我們近年來的研究指出，Sp1的過量表現會促使肺癌細胞的增長，同時也抑制其轉移能力。在本研究中，我們發現Sp1的表現會去增加FOXO3的轉錄活性，然而其蛋白質的表現量卻是下降的。Sp1藉由增加miR-182的表現，進而與FOXO3 mRNA的3'端未轉譯區域結合，抑制其轉譯活性。當miR-182靜默時會抑制肺癌細胞的生長，但是能藉由增加N-cadherin的表現來增強癌細胞的侵略與遷移能力。在miR-182靜默之細胞株抑制FOXO3的表現能部分逆轉miR-182所造成的細胞侵略影響，証明了miR-182促使肺癌細胞的生長與轉移是藉由調控FOXO3的表現所導致。我們也觀察到一群與癌細胞轉移相關之基因，像是ADAM9、CDH9和CD44的表現量，也隨著miR-182的下降其表現量有增加的情形。此外，我們發現Sp1可能透過調控一群miRNAs (miR-106a, miR-150, miR-182, miR-183*, miR-193a-5p and miR-212-5p) 的表現進而透過CD44的3'端未轉譯區域來抑制其表現，Sp1和CD44的表現在臨床關聯性上也呈現高度負相關的情形，CD44表現量的增加會促使肺癌細胞具有高度遷移與侵略能力。這些發現可以更加證明Sp1具有抑制肺癌轉移的能力。最後，我們進行了染色質免疫沉澱結合次世代定序與小片段RNA 定序技術，發現了50個Sp1可能直接調控的miRNAs，功能分析也指出這些miRNAs參與在細胞凋亡和細胞生長的過程中。綜合上述，我們的研究成果對於Sp1如何調控肺癌發展提供了一個新的見解，在肺癌發展的早期，Sp1藉由刺激miR-182的表現進而降低FOXO3的表現，這樣的調控導致腫瘤的生長。然而在晚期，Sp1和Sp1所調控的miRNAs表現量下降，於是FOXO3和CD44的表現量增加，進而導致肺腫瘤的轉移，由此突顯出miRNAs的生合成在癌症中的重要性。

Our recent study indicated that the expression of Sp1 at a high level enhances the proliferation of lung cancer cells, but represses the metastatic activity of lung cancer. In this study, we found that the transcriptional activity of the FOXO3 was increased, but its protein levels decreased following Sp1 expression. Further studies revealed that Sp1 increased the expression of the miRNA, miR-182, which was then recruited to the 3'-untranslated region of FOXO3 mRNA to silence its translational activity. Knockdown of miR-182 inhibited lung cancer cells growth, but enhanced the invasive and migratory abilities of these cells through increased N-cadherin expression. The repression of FOXO3 expression in the miR-182 knockdown cells partially reversed this effect, suggesting that miR-182 promotes cancer cell growth and inhibits cancer metastatic activity by regulating the expression of FOXO3. The expression of several cancer metastasis-related genes such as ADAM9, CDH9 and CD44 was increased following miR-182 knockdown. Furthermore, we found that Sp1 may regulate the expression of a cluster of miRNAs (miR-106a, miR-150, miR-182, miR-183*, miR-193a-5p and miR-212-5p) to negatively regulate CD44 through 3'-UTR regulation. Clinical relevance indicated that Sp1 expression is negatively correlated with CD44 expression. Enhancement of CD44 expression promoted lung cancer cell migration and invasion abilities. These findings could verify why Sp1 suppresses lung cancer metastasis. Finally, we performed chromatin immunoprecipitation coupled to next-generation sequencing combining with small RNA sequencing technology to identify 50 of mature miRNAs which were potential directly regulated by Sp1. Functional analysis also indicated that these miRNAs were involved in apoptotic process and cell proliferation. In conclusion, our findings provide a new insight of Sp1 regulated lung cancer progression through miRNAs regulation. In the early stages of lung cancer progression, Sp1 stimulates miR-182 expression, which in turn decreases FOXO3 expression. This stimulates proliferation and tumor growth. In the late stages, Sp1 and Sp1-regulated miRNAs decline, thus increasing FOXO3 and CD44 expression, which leads to lung metastasis, thereby highlighting the importance of miRNAs biosynthesis in cancer.

