口腔癌在台灣為男性癌症死亡率第四名並且是年輕男性中第一名的癌症。在台灣最常發生的口腔癌部位為口腔舌頭和頰黏膜。癌症幹細胞和腫瘤發生及預後有關。而癌症幹細胞的形成與誘導多功能幹細胞的重新引導因子有關。本研究的目的是探討三個重新引導因子：Octamer-binding Protein 4 (Oct4)、Sex-determining Region Y (SRY)-related Box 2 (Sox2)與Nanog的蛋白質表現程度與口腔舌頭與頰黏膜鱗狀上皮細胞癌之腫瘤發生、臨床病理特性和存活率之間的相關性。利用免疫組織化學染色法檢測組織晶片中Oct4、Sox2和Nanog的表現程度。我們比較Oct4、Sox2和Nanog在正常組織、腫瘤鄰近正常組織及腫瘤組織中的表現程度。發現口腔的舌頭與頰黏膜鱗狀上皮細胞癌中Oct4、Sox2的表現程度顯著地低於腫瘤鄰近正常組織或正常組織，但頰黏膜鱗狀上皮細胞癌中Oct4的表現除外。然而，Nanog-C在口腔舌頭與頰黏膜鱗狀上皮細胞癌則顯著高於腫瘤鄰近正常組織與正常組織。我們檢測248個口腔舌頭鱗狀上皮細胞癌檢體中的Oct4、Sox2、Nanog-N和Nanog-C之中位表現量分別為40、2.50、0和及90。另外，而在188個頰黏膜鱗狀上皮細胞癌中Oct4、Sox2、Nanog-N和Nanog-C的中位表現量則分別為73.75、 4.75、 0及63.75。我們也發現當腫瘤從早期進展到晚期時Oct4、Sox2和Nanog的表現程度都逐漸下降。然而，經過校正臨床病理因素之後發現Sox2蛋白表現量高和延長口腔舌頭鱗癌患者特定疾病存活率具顯著性相關。本研究之結論顯示，除了頰黏膜鱗狀上皮細胞癌中Oct4之外，Oct4、Sox2和Nanog-C可能可作為口腔舌頭與頰黏膜鱗狀上皮細胞癌的腫瘤發生的生物標誌，而Sox2可能是口腔舌頭鱗狀上皮細胞癌的一個預後生物標誌。

In Taiwan, oral cancer is the 4th leading cause of cancer death for males and the top common cancer in young adult males. The most common subsites of oral cancer are the tongue and buccal mucosa in Taiwan. Cancer stem cells (CSCs) have been implicated in tumorigenesis and prognosis. Reprogramming factors employed to induce pluripotent stem cells are associated with CSCs formation. The purpose of this study was to investigate the relationship of the protein expression levels of three reprogramming factors, Octamer-binding Protein 4 (Oct4), Sex-determining Region Y (SRY)-related Box 2 (Sox2), and Nanog, with the tumorigenesis, clinicopathological outcomes and survival in oral tongue SCC and buccal mucosal SCC. Expression levels of Oct4, Sox2, and Nanog were evaluated by immunohistochemistry using tissue microarray slides. We compare the expression levels of the Oct4, Sox2, Nanog-N, and Nanog-C in normal, tumor adjacent normal, and tumor tissues by subsites of oral tongue and buccal mucosa. The expression levels of both Oct4 and Sox2 in oral tongue SCC and buccal mucosal SCC were significantly lower than those in the tumor adjacent normal tissue or normal tissue, except that for Oct4 in buccal mucosal SCC. However, the expression level of Nanog-C in oral tongue SCC and buccal mucosal SCC was significantly higher than those in the tumor adjacent normal tissue and normal tissue. Our IHC results showed that the median expression levels of Oct4, Sox2, Nanog-N, and Nanog-C were 40, 2.50, 0, and 90 in 248 oral tongue SCC specimens, respectively. In addition, the median expression levels of Oct4, Sox2, Nanog-N, and Nanog-C were 73.75, 4.75, 0, and 63.75 in 188 buccal mucosal SCC specimens, respectively. The expression levels of Oct4, Sox2, and Nanog-C gradually decreased when tumor progressed from early stage and advanced stage (AJCC pathological stage, T stage, or N stage). After adjustment of clinicopathologic outcomes, our results showed a significant association between the elevated Sox2 expression and prolonged disease-specific survival in oral tongue SCC. In conclusion, Oct4, Sox2, and Nanog-C could be biomarkers for tumorigenesis in both oral tongue SCC and buccal mucosal SCC, except for Oct4 in buccal mucosal SCC. Additionally, Sox2 might be a prognostic biomarker for oral tongue SCC.

