. Research, Society and Development, 9(9), e587997722.



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