Abd-El-Fattah, A. A., N. A. Sadik, O. G. Shaker and M. L. Aboulftouh (2013). "Differential MicroRNAs Expression in Serum of Patients with Lung Cancer, Pulmonary Tuberculosis, and Pneumonia." Cell Biochem Biophys.
Araldi, E. and E. Schipani (2010). "MicroRNA-140 and the silencing of osteoarthritis." Genes Dev 24(11): 1075-1080.
Bartel, D. P. (2009). "MicroRNAs: target recognition and regulatory functions." Cell 136(2): 215-233.
Bergink, S. and S. Jentsch (2009). "Principles of ubiquitin and SUMO modifications in DNA repair." Nature 458(7237): 461-467.
Blanc, V. and N. O. Davidson (2003). "C-to-U RNA editing: mechanisms leading to genetic diversity." J Biol Chem 278(3): 1395-1398.
Blume, S. W., R. C. Snyder, R. Ray, S. Thomas, C. A. Koller and D. M. Miller (1991). "Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo." J Clin Invest 88(5): 1613-1621.
Boeri, M., U. Pastorino and G. Sozzi (2012). "Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis." Cancer J 18(3): 268-274.
Bonello, M. R. and L. M. Khachigian (2004). "Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter." J Biol Chem 279(4): 2377-2382.
Castello, A., B. Fischer, K. Eichelbaum, R. Horos, B. M. Beckmann, C. Strein, N. E. Davey, D. T. Humphreys, T. Preiss, L. M. Steinmetz, J. Krijgsveld and M. W. Hentze (2012). "Insights into RNA biology from an atlas of mammalian mRNA-binding proteins." Cell 149(6): 1393-1406.
Chen, P. S., J. L. Su and M. C. Hung (2012). "Dysregulation of microRNAs in cancer." J Biomed Sci 19: 90.
Chen, Q., L. Yang, Y. Xiao, J. Zhu and Z. Li (2014). "Circulating microRNA-182 in plasma and its potential diagnostic and prognostic value for pancreatic cancer." Med Oncol 31(11): 225.
Cheng, L., R. E. Alexander, G. T. Maclennan, O. W. Cummings, R. Montironi, A. Lopez-Beltran, H. M. Cramer, D. D. Davidson and S. Zhang (2012). "Molecular pathology of lung cancer: key to personalized medicine." Mod Pathol 25(3): 347-369.
Chintharlapalli, S., S. Papineni, S. K. Ramaiah and S. Safe (2007). "Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors." Cancer Res 67(6): 2816-2823.
Cho, W. C., A. S. Chow and J. S. Au (2009). "Restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor mutation." Eur J Cancer 45(12): 2197-2206.
Chuang, J. Y. and J. J. Hung (2011). "Overexpression of HDAC1 induces cellular senescence by Sp1/PP2A/pRb pathway." Biochem Biophys Res Commun 407(3): 587-592.
Chuang, J. Y., S. A. Wang, W. B. Yang, H. C. Yang, C. Y. Hung, T. P. Su, W. C. Chang and J. J. Hung (2012). "Sp1 phosphorylation by cyclin-dependent kinase 1/cyclin B1 represses its DNA-binding activity during mitosis in cancer cells." Oncogene 31(47): 4946-4959.
Chuang, J. Y., Y. T. Wang, S. H. Yeh, Y. W. Liu, W. C. Chang and J. J. Hung (2008). "Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis." Mol Biol Cell 19(3): 1139-1151.
Chuang, J. Y., C. H. Wu, M. D. Lai, W. C. Chang and J. J. Hung (2009). "Overexpression of Sp1 leads to p53-dependent apoptosis in cancer cells." Int J Cancer 125(9): 2066-2076.
Deniaud, E., J. Baguet, A. L. Mathieu, G. Pages, J. Marvel and Y. Leverrier (2006). "Overexpression of Sp1 transcription factor induces apoptosis." Oncogene 25(53): 7096-7105.
Ding, X. C. and H. Grosshans (2009). "Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins." EMBO J 28(3): 213-222.
Djuranovic, S., A. Nahvi and R. Green (2012). "miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay." Science 336(6078): 237-240.
Dynan, W. S. and R. Tjian (1983). "The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter." Cell 35(1): 79-87.