Abstract in Chinese………………………………………….....i-ii
Abstract in Engilsh……………………………………………..iii-iv
Contents………………………………………………………...v-vi
Abbreviations……………………………………………….......vii

Introduction
1.Epidemiology of Oral Cancer……………..................................1
2.Epidemiology of Oral Tongue Squamous Cell Carcinoma…….2
3.Epidemiology of Buccal Mucosal Squamous Cell Carcinoma...2
4.Stem cell and Cancer stem cells (CSCs).……………………...3-7
Octamer-binding Protein 4 (Oct4)……………………………….5
Sex-determining Region Y (SRY)-related Box 2 (Sox2)..........5-6
Nanog……………………………………………………………....6
Specific Aims………………………………………………………....8
Materials and Methods..……………………………………………9-11
Results
1. The demographic and clinicopathologic characteristics and their impact on survival of patients with oral tongue SCC…............12-13
2. The demographic and clinicopathologic characteristics and their impact on survival of patients with buccal mucosal SCC…….13-14
3. The expression levels of Oct4, Sox2, and Nanog in normal tissue, tumor adjacent normal tissue and tumor tissue……....14-17
4. The association of the expression levels of Oct4, Sox2, and Nanog with the clinicopathological outcomes and survival of patients with oral tongue SCC..................................................17-18
5. The association of the expression levels of Oct4, Sox2, and Nanog with the clinicopathological outcomes and survival of patients with buccal mucosal SCC…………………………...18-19
Discussion……………………………………………………….20-23
Conclusion…………………………………………………………..24
References………………………………………………………25-32
Tables……………………………………………………………33-40
Figures……………………………………………………………41-53
Indexes…………..................................................................54-58
Future perspectives……………………………………………….59

Alatzoglou, K.S., Kelberman, D., and Dattani, M.T. (2009). The role of SOX proteins in normal pituitary development. J Endocrinol 200, 245-258.
Ambrosetti, D.C., Basilico, C., and Dailey, L. (1997). Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol 17, 6321-6329.
Bass, A.J., Watanabe, H., Mermel, C.H., Yu, S., Perner, S., Verhaak, R.G., Kim, S.Y., Wardwell, L., Tamayo, P., Gat-Viks, I., et al. (2009). SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41, 1238-1242.
Behbod, F., and Rosen, J.M. (2005). Will cancer stem cells provide new therapeutic targets? Carcinogenesis 26, 703-711.
Ben-David, U., and Benvenisty, N. (2011). The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11, 268-277.
Bernier, J., and Cooper, J.S. (2005). Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist 10, 215-224.
Bjerkvig, R., Tysnes, B.B., Aboody, K.S., Najbauer, J., and Terzis, A.J. (2005). Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 5, 899-904.
Botquin, V., Hess, H., Fuhrmann, G., Anastassiadis, C., Gross, M.K., Vriend, G., and Scholer, H.R. (1998). New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes Dev 12, 2073-2090.
Bourguignon, L.Y., Wong, G., Earle, C., and Chen, L. (2012). Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem 287, 32800-32824.
Cancer Registry annual Report in Taiwan Area, 2010. Taipei: Department of Health. The Executive Yuan, Taiwan ROC 2013.
Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., and Smith, A. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655.
Chambers, I., and Tomlinson, S.R. (2009). The transcriptional foundation of pluripotency. Development 136, 2311-2322.
Chan, Y.S., Yang, L., and Ng, H.H. (2011). Transcriptional regulatory networks in embryonic stem cells. Prog Drug Res 67, 239-252.
Charafe-Jauffret, E., Monville, F., Ginestier, C., Dontu, G., Birnbaum, D., and Wicha, M.S. (2008). Cancer stem cells in breast: current opinion and future challenges. Pathobiology 75, 75-84.
