肺癌為癌症相關死亡率中排名第一名。然而，肺癌的症狀通常在疾病 惡化
時才會出現，這不僅增加治療上的困難度，並且提高肺癌患者的死亡率。
最近的研究顯示，與男性肺癌患者相比，女性肺癌患者的生存率有較差的情形，但其中的機制尚不清楚。因此，了解導致肺癌形成的詳細機制有助於肺癌患者在治療上的效果。在實驗室以前的研究中，發現Sp1在肺癌患者的病情發展中扮演重要的角色。有趣的是，根據臨床數據的分析，本研究發現Sp1的降低在女性肺癌 晚期 患者中有明顯預後不良的情形，而在男性肺癌晚期患者中則沒有這樣的情形。這樣的結果說明 或許女性肺
癌患者的惡化與 Sp1表達降低有關。在過去的兩年中，同時研究了Sp1和雌二醇如何共同調節肺癌進展的分子機制。首先，本研究發現Sp1抑制上皮 -間質轉化(EMT)和幹細胞特性因子的表達，例如 CD44、ALDH1、
Sox2和β-catenin。其次，本研究發現母鼠比起公鼠有顯著的肺癌產生，這顯示雌激素可能正向調控腫瘤的進展。最後，本研究發現一些靶向 EMT基因的microRNA同時受到雌激素的負向調控與Sp1的正向調控，例如
miR-3194-5p miR-200a-5p和 miR-218-5p。總而言之，Sp1可能通過增加microRNA的表達來抑制雌激素介導的肺癌進展。了解Sp1如何導致女性肺癌患者預後不良的原因有助於將來製定癌症治療的策略。

Lung cancer is the first leading cause of cancer-related death worldwide. However, the symptoms of lung cancer usually don’t occur until the disease is advanced, which not only increases the difficulty of treatment but also enhance the mortality rate of lung cancer patients. Recent studies reveal that poor survival rate is found in women lung cancer patients compared to men, but the mechanism remains unclear. Therefore, understanding the mechanistic details is helpful for lung cancer patients. In our previous studies, we showed that Sp1 plays a critical role in the progression of lung cancer patients. Intriguingly, according to the clinical data analysis, we found that the loss of Sp1 leads to poor prognosis significantly in female late-stage lung cancer patients, but not in male late-stage lung cancer patients. These results indicated that female lung cancer malignancy relates to the reducing expression of Sp1. According to the previous studies of our lab, in the past two years, I studied the molecular mechanism(s) of how Sp1 and estradiol co-regulate lung cancer progression. First, we found that Sp1 reduces the expression of several epithelial-mesenchymal transition (EMT)- and stemness-related factors, such as CD44, ALDH1, Sox2, and β-catenin. Second, we found that lung cancer formation was induced in female mice significantly than in male mice, implying that estrogen may positively regulate tumor progression. Finally, we found some microRNAs that target EMT genes were negatively regulated by estrogen but positively regulated by Sp1, such as miR-3194-5p, miR-200a-5p, and miR-218-5p. In conclusion, Sp1 may inhibit estrogen-mediated lung cancer progression through increasing the expression of microRNAs. Understanding how Sp1 leads to poor prognosis in women lung cancer patients will be beneficial for developing the strategies in women lung cancer therapy in the future.

Adams, B.D., Furneaux, H., and White, B.A. The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines. Molecular Endocrinology 21, 1132-1147, 2007.

Ali, E.S., Mangold, C., and Peiris, A.N. Estriol: emerging clinical benefits. Menopause 24, 1081-1085, 2017.

Beishline, K., and Azizkhan‐Clifford, J. Sp1 and the ‘hallmarks of cancer’. Federation of European Biochemical Societies Journal 282, 224-258, 2015.

Björnström, L., and Sjöberg, M. Mechanisms of Estrogen Receptor Signaling: Convergence of Genomic and Nongenomic Actions on Target Genes. Molecular Endocrinology 19, 833-842, 2005.

Blandin Knight, S., Crosbie, P.A., Balata, H., Chudziak, J., Hussell, T., and Dive, C. Progress and prospects of early detection in lung cancer. Open Biology 7, 170070, 2017.