Gao, Y., Z. Jia, X. Kong, Q. Li, D. Z. Chang, D. Wei, X. Le, S. Huang, L. Wang and K. Xie (2011). "Combining betulinic acid and mithramycin A effectively suppresses pancreatic cancer by inhibiting proliferation, invasion and angiogenesis." Cancer Res.
Geoffroy, M. C. and R. T. Hay (2009). "An additional role for SUMO in ubiquitin-mediated proteolysis." Nat Rev Mol Cell Biol 10(8): 564-568.
Giordano, S. and A. Columbano (2013). "MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma?" Hepatology 57(2): 840-847.
Glisovic, T., J. L. Bachorik, J. Yong and G. Dreyfuss (2008). "RNA-binding proteins and post-transcriptional gene regulation." FEBS Lett 582(14): 1977-1986.
Guo, H., N. T. Ingolia, J. S. Weissman and D. P. Bartel (2010). "Mammalian microRNAs predominantly act to decrease target mRNA levels." Nature 466(7308): 835-840.
Guttilla, I. K. and B. A. White (2009). "Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells." J Biol Chem 284(35): 23204-23216.
Halbeisen, R. E., A. Galgano, T. Scherrer and A. P. Gerber (2008). "Post-transcriptional gene regulation: from genome-wide studies to principles." Cell Mol Life Sci 65(5): 798-813.
Hendrickson, D. G., D. J. Hogan, H. L. McCullough, J. W. Myers, D. Herschlag, J. E. Ferrell and P. O. Brown (2009). "Concordant regulation of translation and mRNA abundance for hundreds of targets of a human microRNA." PLoS Biol 7(11): e1000238.
Hermeking, H. (2012). "MicroRNAs in the p53 network: micromanagement of tumour suppression." Nat Rev Cancer 12(9): 613-626.
Hsu, T. I., M. C. Wang, S. Y. Chen, S. T. Huang, Y. M. Yeh, W. C. Su, W. C. Chang and J. J. Hung (2012). "Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth." Mol Pharmacol 82(6): 1115-1128.
Hsu, T. I., M. C. Wang, S. Y. Chen, Y. M. Yeh, W. C. Su, W. C. Chang and J. J. Hung (2012). "Sp1 expression regulates lung tumor progression." Oncogene 31(35): 3973-3988.
Huang da, W., B. T. Sherman and R. A. Lempicki (2009). "Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists." Nucleic Acids Res 37(1): 1-13.
Huang da, W., B. T. Sherman and R. A. Lempicki (2009). "Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources." Nat Protoc 4(1): 44-57.
Huang, X., L. Ding, K. L. Bennewith, R. T. Tong, S. M. Welford, K. K. Ang, M. Story, Q. T. Le and A. J. Giaccia (2009). "Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation." Mol Cell 35(6): 856-867.
Hung, C. Y., W. B. Yang, S. A. Wang, T. I. Hsu, W. C. Chang and J. J. Hung (2014). "Nucleolin enhances internal ribosomal entry site (IRES)-mediated translation of Sp1 in tumorigenesis." Biochim Biophys Acta 1843(12): 2843-2854.
Hung, J. J., Y. T. Wang and W. C. Chang (2006). "Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription." Mol Cell Biol 26(5): 1770-1785.
Iizasa, H. and K. Nishikura (2009). "A new function for the RNA-editing enzyme ADAR1." Nat Immunol 10(1): 16-18.
Jang, J. S., H. S. Jeon, Z. Sun, M. C. Aubry, H. Tang, C. H. Park, F. Rakhshan, D. A. Schultz, C. P. Kolbert, R. Lupu, J. Y. Park, C. C. Harris, P. Yang and J. Jen (2012). "Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers." Clin Cancer Res 18(13): 3658-3667.
Jemal, A., F. Bray, M. M. Center, J. Ferlay, E. Ward and D. Forman (2011). "Global cancer statistics." CA Cancer J Clin 61(2): 69-90.
Jeong, H. C. (2014). "Clinical Aspect of MicroRNA in Lung Cancer." Tuberc Respir Dis (Seoul) 77(2): 60-64.
Jewer, M., S. D. Findlay and L. M. Postovit (2012). "Post-transcriptional regulation in cancer progression : Microenvironmental control of alternative splicing and translation." J Cell Commun Signal 6(4): 233-248.