Chen, D., Yang, K., Zhang, G., Mei, J., and Xiang, L. (2011). Screen and analysis of key disease genes for precancerous lesions of oral buccal mucosa induced by DMBA in golden hamsters. Oncol Lett 2, 265-271.
Chen, Y.K., Huang, H.C., Lin, L.M., and Lin, C.C. (1999). Primary oral squamous cell carcinoma: an analysis of 703 cases in southern Taiwan. Oral oncology 35, 173-179.
Chhetri, D.K., Rawnsley, J.D., and Calcaterra, T.C. (2000). Carcinoma of the buccal mucosa. Otolaryngol Head Neck Surg 123, 566-571.
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., and Lo, J.F. (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14, 4085-4095.
Cozzio, A., Passegue, E., Ayton, P.M., Karsunky, H., Cleary, M.L., and Weissman, I.L. (2003). Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17, 3029-3035.
Dalerba, P., Cho, R.W., and Clarke, M.F. (2007). Cancer stem cells: models and concepts. Annu Rev Med 58, 267-284.
Dean, M., Fojo, T., and Bates, S. (2005). Tumour stem cells and drug resistance. Nat Rev Cancer 5, 275-284.
Ding, J., Xu, H., Faiola, F., Ma’ayan, A., and Wang, J.(2012). Oct4 links multiple epigenetic pathways to the pluripotency network. Cell Research 22:155-167.
Dong, Z., Zeng, Q., Luo, H., Zou, J., Cao, C., Liang, J., Wu, D., and Liu, L. (2012). Increased expression of OCT4 is associated with low differentiation and tumor recurrence in human hepatocellular carcinoma. Pathol Res Pract 208, 527-533.
Dontu, G., Al-Hajj, M., Abdallah, W.M., Clarke, M.F., and Wicha, M.S. (2003). Stem cells in normal breast development and breast cancer. Cell Prolif 36 Suppl 1, 59-72.
Du, L., Yang, Y., Xiao, X., Wang, C., Zhang, X., Wang, L., Zhang, X., Li, W., Zheng, G., Wang, S., et al. (2011). Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral oncology 47, 709-713.
Efferth, T. (2012). Stem cells, cancer stem-like cells, and natural products. Planta Med 78, 935-942.
Fabian, A., Barok, M., Vereb, G., and Szollosi, J. (2009). Die hard: are cancer stem cells the Bruce Willises of tumor biology? Cytometry A 75, 67-74.
Fang, C., Liu, S., Sheng, Z., Li, Z., and Tang, F. (1997). [Study on the cytotoxic and DNA damaging effects in oral mucosal fibroblasts by areca nut extract]. Hunan Yi Ke Da Xue Xue Bao 22, 105-108.
Feinberg, A.P., Ohlsson, R., and Henikoff, S. (2006). The epigenetic progenitor origin of human cancer. Nat Rev Genet 7, 21-33.
Feldman, B., Poueymirou, W., Papaioannou, V.E., DeChiara, T.M., and Goldfarb, M. (1995). Requirement of FGF-4 for postimplantation mouse development. Science 267, 246-249.
Freier, K., Knoepfle, K., Flechtenmacher, C., Pungs, S., Devens, F., Toedt, G., Hofele, C., Joos, S., Lichter, P., and Radlwimmer, B. (2010). Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma. Genes Chromosomes Cancer 49, 9-16.
Fu, T.Y., Hou, Y.Y., Chu, S.T., Liu, C.F., Huang, C.H., Chen, H.C., Hsiao, M., Lu, P.J., Wang, J.S., and Ger, L.P. (2011). Manganese superoxide dismutase and glutathione peroxidase as prognostic markers in patients with buccal mucosal squamous cell carcinomas. Head & neck 33, 1606-1615.
Gao, F., Kwon, S.W., Zhao, Y., and Jin, Y. (2009). PARP1 poly(ADP-ribosyl)ates Sox2 to control Sox2 protein levels and FGF4 expression during embryonic stem cell differentiation. J Biol Chem 284, 22263-22273.
Garraway, L.A., and Sellers, W.R. (2006). Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 6, 593-602.