Cai, Y., Yu, X., Hu, S., and Yu, J. A brief review on the mechanisms of miRNA regulation. Genomics, Proteomics and Bioinformatics 7, 147-154, 2009.

Chang, J.W., Zhang, W., Yeh, H.S., de Jong, E.P., Jun, S., Kim, K.H., Bae, S.S., Beckman, K., Hwang, T.H., Kim, K.S., Kim, D.H., Griffin, T.J., Kuang, R., and Yong, J. mRNA 3′-UTR shortening is a molecular signature of mTORC1 activation. Nature Communications 6, 7218, 2015

Chiefari, E., Brunetti, A., Arturi, F., Bidart, J.M., Russo, D., Schlumberger, M., and Filetti, S. Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation? Biomed Central Genomics Cancer 2, 1-4, 2002.

Cui, J., Shen, Y., and Li, R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends in Molecular Medicine 19, 197-209, 2013.
Dela Cruz, C.S., Tanoue, L.T., and Matthay, R.A. Lung cancer: epidemiology, etiology, and prevention. Clinics in Chest Medicine 32, 605-644, 2011.

Dynan, W.S., and Tjian, R. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell 35, 79-87, 1983.

Egleston, B.L., Meireles, S.I., Flieder, D.B., and Clapper, M.L. Population-based trends in lung cancer incidence in women. Seminars in Oncology 36, 506-515, 2009.

Esquela-Kerscher, A., and Slack, F.J. Oncomirs-microRNAs with a role in cancer. Nature Reviews Cancer 6, 259-269, 2006.

Fuentes, N., and Silveyra, P. Estrogen receptor signaling mechanisms. Advances in Protein Chemistry and Structural Biology 116, 135-170. 2019.

Ganti, A.K., Sahmoun, A.E., Panwalkar, A.W., Tendulkar, K.K., and Potti, A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. Journal of Clinical Oncology 24, 59-63, 2006.

Gao, X., Cai, Y., Wang, Z., He, W., Cao, S., Xu, R., and Chen, H. Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective. Journal of Translational Medicine 17, 308, 2019.

Hammond, S.M. An overview of microRNAs. Advanced Drug Delivery Reviews 87, 3-14, 2015.

Harada, M., Luo, X., Murohara, T., Yang, B., Dobrev, D., and Nattel, S. MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circulation Research 114, 689-705, 2014.

Hung, C.Y., Wang, Y.C., Chuang, J.Y., Young, M.J., Liaw, H., Chang, W.C., and Hung, J.J. Nm23-H1-stabilized hnRNPA2/B1 promotes internal ribosomal entry site (IRES)-mediated translation of Sp1 in the lung cancer progression. Scientific Report 7, 9166, 2017

Hsu, L.H., Chu, N.M., and Kao, S.H. Estrogen, Estrogen Receptor and Lung Cancer. International Journal of Molecular Sciences 18, 1713-1730, 2017.

Hsu, L.H., Liu, K.J., Tsai, M.F., Wu, C.R., Feng, A.C., Chu, N.M., and Kao, S.H. Estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Cancer Science 106, 51-59, 2015.

Hsu, T.I., Wang, M.C., Chen, S.Y., Yeh, Y.M., Su, W.C., Chang, W.C., and Hung, J.J. Sp1 expression regulates lung tumor progression. Oncogene 31, 3973-3988, 2012.

Ishibashi, H., Suzuki, T., Suzuki, S., Niikawa, H., Lu, L., Miki, Y., Moriya, T., Hayashi, S.i., Handa, M., and Kondo, T. Progesterone receptor in non-small cell lung cancer-a potent prognostic factor and possible target for endocrine therapy. Cancer Research 65, 6450-6458, 2005.

Jiang, N.Y., Woda, B.A., Banner, B.F., Whalen, G.F., Dresser, K.A., and Lu, D. Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiology and Prevention Biomarkers 17, 1648-1652, 2008.

Jones, K.A., Kadonaga, J.T., Luciw, P.A., and Tjian, R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science 232, 755-759, 1986.

Kaczynski, J., Cook, T., and Urrutia, R. Sp1-and Krüppel-like transcription factors. Genome Biology 4, 206, 2003.