Johnson, C. D., A. Esquela-Kerscher, G. Stefani, M. Byrom, K. Kelnar, D. Ovcharenko, M. Wilson, X. Wang, J. Shelton, J. Shingara, L. Chin, D. Brown and F. J. Slack (2007). "The let-7 microRNA represses cell proliferation pathways in human cells." Cancer Res 67(16): 7713-7722.
Josson, S., C. S. Anderson, S. Y. Sung, P. A. Johnstone, H. Kubo, C. L. Hsieh, R. Arnold, M. Gururajan, C. Yates and L. W. Chung (2011). "Inhibition of ADAM9 expression induces epithelial phenotypic alterations and sensitizes human prostate cancer cells to radiation and chemotherapy." Prostate 71(3): 232-240.
Kechavarzi, B. and S. C. Janga (2014). "Dissecting the expression landscape of RNA-binding proteins in human cancers." Genome Biol 15(1): R14.
Kertesz, M., N. Iovino, U. Unnerstall, U. Gaul and E. Segal (2007). "The role of site accessibility in microRNA target recognition." Nat Genet 39(10): 1278-1284.
Lai, E. C. (2002). "Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation." Nat Genet 30(4): 363-364.
Lee, Y., M. Kim, J. Han, K. H. Yeom, S. Lee, S. H. Baek and V. N. Kim (2004). "MicroRNA genes are transcribed by RNA polymerase II." EMBO J 23(20): 4051-4060.
Leung, E. L., R. R. Fiscus, J. W. Tung, V. P. Tin, L. C. Cheng, A. D. Sihoe, L. M. Fink, Y. Ma and M. P. Wong (2010). "Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties." Plos One 5(11): e14062.
Levine, M. and R. Tjian (2003). "Transcription regulation and animal diversity." Nature 424(6945): 147-151.
Li, L. and J. R. Davie (2010). "The role of Sp1 and Sp3 in normal and cancer cell biology." Ann Anat 192(5): 275-283.
Li, P., C. Sheng, L. Huang, H. Zhang, L. Huang, Z. Cheng and Q. Zhu (2014). "MiR-183/-96/-182 cluster is up-regulated in most breast cancers and increases cell proliferation and migration." Breast Cancer Res 16(6): 473.
Lin, P. Y., S. L. Yu and P. C. Yang (2010). "MicroRNA in lung cancer." Br J Cancer 103(8): 1144-1148.
Liu, S., L. C. Wu, J. Pang, R. Santhanam, S. Schwind, Y. Z. Wu, C. J. Hickey, J. Yu, H. Becker, K. Maharry, M. D. Radmacher, C. Li, S. P. Whitman, A. Mishra, N. Stauffer, A. M. Eiring, R. Briesewitz, R. A. Baiocchi, K. K. Chan, P. Paschka, M. A. Caligiuri, J. C. Byrd, C. M. Croce, C. D. Bloomfield, D. Perrotti, R. Garzon and G. Marcucci (2010). "Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia." Cancer Cell 17(4): 333-347.
Liu, Y. W., T. Arakawa, S. Yamamoto and W. C. Chang (1997). "Transcriptional activation of human 12-lipoxygenase gene promoter is mediated through Sp1 consensus sites in A431 cells." Biochem J 324 ( Pt 1): 133-140.
Liu, Z., J. Liu, M. F. Segura, C. Shao, P. Lee, Y. Gong, E. Hernando and J. J. Wei (2012). "MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma." J Pathol 228(2): 204-215.
Loya, C. M., D. Van Vactor and T. A. Fulga (2010). "Understanding neuronal connectivity through the post-transcriptional toolkit." Genes Dev 24(7): 625-635.
Lyst, M. J. and I. Stancheva (2007). "A role for SUMO modification in transcriptional repression and activation." Biochem Soc Trans 35(Pt 6): 1389-1392.
Ma, L., Y. Huang, W. Zhu, S. Zhou, J. Zhou, F. Zeng, X. Liu, Y. Zhang and J. Yu (2011). "An integrated analysis of miRNA and mRNA expressions in non-small cell lung cancers." PLoS One 6(10): e26502.
Maltzman, J. S., J. A. Carman and J. G. Monroe (1996). "Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B lymphocytes." Mol Cell Biol 16(5): 2283-2294.