Ge, N., Lin, H.X., Xiao, X.S., Guo, L., Xu, H.M., Wang, X., Jin, T., Cai, X.Y., Liang, Y., Hu, W.H., et al. (2010). Prognostic significance of Oct4 and Sox2 expression in hypopharyngeal squamous cell carcinoma. J Transl Med 8, 94.
Goel, S., Fujihara1, M., Minami, N., Yamada1, M., and Imai, H. (2008). Expression of NANOG, but not POU5F1, points to the stem cell potential of primitive germ cells in neonatal pig testis. Reproduction 135, 785–795.
Gontan, C., de Munck, A., Vermeij, M., Grosveld, F., Tibboel, D., and Rottier, R. (2008). Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Dev Biol 317, 296-309.
Graziano, A., d'Aquino, R., Tirino, V., Desiderio, V., Rossi, A., and Pirozzi, G. (2008). The stem cell hypothesis in head and neck cancer. J Cell Biochem 103, 408-412.
Herr, W., and Cleary, M.A. (1995). The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev 9, 1679-1693.
Huang, C.H., Chu, S.T., Ger, L.P., Hou, Y.Y., and Sun, C.P. (2007). Clinicopathologic evaluation of prognostic factors for squamous cell carcinoma of the buccal mucosa. J Chin Med Assoc 70, 164-170.
Hussenet, T., and du Manoir, S. (2010). SOX2 in squamous cell carcinoma: amplifying a pleiotropic oncogene along carcinogenesis. Cell Cycle 9, 1480-1486.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., and Thun, M.J. (2008). Cancer statistics, 2008. CA Cancer J Clin 58, 71-96.
Jordan, C.T., Guzman, M.L., and Noble, M. (2006). Cancer stem cells. N Engl J Med 355, 1253-1261.
Kademani, D., Bell, R.B., Schmidt, B.L., Blanchaert, R., Fernandes, R., Lambert, P., Tucker, W.M. (2008). Oral and maxillofacial surgeons treating oral cancer: a preliminary report from the American Association of Oral and Maxillofacial Surgeons Task Force on Oral Cancer. J Oral Maxillofac Surg 66, 2151-2157.
Kamachi, Y., Uchikawa, M., and Kondoh, H. (2000). Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet 16, 182-187.
Kao, S.Y., Chu, Y.W., Chen, Y.W., Chang, K.W., and Liu, T.Y. (2009). Detection and screening of oral cancer and pre-cancerous lesions. J Chin Med Assoc 72, 227-233.
Ko, Y.C., Huang, Y.L., Lee, C.H., Chen, M.J., Lin, L.M., and Tsai, C.C. (1995). Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med 24, 450-453.
Krivtsov, A.V., Twomey, D., Feng, Z., Stubbs, M.C., Wang, Y., Faber, J., Levine, J.E., Wang, J., Hahn, W.C., Gilliland, D.G., Golub, T. R., and Armstrong, S. A. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818-822.
Lagadec, C., Vlashi, E., Della Donna, L., Dekmezian, C., and Pajonk, F. (2012). Radiation-induced reprogramming of breast cancer cells. Stem cells 30, 833-844.
Lee, H.E., Kim, J.H., Kim, Y.J., Choi, S.Y., Kim, S.W., Kang, E., Chung, I.Y., Kim, I.A., Kim, E.J., Choi, Y., et al. (2011). An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 104, 1730-1738.
Leis, O., Eguiara, A., Lopez-Arribillaga, E., Alberdi, M.J., Hernandez-Garcia, S., Elorriaga, K., Pandiella, A., Rezola, R., and Martin, A.G. (2012). Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 31, 1354-1365.
Li, X., Wang, J., Xu, Z., Ahmad, A., Li, E., Wang, Y., Qin, S., and Wang, Q. (2012). Expression of sox2 and oct4 and their clinical significance in human non-small-cell lung cancer. Int J Mol Sci 13, 7663-7675.
Liang, J., Wan, M., Zhang, Y., Gu, P., Xin, H., Jung, S.Y., Qin, J., Wong, J., Cooney, A.J., Liu, D., et al. (2008). Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol 10, 731-739.
Lin, C.S., Jen, Y.M., Cheng, M.F., Lin, Y.S., Su, W.F., Hwang, J.M., Chang, L.P., Chao, H.L., Liu, D.W., Lin, H.Y., et al. (2006). Squamous cell carcinoma of the buccal mucosa: an aggressive cancer requiring multimodality treatment. Head & neck 28, 150-157.