Kawai, H., Ishii, A., Washiya, K., Konno, T., Kon, H., Yamaya, C., Ono, I., Minamiya, Y., and Ogawa, J. Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer. Clinical Cancer Research 11, 5084-5089, 2005.

Khan, D., and Ansar Ahmed, S. The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases. Frontiers in Immunology 6, 635, 2015.

Kim, C.K., He, P., Bialkowska, A.B., and Yang, V.W. SP and KLF transcription factors in digestive physiology and diseases. Gastroenterology 152, 1845-1875, 2017.

Kim, I.K., Lee, Y.S., Kim, H.S., Dong, S.M., Park, J.S., and Yoon, D.S. Specific protein 1(SP1) regulates the epithelial-mesenchymal transition via lysyl oxidase-like 2(LOXL2) in pancreatic ductal adenocarcinoma. Scientific Reports 9, 5933, 2019.

Kligerman, S., and White, C. Epidemiology of Lung Cancer in Women: Risk Factors, Survival, and Screening. American Journal of Roentgenology 196, 287-295, 2011.

Kurtev, V., Margueron, R., Kroboth, K., Ogris, E., Cavailles, V., and Seiser, C. Transcriptional regulation by the repressor of estrogen receptor activity via recruitment of histone deacetylases. Journal of Biological Chemistry 279, 24834-24843, 2004.

Lagger, G., Doetzlhofer, A., Schuettengruber, B., Haidweger, E., Simboeck, E., Tischler, J., Chiocca, S., Suske, G., Rotheneder, H., and Wintersberger, E. The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Molecular and Cellular Biology 23, 2669-2679, 2003.

Lemjabbar-Alaoui, H., Hassan, O.U., Yang, Y.W., and Buchanan, P. Lung cancer: Biology and treatment options. Biochimica et Biophysica Acta 1856, 189-210, 2015.

Li, X., Li, J., Wu, P., Zhou, L., Lu, B., Ying, K., Chen, E., Lu, Y., and Liu, P. Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments. Oncoimmunology 7, e1494677, 2018.

Liu, Y.N., Lee, W.W., Wang, C.Y., Chao, T.H., Chen, Y., and Chen, J.H. Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24, 8277-8290, 2005.

Lynch, T.J., Bell, D.W., Sordella, R., Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Haserlat, S.M., Supko, J.G., and Haluska, F.G. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine 350, 2129-2139, 2004.

Macfarlane, L.A., and Murphy, P.R. MicroRNA: Biogenesis, Function and Role in Cancer. Current Genomics 11, 537-561, 2010.

Malhotra, J., Malvezzi, M., Negri, E., La Vecchia, C., and Boffetta, P. Risk factors for lung cancer worldwide. European Respiratory Journal 48, 889-902, 2016.

Marino, M., Galluzzo, P., and Ascenzi, P. Estrogen signaling multiple pathways to impact gene transcription. Current Genomics 7, 497-508, 2006.

Mazure, N., Brahimi-Horn, M., and Pouyssgur, J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Current Pharmaceutical Design 9, 531-541, 2003.

Nelson, L.R., and Bulun, S.E. Estrogen production and action. Journal of the American Academy of Dermatology 45, S116-124, 2001.

North, C.M., and Christiani, D.C. Women and lung cancer: what is new? Seminars in Thoracic and Cardiovascular Surgery 25, 87-94, 2013.

O'Brien, J., Hayder, H., Zayed, Y., and Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in Endocrinology 9, 402-414, 2018.

Opitz, O.G., and Rustgi, A.K. Interaction between Sp1 and cell cycle regulatory proteins is important in transactivation of a differentiation-related gene. Cancer Research 60, 2825-2830, 2000.

Oton, A., Belani, C., Cai, C., Owonikoko, T., Gooding, W., Siegfried, J., and Ramalingam, S. Comparison of survival for non-small cell lung cancer (NSCLC) between premenopausal and postmenopausal women: An analysis of the National Surveillance, Epidemiology and End Results (SEER) Database. Journal of Clinical Oncology 24, 7038, 2006.

Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., and Fulton, L. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America 101, 13306-13311, 2004.