Marinova, Z., M. Ren, J. R. Wendland, Y. Leng, M. H. Liang, S. Yasuda, P. Leeds and D. M. Chuang (2009). "Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation." J Neurochem 111(4): 976-987.
Melo, S. A. and R. Kalluri (2012). "Molecular pathways: microRNAs as cancer therapeutics." Clin Cancer Res 18(16): 4234-4239.
Milanini-Mongiat, J., J. Pouyssegur and G. Pages (2002). "Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription." J Biol Chem 277(23): 20631-20639.
Mitchell, P. S., R. K. Parkin, E. M. Kroh, B. R. Fritz, S. K. Wyman, E. L. Pogosova-Agadjanyan, A. Peterson, J. Noteboom, K. C. O'Briant, A. Allen, D. W. Lin, N. Urban, C. W. Drescher, B. S. Knudsen, D. L. Stirewalt, R. Gentleman, R. L. Vessella, P. S. Nelson, D. B. Martin and M. Tewari (2008). "Circulating microRNAs as stable blood-based markers for cancer detection." Proc Natl Acad Sci U S A 105(30): 10513-10518.
Molina, J. R., P. Yang, S. D. Cassivi, S. E. Schild and A. A. Adjei (2008). "Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship." Mayo Clin Proc 83(5): 584-594.
Nacerddine, K., F. Lehembre, M. Bhaumik, J. Artus, M. Cohen-Tannoudji, C. Babinet, P. P. Pandolfi and A. Dejean (2005). "The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice." Dev Cell 9(6): 769-779.
Nishikura, K. (2010). "Functions and regulation of RNA editing by ADAR deaminases." Annu Rev Biochem 79: 321-349.
Perilli, L., C. Vicentini, M. Agostini, S. Pizzini, M. Pizzi, E. D'Angelo, S. Bortoluzzi, S. Mandruzzato, E. Mammano, M. Rugge, D. Nitti, A. Scarpa, M. Fassan and P. Zanovello (2014). "Circulating miR-182 is a biomarker of colorectal adenocarcinoma progression." Oncotarget 5(16): 6611-6619.
Petersen, C. P., M. E. Bordeleau, J. Pelletier and P. A. Sharp (2006). "Short RNAs repress translation after initiation in mammalian cells." Mol Cell 21(4): 533-542.
Pichler, A. and F. Melchior (2002). "Ubiquitin-related modifier SUMO1 and nucleocytoplasmic transport." Traffic 3(6): 381-387.
Pore, N., S. Liu, H. K. Shu, B. Li, D. Haas-Kogan, D. Stokoe, J. Milanini-Mongiat, G. Pages, D. M. O'Rourke, E. Bernhard and A. Maity (2004). "Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism." Mol Biol Cell 15(11): 4841-4853.
Qu, Y., W. C. Li, M. R. Hellem, K. Rostad, M. Popa, E. McCormack, A. M. Oyan, K. H. Kalland and X. S. Ke (2013). "MiR-182 and miR-203 induce mesenchymal to epithelial transition and self-sufficiency of growth signals via repressing SNAI2 in prostate cells." Int J Cancer 133(3): 544-555.
Raponi, M., L. Dossey, T. Jatkoe, X. Wu, G. Chen, H. Fan and D. G. Beer (2009). "MicroRNA classifiers for predicting prognosis of squamous cell lung cancer." Cancer Res 69(14): 5776-5783.
Ryu, H., J. Lee, B. A. Olofsson, A. Mwidau, A. Dedeoglu, M. Escudero, E. Flemington, J. Azizkhan-Clifford, R. J. Ferrante and R. R. Ratan (2003). "Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway." Proc Natl Acad Sci U S A 100(7): 4281-4286.
Samuel, C. E. (2003). "RNA editing minireview series." J Biol Chem 278(3): 1389-1390.
Segura, M. F., D. Hanniford, S. Menendez, L. Reavie, X. Zou, S. Alvarez-Diaz, J. Zakrzewski, E. Blochin, A. Rose, D. Bogunovic, D. Polsky, J. Wei, P. Lee, I. Belitskaya-Levy, N. Bhardwaj, I. Osman and E. Hernando (2009). "Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor." Proc Natl Acad Sci U S A 106(6): 1814-1819.