Liu, S., Dontu, G., and Wicha, M.S. (2005). Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7, 86-95.
Liu, Y., Zhang, C., Fan, J., Xiao, L., Yin, B., Zhou, L., and Xia, S. (2011). Comprehensive analysis of clinical significance of stem-cell related factors in renal cell cancer. World J Surg Oncol 9, 5.
Loh, Y.H., Wu, Q., Chew, J.L., Vega, V.B., Zhang, W., Chen, X., Bourque, G., George, J., Leong, B., Liu, J., et al. (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38, 431-440.
Lu, Y., Futtner,C., Jason R. Rock, Xia Xu, Walter Whitworth, Brigid L. M. Hogan, and Onaitis, M.W. (2010). Evidence That SOX2 Overexpression Is Oncogenic in the Lung. PLoS ONE /journalpone 5, e11022.
Luo, W., Li, S., Peng, B., Ye, Y., Deng, X., Yao, K. (2013). Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma. PLoS ONE /journalpone 8, e56324.
Massano, J., Regateiro, F.S., Januario, G., and Ferreira, A. (2006). Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102, 67-76.
Meng, H.M., Zheng, P., Wang, X.Y., Liu, C., Sui, H.M., Wu, S.J., Zhou, J., Ding, Y.Q., and Li, J.M. (2010). Overexpression of nanog predicts tumor progression and poor prognosis in colorectal cancer. Cancer biology & therapy 9, 295-302.
Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M., and Yamanaka, S. (2003). The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631-642.
Molyneux, G., Regan, J., and Smalley, M.J. (2007). Mammary stem cells and breast cancer. Cell Mol Life Sci 64, 3248-3260.
Myers, J.N., Elkins, T., Roberts, D., and Byers, R.M. (2000). Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol Head Neck Surg 122, 44-51.
Nakshatri, H., Srour, E.F., and Badve, S. (2009). Breast cancer stem cells and intrinsic subtypes: controversies rage on. Curr Stem Cell Res Ther 4, 50-60.
Navarro, P., Festuccia, N., Colby, D., Gagliardi, A., Mullin, N.P., Zhang, W., Karwacki-Neisius, V., Osorno, R., Kelly, D., Robertson, M., et al. (2012). OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J 31, 4547-4562.
Nishimoto, M., Fukushima, A., Okuda, A., and Muramatsu, M. (1999). The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol 19, 5453-5465.
Niswander, L., and Martin, G.R. (1992). Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 114, 755-768.
Niwa, H., Miyazaki, J., and Smith, A.G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-376.
Ogura, A., Watanabe, Y., Iizuka, D., Yasui, H., Amitani, M., Kobayashi, S., Kuwabara, M., and Inanami, O. (2008). Radiation-induced apoptosis of tumor cells is facilitated by inhibition of the interaction between Survivin and Smac/DIABLO. Cancer Lett 259, 71-81.
Pan, G., and Thomson, J.A. (2007). Nanog and transcriptional networks in embryonic stem cell Pluripotency. Cell Research 17: 42-49.
Pardo, M., Lang, B., Yu, L., Prosser, H., Bradley, A., Babu, M.M., and Choudhary, J. (2010). An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 6, 382-395.
Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2005). Global cancer statistics, 2002. CA Cancer J Clin 55, 74-108.
Pei, D. (2009). Regulation of pluripotency and reprogramming by transcription factors. J Biol Chem 284, 3365-3369.
Pesce, M., and Scholer, H.R. (2000). Oct-4: control of totipotency and germline determination. Mol Reprod Dev 55, 452-457.
Pesce, M., and Scholer, H.R. (2001). Oct-4: gatekeeper in the beginnings of mammalian development. Stem cells 19, 271-278.
Petersen, P.E. (2005). Strengthening the prevention of oral cancer: the WHO perspective. Community Dent Oral Epidemiol 33, 397-399.
Phillips, T.M., McBride, W.H., and Pajonk, F. (2006). The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98, 1777-1785.
Poppe, S.M., Marks, T.A., and Renis, H.E. (1989). Bropirimine-induced embryolethality after oral administration to the pregnant rat. Fundam Appl Toxicol 13, 87-101.
