探討CSC-3436經由Twist/Bmi1/Akt 訊息路徑抑制頭頸鱗狀上皮癌的上皮細胞間質轉換現象

簡易檢索 / 詳目顯示

回結果列表

研究生：	賴瀅如 Lai, Ying-Ju
論文名稱：	探討CSC-3436經由Twist/Bmi1/Akt 訊息路徑抑制頭頸鱗狀上皮癌的上皮細胞間質轉換現象 CSC-3436 Inhibits Twist-Induced Epithelial-Mesenchymal Transition via the Suppression of Twist/Bmi1/Akt Pathway in Head and Neck Squamous Cell Carcinoma
指導教授：	陳炯東 Chen, Chiung-Tong 魏宗德 Way, Tzong-Der 莊永仁 Chuang, Yung-Jen
口試委員:	張文祥 Chang, Wun-Shaing 馬念涵 Ma, Nian-han 李易展 Lee, Yi-Jang
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	76
中文關鍵詞：	頭頸鱗狀上皮癌、上皮細胞間質轉換、癌症幹細胞
外文關鍵詞：	Head and neck squamous cell carcinoma (HNSCC), Epithelial-mesenchymal transition (EMT), Bmi1, CSC-3436
相關次數：	點閱：2 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

頭頸部鱗狀細胞癌（HNSCC）占全球癌症好發率的第六位，而在先進國家則為第三位，尤其發生於男性。20% HNSCC患者即使接受化療和靶向治療仍舊發生腫瘤復發和轉移，導致預後不良，研究顯示與產生腫瘤復發和轉移過程有極大相關，即為上皮細胞間質轉換現象(EMT)。我們將HNSCC FaDu細胞大量異位表達在EMT過程中極為關鍵的轉錄因子Twist蛋白 (FaDu-pCDH-Twist cells)，使其產生EMT、增加細胞遷移/侵襲能力，並誘發腫瘤幹細胞(CSCs)能力作為研究模型，研究結果顯示將FaDu-pCDH-Twist細胞以新合成的CSC-3436 （黃酮類化合物）處理, 可造成癌細胞形態改變回正常上皮細胞型態，回復Fadu-pCDH-Twist 細胞中下降的E-鈣粘蛋白 (E-cadherin) mRNA和蛋白表現，下調N-鈣粘蛋白 (N-cadherin)，波形蛋白 (vimentin) 和CD133（腫瘤幹細胞表面標誌蛋白）。此外，CSC-3436亦可直接減少Bmi1蛋白表達，並進一步抑制Twist蛋白和Bmi1蛋白對E-鈣粘蛋白的直接共同調節作用，另外我們使用抑制劑證實，在Fadu-pCDH-Twist 細胞中，CSC-3436經由抑制Twist / Bmi1 / Akt訊息路徑降低了EMT、遷移/侵襲與誘發腫瘤幹細胞能力。我們的研究結果在HNSCC治療上提供了一個新的證據，即CSC-3436可直接抑制Bmi1蛋白表現及Bmi1在HNSCC中的致癌分子途徑，這項發現對於HNSCC患者在治療和未來預後追蹤上也扮演極重要價值。

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide, especially in male. 20% HNSCC patients undergo tumor recurrence and metastasis even with chemotherapy and targeted therapy, resulting in a poor prognosis. Twist, a key transcriptional factor of epithelial-mesenchymal transition (EMT), was ectopically expressed in HNSCC FaDu cells, which triggered EMT and resulted in the acquisition of a mesenchymal phenotype as a cell model in this thesis. Our results demonstrated that treatment with newly synthesized CSC-3436, a flavonoid derivative, reduced Twist-induced scattering of its cell morphology, upregulated E-cadherin mRNA and protein expression, downregulated N-cadherin, vimentin, and CD133 (a marker associated with tumor-initiating cells) in FaDu-pCDH-Twist cells. Moreover, CSC-3436 exposure reduced Bmi1 expression regulated by Twist and further suppressed the direct co-regulation of E-cadherin by Twist and Bmi1. Interestingly, CSC-3436 reduced EMT, cancer stemness and migration/invasion abilities through the inhibition of Twist/Bmi1/Akt pathway. Most importantly, our findings provide a new evidence that CSC-3436 plays a crucial role in therapeutic targeting to Bmi1 and its molecular pathway in HNSCC and will be valuable in prognostic prediction and treatment.