Seike, M., A. Goto, T. Okano, E. D. Bowman, A. J. Schetter, I. Horikawa, E. A. Mathe, J. Jen, P. Yang, H. Sugimura, A. Gemma, S. Kudoh, C. M. Croce and C. C. Harris (2009). "MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers." Proc Natl Acad Sci U S A 106(29): 12085-12090.
Shen, J., S. A. Stass and F. Jiang (2013). "MicroRNAs as potential biomarkers in human solid tumors." Cancer Lett 329(2): 125-136.
Sher, Y. P., L. J. Wang, L. L. Chuang, M. H. Tsai, T. T. Kuo, C. C. Huang, E. Y. Chuang and L. C. Lai (2014). "ADAM9 up-regulates N-cadherin via miR-218 suppression in lung adenocarcinoma cells." Plos One 9(4): e94065.
Siegel, R., D. Naishadham and A. Jemal (2013). "Cancer statistics, 2013." CA Cancer J Clin 63(1): 11-30.
Spengler, M. L. and M. G. Brattain (2006). "Sumoylation inhibits cleavage of Sp1 N-terminal negative regulatory domain and inhibits Sp1-dependent transcription." J Biol Chem 281(9): 5567-5574.
Sun, Y., R. Fang, C. Li, L. Li, F. Li, X. Ye and H. Chen (2010). "Hsa-mir-182 suppresses lung tumorigenesis through down regulation of RGS17 expression in vitro." Biochem Biophys Res Commun 396(2): 501-507.
Suzuki, H., R. Maruyama, E. Yamamoto and M. Kai (2012). "DNA methylation and microRNA dysregulation in cancer." Mol Oncol 6(6): 567-578.
Tan, N. Y. and L. M. Khachigian (2009). "Sp1 phosphorylation and its regulation of gene transcription." Mol Cell Biol 29(10): 2483-2488.
Tan, X., W. Qin, L. Zhang, J. Hang, B. Li, C. Zhang, J. Wan, F. Zhou, K. Shao, Y. Sun, J. Wu, X. Zhang, B. Qiu, N. Li, S. Shi, X. Feng, S. Zhao, Z. Wang, X. Zhao, Z. Chen, K. Mitchelson, J. Cheng, Y. Guo and J. He (2011). "A 5-microRNA signature for lung squamous cell carcinoma diagnosis and hsa-miR-31 for prognosis." Clin Cancer Res 17(21): 6802-6811.
Thomas, M., J. Lieberman and A. Lal (2010). "Desperately seeking microRNA targets." Nat Struct Mol Biol 17(10): 1169-1174.
Townsend, K. J., P. Zhou, L. Qian, C. K. Bieszczad, C. H. Lowrey, A. Yen and R. W. Craig (1999). "Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation." J Biol Chem 274(3): 1801-1813.
Vazquez, B. N., T. Laguna, J. Carabana, M. S. Krangel and P. Lauzurica (2009). "CD69 Gene Is Differentially Regulated in T and B Cells Evolutionarily Conserved Promoter-Distal by Elements." Journal of Immunology 183(10): 6513-6521.
Verkaik, N. S., G. J. van Steenbrugge, W. M. van Weerden, M. J. Bussemakers and T. H. van der Kwast (2000). "Silencing of CD44 expression in prostate cancer by hypermethylation of the CD44 promoter region." Lab Invest 80(8): 1291-1298.
Vosa, U., T. Vooder, R. Kolde, J. Vilo, A. Metspalu and T. Annilo (2013). "Meta-analysis of microRNA expression in lung cancer." Int J Cancer 132(12): 2884-2893.
Waby, J. S., H. Chirakkal, C. Yu, G. J. Griffiths, R. S. Benson, C. D. Bingle and B. M. Corfe (2010). "Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line." Mol Cancer 9: 275.
Wang, J., J. Li, J. Shen, C. Wang, L. Yang and X. Zhang (2012). "MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma." BMC Cancer 12: 227.
Wang, S., M. H. Yang, X. Y. Wang, J. Lin and Y. Q. Ding (2014). "Increased expression of miRNA-182 in colorectal carcinoma: an independent and tissue-specific prognostic factor." Int J Clin Exp Pathol 7(6): 3498-3503.