Reya, T., Morrison, S.J., Clarke, M.F., and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105-111.
Regenerative Medicine 2006, Chapter 9: Are Stem Cells Involved in Cancer? Charles A. Goldthwaite, Jr., PhD. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2011, p89-p95.
Rodda, D.J., Chew, J.L., Lim, L.H., Loh, Y.H., Wang, B., Ng, H.H., and Robson, P. (2005). Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280, 24731-24737.
Rodgers, G.K., and Myers, E.N. (1988). Surgical management of the mass in the buccal space. Laryngoscope 98, 749-753.
Sakurai, M., Miki, Y., Masuda, M., Hata, S., Shibahara, Y., Hirakawa, H., Suzuki, T., and Sasano, H. (2012). LIN28: a regulator of tumor-suppressing activity of let-7 microRNA in human breast cancer. J Steroid Biochem Mol Biol 131, 101-106.
Scaffidi, P., and Bianchi, M.E. (2001). Spatially precise DNA bending is an essential activity of the sox2 transcription factor. J Biol Chem 276, 47296-47302.
Scholer, H.R. (1991). Octamania: the POU factors in murine development. Trends Genet 7, 323-329.
Schulenburg, A., Ulrich-Pur, H., Thurnher, D., Erovic, B., Florian, S., Sperr, W.R., Kalhs, P., Marian, B., Wrba, F., Zielinski, C.C.,and Valent, P. (2006). Neoplastic stem cells: a novel therapeutic target in clinical oncology. Cancer 107, 2512-2520.
Shi, G., and Jin, Y. (2010). Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther 1, 39.
Silva, J., Nichols, J., Theunissen, T.W., Guo, G., van Oosten, A.L., Barrandon, O., Wray, J., Yamanaka, S., Chambers, I., and Smith, A. (2009). Nanog is the gateway to the pluripotent ground state. Cell 138, 722-737.
Simoes, B.M., Piva, M., Iriondo, O., Comaills, V., Lopez-Ruiz, J.A., Zabalza, I., Mieza, J.A., Acinas, O., and Vivanco, M.D. (2011). Effects of estrogen on the proportion of stem cells in the breast. Breast Cancer Res Treat 129, 23-35.
Strome, S.E., To, W., Strawderman, M., Gersten, K., Devaney, K.O., Bradford, C.R., and Esclamado, R.M. (1999). Squamous cell carcinoma of the buccal mucosa. Otolaryngol Head Neck Surg 120, 375-379.
Su, C.C., Yang, H.F., Huang, S.J., and Lian Ie, B. (2007). Distinctive features of oral cancer in Changhua County: high incidence, buccal mucosa preponderance, and a close relation to betel quid chewing habit. J Formos Med Assoc 106, 225-233.
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872.
Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
Tsai, L.L., Yu, C.C., Chang, Y.C., Yu, C.H., and Chou, M.Y. (2011). Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med 40, 621-628.
Verga Falzacappa, M.V., Ronchini, C., Reavie, L.B., and Pelicci, P.G. (2012). Regulation of self-renewal in normal and cancer stem cells. FEBS J 279, 3559-3572.
Wang, Q., He, W., Lu, C., Wang, Z., Wang, J., Giercksky, K.E., Nesland, J.M., and Suo, Z. (2009). Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29, 1233-1241.
Wang, X., and Dai, J. (2010). Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem cells 28, 885-893.
Warnakulasuriya, S. (2009). Global epidemiology of oral and oropharyngeal cancer. Oral oncology 45, 309-316.
Wilbertz, T., Wagner, P., Petersen, K., Stiedl, A.C., Scheble, V.J., Maier, S., Reischl, M., Mikut, R., Altorki, N.K., Moch, H., et al. (2011). SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol 24, 944-953.
Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
Yuan, H., Corbi, N., Basilico, C., and Dailey, L. (1995). Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9, 2635-2645.
Zhou, B.B., Zhang, H., Damelin, M., Geles, K.G., Grindley, J.C., and Dirks, P.B. (2009). Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8, 806-823.
Zullig, L., Roessle, M., Weber, C., Graf, N., Haerle, S.K., Jochum, W., Stoeckli, S.J., Moch, H., and 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. Eur J Cancer 49, 1915-1922.