Contents
Contents…………………………………………………………………………… …I
Acknowledgements………………………………………………………………….VI
中文摘要…………………………………………………………………………....VII
Abstract………………..…………………………………………………………..ⅤIII
Abbreviations……………….………………………………………………………IX
1. Introduction………………………………………………………………………..1
1.1 Head and neck squamous cell carcinoma (HNSCC)…………………………..1
1.2 Current diagnosis and treatment of HNSCC…………………..........................2
1.3 Epithelial-mesenchymal transition (EMT) and the related protein……………4
1.4 Cancer stem cells (CSCs)……………………………………………………...6
1.5 The important molecular mechanism of EMT and CSCs stemness in HNSCC.9
1.6 CSC-3436…………………………………………………………………….11
1.7 Objectives and significant findings of this study……………….....................12
2. Materials and methods……………………………………………..…………….14
2.1 Cell lines and plasmids……………………………………………….………14
2.2 Generation of stable cells using retroviral infection………………………....14
2.3 Reagents and antibodies……………………………………………………...15
2.4 MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell
viability assay………………………………………………………………..16
2.5 Western blot analysis………………………………………………………...16
2.6 Cell migration assay………………………………………………………....17
2.7 Cell invasion assay…………………………………………..........................17
2.8 Soft-agar colony formation assay…………………………………………....18
2.9 Immunofluorescence assay (Confocal microscopy) …………………….......18
2.10 Quantitative real-time polymerase chain reaction………………………….19
2.11 Immunoprecipitation assay………………………………………………....20
2.12 Reporter construct generation, transient transfection and dual-luciferase reporter assay……………………………………………………………….20
2.13 Quantitative chromatin immunoprecipitation………………...……….…....21
2.14 In vivo tail vein metastasis assay………………………………………........23
2.15 Statistical analysis…………………………………………………...……...23
3. Results…………………………………………………………………….………25
3.1 CSC-3436 inhibits Twist-induced EMT abilities in FaDu-pCDH-Twist cell.25
3.2 CSC-3436 inhibits the EMT-related transcription factor in FaDu-pCDH-
Twist cells…………………………………………………………………...26
3.3 CSC-3436 inhibits EMT, migration/invasion and tumor-initiating abilities of FaDu-pCDH-Twist through suppressing Bmi1 expression……………….…27
3.4 CSC-3436 inhibits EMT, migration/invasion and tumor-initiating abilities induced by Twist overexpression through suppressing Akt pathway...............28
3.5 CSC-3436 inhibits Twist-induced EMT through blocking the co-occupancy of Twist and Bmi1 on E-cadherin promoter in HNSCC………………………...30
3.6 CSC-3436 inhibits Twist-induced invasion in vivo……………………….…31
4. Discussion…………………………………………………………………………33
5. Future perspectives………………………………………………………………38
6. References…………………………………………………………………...……40
7. Figures and Table………………………………………..……………………….49
Figure 1. The structure of CSC-3436…………………………………………....49
Figure 2. Map of pCDH-CMV-MCS-EF1-copGFP plasmid…………………….49
Figure 3. Map of pXP2 Luciferase reporter plasmid…………………………….49
Figure 4. (a). Map of pCMVDR8.91 plasmid……………………………………50
Figure 4. (b). Map of pMD.G plasmid…………………………………………..50
Figure 5. Cell viability was assessed by MTT assay…………………………….51
Figure 6. CSC-3436 inhibits Twist-induced EMT abilities in FaDu-pCDH-Twist cells………………………………………………………………..…...54
Figure 7. CSC-3436 inhibits the EMT - related transcription factor in FaDu-pCDH-Twist cells………………………………………………...........57
Figure 8. CSC-3436 inhibits EMT, migration/invasion and tumor-initiating abilities of FaDu-pCDH-Twist through suppressing Bmi1expression...58
Figure 9. CSC-3436 inhibits EMT, migration/invasion and tumor-initiating abilities induced by Twist overexpression through suppressing Akt pathway………………………………………………………………...59
Figure 10. CSC-3436 inhibits Twist-induced EMT through blocking the co-
occupancy of Twist and Bmi1 on E-cadherin promoter in HNSCC....62
Figure 11. CSC-3436 inhibits Twist-induced invasion in vivo…………………..65
Figure 12. Summary………………………………………………...…………...66
Table 1. cDNA synthesis reaction……………………………………………….67
Table 2. Quantitative real-time PCR reaction…………………………………...67
8. Supporting Information……………………………………………........68
Figure S1. Effect of CSC-3436 on the EMT marker expression and tumor
initiated activity in HNSCC OECM and SAS cells…………….…68
Figure S2. Effect of CSC-3436 on the EMT related transcription factor expression in HNSCC OECM and SAS cells……………………...69
Figure S3. Effect of CSC-3436 on the Akt activity in HNSCC OECM and SAS
cells…………………………………………………………..……..70
9. Appendix (Raw data)……………………………………………………………..71
Publications
CSC-3436 inhibits TWIST-induced epithelial-mesenchymal transition via the suppression of Twist/Bmi1/Akt pathway in head and neck squamous cell carcinoma.
