在肺癌病人中若有 octamer4 (亦稱為 Oct4 或 Pou5f1) 和osteopontin (OPN) 這兩種因子的表現會有較差的預後。Oct4 是 POU 轉錄因子的一員，可視為一個多功能性因子，且在癌症中藉由維持癌幹細胞特性而扮演致癌因子的角色。在先前已發表的論文中已證實減少 Oct4 的表現會降低膀胱癌細胞的移動和侵犯能力，因此，我們猜測 Oct4 可能和癌細胞的轉移有關。OPN 是一個O-glycosylated 磷酸化蛋白，且會藉由與 αvβ integrin 和 CD44 變異性受體 (variant receptors) 進行結合，以調控癌細胞的移動與侵犯能力。此外，在已經發表的微陣列數據中指出在胚胎幹細胞中抑制 Oct4 會減少 OPN 信息核醣核酸的表現。因此我們進一步探討 Oct4 所調控的 OPN 表現是否與肺癌細胞的轉移與侵犯能力有關。本研究發現在肺癌病人病兆較惡化的臨床檢體中，Oct4 與 OPN 均有較高的表現。此外，在 Oct4 穩定表現的 A549 肺癌細胞株中， OPN 的 mRNA 和蛋白質的表現量也會增加。在 Boyden chamber 實驗發現當Oct4 過量表現且同時抑制OPN時，會抑制 A549 肺癌細胞株的爬行能力，因此推測 Oct4 促進腫瘤轉移的現象，可能是透過 Oct4 正向調控 OPN 啟動子活性所導致的。因此，未來的研究將進一步在體外與動物模式探討肺癌中由 Oct4 調控的 OPN 表現是否與上皮-間葉細胞轉換 (epithelial-mesenchymal transition，EMT)以及腫瘤細胞的移動、侵犯能力有關。

Octamer 4 (also known as Oct4 and Pou5f1) and osteopontin (OPN) are two prognostic factors for survival in lung cancer patients. Oct4, a member of the POU transcription factors, is regarded as a multifunctional factor and plays an oncogenic role through maintaining characteristics of cancer stem cells. Our previous results demonstrated that downregulation of Oct4 expression reduced bladder cancer cell migration and invasive ability. Therefore, we proposed that Oct4 might correlate with cancer cell metastasis. OPN is an O-glycosylated phosphoprotein and regulates cancer cell migration and invasion through binding to αvβ integrin and CD44 variant receptors. Previous microarray data revealed that knockdown of Oct4 in embryonic stem cell decreased OPN expression. In this study, we investigated whether modulation of OPN expression by Oct4 correlated with the migration and invasion of lung cancer cells. High levels of Oct4 and OPN expression were detected in the clinical samples of late-stage human lung tumors. Furthermore, mRNA and protein levels of OPN were also increased in Oct4-overexpressing A549 cells. Knockdown of OPN expression in Oct4-overexpressing lung cancer cells promoted migratory ability in the Boyden chamber assay. These results suggest that the promotion of tumor metastasis by Oct4 may be mediated through the enhancement of the OPN promoter activity. We will further study whether Oct4-mediated OPN expression is associated with epithelial-mesenchymal transition (EMT) and migration and invasion of lung cancer cells in vitro and in animal models.

Agrawal, D., Chen, T., Irby, R., Quackenbush, J., Chambers, A.F., Szabo, M., Cantor, A., Coppola, D., and Yeatman, T.J. (2002). Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 94, 513-521.

Araujo, A., Ribeiro, R., Azevedo, I., Coelho, A., Soares, M., Sousa, B., Pinto, D., Lopes, C., Medeiros, R., and Scagliotti, G.V. (2007). Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist 12, 201-210.

Boldrini, L., Donati, V., Dell'Omodarme, M., Prati, M.C., Faviana, P., Camacci, T., Lucchi, M., Mussi, A., Santoro, M., Basolo, F., et al. (2005). Prognostic significance of osteopontin expression in early-stage non-small-cell lung cancer. Br J Cancer 93, 453-457.

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.

Buback, F., Renkl, A.C., Schulz, G., and Weiss, J.M. (2009). Osteopontin and the skin: multiple emerging roles in cutaneous biology and pathology. Exp Dermatol 18, 750-759.

Chambers, A.F., Wilson, S.M., Kerkvliet, N., O'Malley, F.P., Harris, J.F., and Casson, A.G. (1996). Osteopontin expression in lung cancer. Lung Cancer 15, 311-323.

Chang, C.C., Shieh, G.S., Wu, P., Lin, C.C., Shiau, A.L., and Wu, C.L. (2008). Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells. Cancer Res 68, 6281-6291.