Parisi, F., Wirapati, P., and Naef, F. Identifying synergistic regulation involving c-Myc and sp1 in human tissues. Nucleic Acids Research 35, 1098-1107, 2007.

Peng, Y., and Croce, C.M. The role of MicroRNAs in human cancer. Signal Transduction and Targeted Therapy 1, 1-9, 2016.

Politi, K., Zakowski, M.F., Fan, P.D., Schonfeld, E.A., Pao, W., and Varmus, H.E. Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors. Genes and Development 20, 1496-1510, 2006.

Sagerup, C.M.T., Småstuen, M., Johannesen, T.B., Helland, Å., and Brustugun, O.T. Sex-specific trends in lung cancer incidence and survival: a population study of 40 118 cases. Thorax 66, 301-307, 2011.

Seto, E., Lewist, B., and Shenk, T. Interaction between transcription factors Spl and YY1. Nature 365, 462-464, 1993.

Siegel, R.L., Miller, K.D., and Jemal, A. Cancer statistics, 2019. CA-A Cancer Journal for Alinicians 69, 7-34, 2019.

Smith, K.M., and Dahodwala, N. Sex differences in Parkinson's disease and other movement disorders. Experimental Neurology 259, 44-56, 2014.

Sun, S., Schiller, J.H., and Gazdar, A.F. Lung cancer in never smokers-a different disease. Nature Reviews Cancer 7, 778-790, 2007.

Suzuki, T., Kimura, A., Nagai, R., and Horikoshi, M. Regulation of interaction of the acetyltransferase region of p300 and the DNA‐binding domain of Sp1 on and through DNA binding. Genes to Cells 5, 29-41, 2000.

Tan, N.Y., and Khachigian, L.M. Sp1 phosphorylation and its regulation of gene transcription. Molecular and Cellular Biology 29, 2483-2488, 2009.

Thomas, M.P., and Potter, B.V. The structural biology of oestrogen metabolism. The Journal of Steroid Biochemistry and Molecular Biology 137, 27-49, 2013.

Vellingiri, B., Iyer, M., Devi Subramaniam, M., Jayaramayya, K., Siama, Z., Giridharan, B., Narayanasamy, A., Abdal Dayem, A., and Cho, S.G. Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice. International Journal of Molecular Sciences 21, 1153-1170, 2020.

Vrtačnik, P., Ostanek, B., Mencej-Bedrač, S., and Marc, J. The many faces of estrogen signaling. Biochemical Medicine (Zagreb) 24, 329-342, 2014.

Wang, S.A., Wang, Y.C., Chuang, Y.P., Huang, Y.H., Su, W.C., Chang, W.C., and Hung, J.J. EGF-mediated inhibition of ubiquitin-specific peptidase 24 expression has a crucial role in tumorigenesis. Oncogene 36, 2930-2945, 2017.

Wang, X., Peng, W., Yi, Z., Zhu, S., and Gan, Q. Expression and prognostic value of transcriptional factor sp1 in breast cancer. Chinese Journal of Cancer 26, 996-1000, 2007.

Wang, Y.C., Wu, Y.S., Hung, C.Y., Wang, S.A., Young, M.J., Hsu, T.I., and Hung, J.J. USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy. Nature Communications 9, 3996, 2018.

Wang, Y.T., Yang, W.B., Chang, W.C., and Hung, J.J. Interplay of posttranslational modifications in Sp1 mediates Sp1 stability during cell cycle progression. Journal of Molecular Biology 414, 1-14, 2011.

Yang, W.B., Chen, P.H., Hsu, T.s., Fu, T.F., Su, W.C., Liaw, H., Chang, W.C., and Hung, J.J. Sp1-mediated microRNA-182 expression regulates lung cancer progression. Oncotarget 5, 740-753, 2014.
Yao, J.C., Wang, L., Wei, D., Gong, W., Hassan, M., Wu, T.T., Mansfield, P., Ajani, J., and Xie, K. Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clinical Cancer Research 10, 4109-4117, 2004.

Zhao, S., Venkatasubbarao, K., Li, S., and Freeman, J.W. Requirement of a specific Sp1 site for histone deacetylase-mediated repression of transforming growth factor β type II receptor expression in human pancreatic cancer cells. Cancer Research 63, 2624-2630, 2003.