J Cell Physiol. 2019 Jun;234(6):9118-9129. doi: 10.1002/jcp.27589.

                                

Abd El hafez A, El-Hadaad HA. 2014. Immunohistochemical expression and prognostic relevance of Bmi-1, a stem cell factor, in epithelial ovarian cancer. Ann Diagn Pathol. 18(2):58-62. doi: 10.1016/j.anndiagpath.2013.11.004.
Afshari K, Haddadi NS, Haj-Mirzaian A, Farzaei MH, Rohani MM, Akramian F, Naseri R, Sureda A, Ghanaatian N, Abdolghaffari AH. 2019. Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies. J Cell Physiol. doi: 10.1002/jcp.28777. [Epub ahead of print].
Allegra E, Trapasso S, Pisani D, Puzzo L. 2014. The role of Bmi1 as a biomarker of cancer stem cells in head and neck cancer: a review. Oncology. 86(4):199-205. doi: 10.1159/000358598.
American Cancer Society. Cancer Facts & Figures 2019. A Cancer Journal for Clinicians.
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. 2010. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 363(1):24-35. doi: 10.1056/NEJMoa0912217.
Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, Tanger E, Hulsman D, Leung C, Arsenijevic Y, Marino S, van Lohuizen M. 2005. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 19(12):1438-1443. doi: 10.1101/gad.1299305.
Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT, ME LL. 2016. The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev. 49:25-36. doi: 10.1016/j.ctrv.2016.07.001.
Chang CJ, Hsu CC, Chang CH, Tsai LL, Chang YC, Lu SW, Yu CH, Huang HS, Wang JJ, Tsai CH, Chou MY, Yu CC, Hu FW. 2011. Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep. 26(4):1003-1010. doi: 10.3892/or.2011.1360.
Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y. 2013. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 4:e875. doi: 10.1038/cddis.2013.407.
Chang LC, Yu YL, Liu CY, Cheng YY, Chou RH, Hsieh MT, Lin HY, Hung HY, Huang LJ, Wu YC, Kuo SC. 2015a. The newly synthesized 2-arylnaphthyridin-4-one, CSC-3436, induces apoptosis of non-small cell lung cancer cells by inhibiting tubulin dynamics and activating CDK1. Cancer Chemother Pharmacol. 75(6):1303-1315. doi: 10.1007/s00280-015-2765-0.
Chang YC, Jan CI, Peng CY, Lai YC, Hu FW, Yu CC. 2015b. Activation of microRNA-494-targeting Bmi1 and ADAM10 by silibinin ablates cancer stemness and predicts favourable prognostic value in head and neck squamous cell carcinomas. Oncotarget. 6(27):24002-24016. doi: 10.18632/oncotarget.4365.
Chang YW, Su YJ, Hsiao M, Wei KC, Lin WH, Liang CL, Chen SC, Lee JL. 2015c. Diverse targets of beta-Catenin during the epithelial-mesenchymal transition define cancer stem cells and predict disease relapse. Cancer Res. 75(16):3398-3410. doi: 10.1158/0008-5472.CAN-14-3265.
Chen CC, You JY, Gau JP, Huang CE, Chen YY, Tsai YH, Chou HJ, Lung J, Yang MH. 2015. Favorable clinical outcome and unique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia. Blood cancer J. 5:e339. doi: 10.1038/bcj.2015.67.
Chen D, Wu M, Li Y, Chang I, Yuan Q, Ekimyan-Salvo M, Deng P, Yu B, Yu Y, Dong J, Szymanski JM, Ramadoss S, Li J, Wang CY. 2017. Targeting Bmi1(+) cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell stem cell. 20(5):621-634.e6. doi: 10.1016/j.stem.2017.02.003.
Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, Wicha MS, Prince ME. 2010. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 32(9):1195-1201. doi: 10.1002/hed.21315.