Crawford, N.P., and Hunter, K.W. (2006). New perspectives on hereditary influences in metastatic progression. Trends Genet 22, 555-561.

Donati, V., Boldrini, L., Dell'Omodarme, M., Prati, M.C., Faviana, P., Camacci, T., Lucchi, M., Mussi, A., Santoro, M., Basolo, F., et al. (2005). Osteopontin expression and prognostic significance in non-small cell lung cancer. Clin Cancer Res 11, 6459-6465.

El-Tanani, M.K., Campbell, F.C., Kurisetty, V., Jin, D., McCann, M., and Rudland, P.S. (2006). The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev 17, 463-474.

Ezeh, U.I., Turek, P.J., Reijo, R.A., and Clark, A.T. (2005). Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104, 2255-2265.

Fong, Y.C., Liu, S.C., Huang, C.Y., Li, T.M., Hsu, S.F., Kao, S.T., Tsai, F.J., Chen, W.C., Chen, C.Y., and Tang, C.H. (2009). Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin/FAK/Akt and NF-kappaB-dependent pathway. Lung Cancer 64, 263-270.

Friedl, P. (2004). Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 16, 14-23.

Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57-70.

Hansis, C., Grifo, J.A., and Krey, L.C. (2000). Oct-4 expression in inner cell mass and trophectoderm of human blastocysts. Mol Hum Reprod 6, 999-1004.

Herbst, R.S., Davies, A.M., Natale, R.B., Dang, T.P., Schiller, J.H., Garland, L.L., Miller, V.A., Mendelson, D., Van den Abbeele, A.D., Melenevsky, Y., et al. (2007). Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin Cancer Res 13, 6175-6181.

Huber, M.A., Kraut, N., and Beug, H. (2005). Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17, 548-558.

Kakinuma, T., and Hwang, S.T. (2006). Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol 79, 639-651.

Karoubi, G., Gugger, M., Schmid, R., and Dutly, A. (2009). OCT4 expression in human non-small cell lung cancer: implications for therapeutic intervention. Interact Cardiovasc Thorac Surg 8, 393-397.

Minucci, S., Botquin, V., Yeom, Y.I., Dey, A., Sylvester, I., Zand, D.J., Ohbo, K., Ozato, K., and Scholer, H.R. (1996). Retinoic acid-mediated down-regulation of Oct3/4 coincides with the loss of promoter occupancy in vivo. EMBO J 15, 888-899.

Monk, M., and Holding, C. (2001). Human embryonic genes re-expressed in cancer cells. Oncogene 20, 8085-8091.

O'Regan, A., and Berman, J.S. (2000). Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol 81, 373-390.
Pan, G.J., Chang, Z.Y., Scholer, H.R., and Pei, D. (2002). Stem cell pluripotency and transcription factor Oct4. Cell Res 12, 321-329.

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.

Sharov, A.A., Masui, S., Sharova, L.V., Piao, Y., Aiba, K., Matoba, R., Xin, L., Niwa, H., and Ko, M.S. (2008). Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. BMC Genomics 9, 269.

Song, G., Cai, Q.F., Mao, Y.B., Ming, Y.L., Bao, S.D., and Ouyang, G.L. (2008). Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1alpha expression through the PI3-K/Akt pathway. Cancer Sci 99, 1901-1907.

Tai, M.H., Chang, C.C., Kiupel, M., Webster, J.D., Olson, L.K., and Trosko, J.E. (2005). Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 26, 495-502.

Tomilin, A., Remenyi, A., Lins, K., Bak, H., Leidel, S., Vriend, G., Wilmanns, M., and Scholer, H.R. (2000). Synergism with the coactivator OBF-1 (OCA-B, BOB-1) is mediated by a specific POU dimer configuration. Cell 103, 853-864.
Travis, W.D., Travis, L.B., and Devesa, S.S. (1995). Lung cancer. Cancer 75, 191-202.

Wai, P.Y., and Kuo, P.C. (2004). The role of Osteopontin in tumor metastasis. J Surg Res 121, 228-241.

Wai, P.Y., and Kuo, P.C. (2008). Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev 27, 103-118.

Wang, K.X., and Denhardt, D.T. (2008). Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev 19, 333-345.

Wang, P., Branch, D.R., Bali, M., Schultz, G.A., Goss, P.E., and Jin, T. (2003). The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells. Biochem J 375, 199-205.

Weber, G.F. (2001). The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta 1552, 61-85.

Weber, G.F., and Ashkar, S. (2000). Stress response genes: the genes that make cancer metastasize. J Mol Med 78, 404-408.

Yilmaz, M., Christofori, G., and Lehembre, F. (2007). Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 13, 535-541.