Wang, S. A., J. Y. Chuang, S. H. Yeh, Y. T. Wang, Y. W. Liu, W. C. Chang and J. J. Hung (2009). "Heat shock protein 90 is important for Sp1 stability during mitosis." J Mol Biol 387(5): 1106-1119.
Wang, Y. T., J. Y. Chuang, M. R. Shen, W. B. Yang, W. C. Chang and J. J. Hung (2008). "Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process." J Mol Biol 380(5): 869-885.
Wang, Y. T., W. B. Yang, W. C. Chang and J. J. Hung (2011). "Interplay of posttranslational modifications in Sp1 mediates Sp1 stability during cell cycle progression." J Mol Biol 414(1): 1-14.
Wang, Z., H. Yao, S. Lin, X. Zhu, Z. Shen, G. Lu, W. S. Poon, D. Xie, M. C. Lin and H. F. Kung (2013). "Transcriptional and epigenetic regulation of human microRNAs." Cancer Lett 331(1): 1-10.
Wierstra, I. (2008). "Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes." Biochem Biophys Res Commun 372(1): 1-13.
Williams, K., K. Motiani, P. V. Giridhar and S. Kasper (2013). "CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches." Exp Biol Med (Maywood) 238(3): 324-338.
Wong, H. K., T. Veremeyko, N. Patel, C. A. Lemere, D. M. Walsh, C. Esau, C. Vanderburg and A. M. Krichevsky (2013). "De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease." Hum Mol Genet.
Xu, X., S. Wang, J. Liu, D. Dou, L. Liu, Z. Chen, L. Ye, H. Liu, Q. He, J. U. Raj and Y. Gao (2012). "Hypoxia induces downregulation of soluble guanylyl cyclase beta1 by miR-34c-5p." J Cell Sci 125(Pt 24): 6117-6126.
Xu, Z., S. B. Xiao, P. Xu, Q. Xie, L. Cao, D. Wang, R. Luo, Y. Zhong, H. C. Chen and L. R. Fang (2011). "miR-365, a novel negative regulator of interleukin-6 gene expression, is cooperatively regulated by Sp1 and NF-kappaB." J Biol Chem 286(24): 21401-21412.
Yan, G. Z. and E. B. Ziff (1997). "Nerve growth factor induces transcription of the p21 WAF1/CIP1 and cyclin D1 genes in PC12 cells by activating the Sp1 transcription factor." J Neurosci 17(16): 6122-6132.
Yanaihara, N., N. Caplen, E. Bowman, M. Seike, K. Kumamoto, M. Yi, R. M. Stephens, A. Okamoto, J. Yokota, T. Tanaka, G. A. Calin, C. G. Liu, C. M. Croce and C. C. Harris (2006). "Unique microRNA molecular profiles in lung cancer diagnosis and prognosis." Cancer Cell 9(3): 189-198.
Yang, H. C., J. Y. Chuang, W. Y. Jeng, C. I. Liu, A. H. Wang, P. J. Lu, W. C. Chang and J. J. Hung (2014). "Pin1-mediated Sp1 phosphorylation by CDK1 increases Sp1 stability and decreases its DNA-binding activity during mitosis." Nucleic Acids Res.
Yeh, S. H., W. B. Yang, P. W. Gean, C. Y. Hsu, J. T. Tseng, T. P. Su, W. C. Chang and J. J. Hung (2011). "Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway." Nucleic Acids Res 39(13): 5412-5423.
Yuan, J. H., F. Yang, B. F. Chen, Z. Lu, X. S. Huo, W. P. Zhou, F. Wang and S. H. Sun (2011). "The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma." Hepatology 54(6): 2025-2035.
Zeisberg, M. and E. G. Neilson (2009). "Biomarkers for epithelial-mesenchymal transitions." J Clin Invest 119(6): 1429-1437.
Zhang, L., T. Liu, Y. Huang and J. Liu (2011). "microRNA-182 inhibits the proliferation and invasion of human lung adenocarcinoma cells through its effect on human cortical actin-associated protein." Int J Mol Med 28(3): 381-388.
Zhang, S., J. Hao, F. Xie, X. Hu, C. Liu, J. Tong, J. Zhou, J. Wu and C. Shao (2011). "Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development." Carcinogenesis 32(8): 1183-1189.
Zoller, M. (2011). "CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?" Nature Reviews Cancer 11(4): 254-267.