Crea F, Duhagon Serrat MA, Hurt EM, Thomas SB, Danesi R, Farrar WL. 2011. BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer. 128(8):1946-1954. doi: 10.1002/ijc.25522.
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC. 2009. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 106(33):13820-13825. doi: 10.1073/pnas.0905718106.
da Silva AB, Cerqueira Coelho PL, das Neves Oliveira M, Oliveira JL, Oliveira Amparo JA, da Silva KC, Soares JRP, Pitanga BPS, Dos Santos Souza C, de Faria Lopes GP, da Silva VDA, de Fatima Dias Costa M, Junier MP, Chneiweiss H, Moura-Neto V, Costa SL. 2019. The flavonoid rutin and its aglycone quercetin modulate the microglia inflammatory profile improving antiglioma activity. Brain Behav Immun. pii: S0889-1591(19)30042- X. doi: 10.1016/j.bbi.2019.05.003. [Epub ahead of print].
da Silva SD, Alaoui-Jamali MA, Soares FA, Carraro DM, Brentani HP, Hier M, Rogatto SR, Kowalski LP. 2014. Twist1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. Cancer 120(3):352-362. doi: 10.1002/cncr.28404.
Du R, Xia L, Ning X, Liu L, Sun W, Huang C, Wang H, Sun S. 2014. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell 25(17):2650-2659. doi: 10.1091/mbc.E14-01-0044.
Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA. 2009. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 106(1):268-273. doi: 10.1073/pnas.0810956106.
Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z. 2007. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 282(15):11221-11229. doi: 10.1074/jbc.M611871200.
Glackin CA. 2014. Targeting the Twist and Wnt signaling pathways in metastatic breast cancer. Maturitas. 79(1):48-51. doi: 10.1016/j.maturitas.2014.06.015.
Godwin JL, Jaggi S, Sirisena I, Sharda P, Rao AD, Mehra R, Veloski C. 2017. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer. 5:40. doi: 10.1186/s40425-017-0245-2.
Griffith J, Andrade D, Mehta M, Berry W, Benbrook DM, Aravindan N, Herman TS, Ramesh R, Munshi A. 2017. Silencing Bmi1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy. Oncol Rep. 37(4):2382-2390. doi: 10.3892/or.2017.5478.
Harper LJ, Piper K, Common J, Fortune F, Mackenzie IC. 2007. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med. 36(10):594-603. doi : 10.1111/j.1600-0714.2007.00617.x.
He J, Lee HJ, Saha S, Ruan D, Guo H, Chan CH. 2019. Inhibition of USP2 eliminates cancer stem cells and enhances TNBC responsiveness to chemotherapy. Cell Death Dis. 10(4):285. doi: 10.1038/s41419-019-1512-6.
Henson DE, Ries L, Shambaugh EM. 1992. Survival results depend on the staging system. Semin Surg Oncol. 8(2):57-61. PMID: 1615264.
Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H, van Lohuizen M, Nakauchi H. 2004. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 21(6):843-851. doi: 10.1016/j.immuni.2004.11.004.
Javed Z, Muhammad Farooq H, Ullah M, Zaheer Iqbal M, Raza Q, Sadia H, Pezzani R, Salehi B, Sharifi-Rad J, Cho WC. 2019. Wnt signaling: a potential therapeutic target in head and neck squamous cell carcinoma. Asian Pac J Cancer Prev. 20(4):995-1003. doi : 10.31557/APJCP.2019.20.4.995.
Jeon K. 2012. International Review of Cell and Molecular Biology. Volume 294. eBook ISBN: 9780123946416.
Kamijo T. 2012. Role of stemness-related molecules in neuroblastoma. Pediatr
Res. 71(4 Pt 2):511-515. doi: 10.1038/pr.2011.54.
Karabajakian A, Toussaint P, Neidhardt EM, Paulus V, Saintigny P, Fayette J. 2017. Chemotherapy for recurrent/metastatic head and neck cancers. Anticancer Drugs. 28(4):357-361. doi: 10.1097/CAD.0000000000000473.
Kim JY, Shim SH. 2019. Epimedium koreanum extract and its flavonoids reduced atherosclerotic risk via suppressing modification of human HDL. Nutrients. 11(5). pii: E1110. doi: 10.3390/nu11051110.
Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. 1995. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 24(10):450-453. PMID: 8600280.
Kolenda T, Guglas K, Kopczynska M, Teresiak A, Blizniak R, Mackiewicz A, Lamperska K, Mackiewicz J. 2019. Oncogenic role of ZFAS1 incRNA in head and neck squamous cell carcinomas. Cells. 8(4). pii: E366. doi: 10.3390/cells8040366.
Kong Y, Peng Y, Liu Y, Xin H, Zhan X, Tan W. 2015. Twist1 and Snail link Hedgehog signaling to tumor-initiating cell-like properties and acquired chemoresistance independently of ABC transporters. Stem Cells. 33(4):1063-1074. doi: 10.1002/stem.1955.
Koren A, Rijavec M, Kern I, Sodja E, Korosec P, Cufer T. 2016. Bmi1, ALDH1A1, and CD133 transcripts connect Epithelial-Mesenchymal Transition to cancer stem cells in lung carcinoma. Stem Cells Int. 2016:9714315. doi: 10.1155/2016/9714315.
Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. 2012. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation. 125(14):1795-1808. doi: 10.1161/CIRCULATIONAHA.111.040352.
Kurth I, Hein L, Mabert K, Peitzsch C, Koi L, Cojoc M, Kunz-Schughart L, Baumann M, Dubrovska A. 2015. Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget. 6(33):34494-34509. doi: 10.18632/oncotarget.5417.
Larue L, Bellacosa A. 2005. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 24(50):7443-7454. doi : 10.1038/sj.onc.1209091
Lee CH, Hur DG, Roh HJ, Rha KS, Jin HR, Rhee CS, Min YG. 2007. Survival rates of sinonasal squamous cell carcinoma with the new AJCC staging system. Arch Otolaryngol Head Neck Surg. 133(2):131-134. doi: 10.1001/archotol.133.2.131.
Lee J, Park M, Ko Y, Kim B, Kim O, Hyun H, Kim D, Sohn H, Moon YL, Lim W. 2017. Ectopic overexpression of CD133 in HNSCC makes it resistant to commonly used chemotherapeutics. Tumour Biol. 39(4):1010428317695534. doi: 10.1177/1010428317695534.
Lee K, Nelson CM. 2012. New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol. 294:171-221. doi: 10.1016/B978-0-12-394305-7.00004-5.
Lee KW, Sung CO, Kim JH, Kang M, Yoo HY, Kim HH, Um SH, Kim SH. 2015. CD10 expression is enhanced by Twist1 and associated with poor prognosis in esophageal squamous cell carcinoma with facilitating tumorigenicity in vitro and in vivo. Int J Cancer. 136(2):310-321. doi: 10.1002/ijc.29006.
Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST. 2006. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 12(18):5369-5376. doi: 10.1158/1078-0432.CCR-05-2722.
Lee YS, Johnson DE, Grandis JR. 2018. An update: emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs. 23(4):283-299. doi: 10.1080/14728214.2018.1543400.
Li J, Zhou BP. 2011. Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 11:49. doi: 10.1186/1471-2407-11-49.
Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, Chen ZQ, Liu XP, Xu ZD. 2009. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 15(8):2657-2665. doi: 10.1158/1078-0432.CCR-08-2372.
Li Z. 2013. CD133: a stem cell biomarker and beyond. Exp Hematol Oncol. 2(1):17. doi: 10.1186/2162-3619-2-17.
Lim H, Kim DH, Jung HY, Gong EJ, Na HK, Ahn JY, Kim MY, Lee JH, Choi KS, Choi KD, Song HJ, Lee GH, Kim JH. 2015. Clinical significance of early detection of esophageal cancer in patients with head and neck cancer. Gut Liver. 9(2):159-165. doi: 10.5009/gnl13401.
Liu K, Sun B, Zhao X, Wang X, Li Y, Qiu Z, Liu T, Gu Q, Dong X, Zhang Y, Wang Y, Zhao N. 2015. Hypoxia promotes vasculogenic mimicry formation by the Twist1-Bmi1 connection in hepatocellular carcinoma. Int J Mol Med. 36(3):783-791. doi: 10.3892/ijmm.2015.2293.
Liu W, Wu L, Shen XM, Shi LJ, Zhang CP, Xu LQ, Zhou ZT. 2013. Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia. Int J Cancer. 132(4):868-874. doi: 10.1002/ijc.27720.
Lu S, Yu L, Mu Y, Ma J, Tian J, Xu W, Wang H. 2014. Role and mechanism of Twist1 in modulating the chemosensitivity of FaDu cells. Mol Med Rep. 10(1):53-60. doi: 10.3892/mmr.2014.2212.
Lv D, Cheng X, Tang L, Jiang M. 2017. The cardioprotective effect of total flavonoids on myocardial ischemia/reperfusion in rats. Biomed Pharmacother. 88:277-284. doi: 10.1016/j.biopha.2017.01.060.
Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, Ganly I, Hakimi AA, Chan TA, Morris LG. 2016. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI insight. 1(17):e89829. doi: 10.1172/jci.insight.89829.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133(4):704-715. doi: 10.1016/j.cell.2008.03.027.
Manthey JA, Grohmann K, Guthrie N. 2001. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem. 8(2):135-153. PMID: 11172671.
McCullough MJ, Prasad G, Farah CS. 2010. Oral mucosal malignancy and potentially malignant lesions: an update on the epidemiology, risk factors, diagnosis and management. Aust Dent J. 55 Suppl 1:61-65. doi: 10.1111/j.1834-7819.2010.01200.x.
Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, Hirsch IB. 2015. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 38(9):e137-138. doi: 10.2337/dc15-0889.
Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. 2008. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 3(8):e2888. doi: 10.1371/journal.pone.0002888.
No. 2015. Expanding the reach of anti-PD-1 therapy. Cancer Discov. 5(7):684-685. doi: 10.1158/2159-8290.CD-NB2015-082.
Pan C, Issaeva N, Yarbrough WG. 2018. HPV-driven oropharyngeal cancer: current knowledge of molecular biology and mechanisms of carcinogenesis. Cancers of the head & neck. 3:12. doi: 10.1186/s41199-018-0039-3.
Paranjape AN, Balaji SA, Mandal T, Krushik EV, Nagaraj P, Mukherjee G, Rangarajan A. 2014. Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog. BMC Cancer. 14:785. doi: 10.1186/1471-2407-14-785.
Park JW, Lee SW. 2015. Clinical outcomes of synchronous head and neck and esophageal cancer. Radiat Oncol J. 33(3):172-178. doi: 10.3857/roj.2015.33.3.172.
Price KA, Cohen EE. 2012. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol. 13(1):35-46. doi: 10.1007/s11864-011-0176-y.
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL,
Clarke MF, Ailles LE. 2007. Identification of a subpopulation of cells with
cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 104(3):973-978. doi: 10.1073/pnas.0610117104.
Randen-Brady R, Carpen T, Jouhi L, Syrjanen S, Haglund C, Tarkkanen J, Remes S, Makitie A, Mattila PS, Silen S, Hagstrom J. 2019. In situ hybridization for high-risk HPV E6/E7 mRNA is a superior method for detecting transcriptionally active HPV in oropharyngeal cancer. Hum Pathol. 90:97-105. doi: 10.1016/j.humpath.2019.05.006.
Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, Bernet V, Burman KD, Kohn LD, Saji M. 2001. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res. 61(16):6105-6111. PMID: 11507060.
Seong RK, Kim JA, Shin OS. 2018. Wogonin, a flavonoid isolated from Scutellaria baicalensis, has anti-viral activities against influenza infection via modulation of AMPK pathways. Acta Virol. 62(1):78-85. doi: 10.4149/av_2018_109.
Siddique HR, Saleem M. 2012. Role of Bmi1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 30(3):372-378. doi: 10.1002/stem.1035.
Siegel RL, Miller KD, Jemal A. 2019. Cancer statistics, 2019. CA Cancer J Clin. 69(1):7-34. doi: 10.3322/caac.21551.
Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS. 2009. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Investjm. 119(12):3626-3636. doi: 10.1172/JCI39374.
Song LB, Zeng MS, Liao WT, Zhang L, Mo HY, Liu WL, Shao JY, Wu QL, Li MZ, Xia YF, Fu LW, Huang WL, Dimri GP, Band V, Zeng YX. 2006. Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res. 66(12):6225-6232. doi: 10.1158/0008-5472.CAN-06-0094.
Sun Y, Han J, Lu Y, Yang X, Fan M. 2012. Biological characteristics of a cell subpopulation in tongue squamous cell carcinoma. Oral Dis. 18(2):169-177. doi: 10.1111/j.1601-0825.2011.01860.x.
Tan FH, Bai Y, Saintigny P, Darido C. 2019. mTOR signalling in head and neck cancer: heads up. Cells. 8(4). pii: E333. doi: 10.3390/cells8040333.
Testa JR, Bellacosa A. 2001. AKT plays a central role in tumorigenesis. Proc Natl Acad
Sci USA. 98(20):10983-10985. doi: 10.1073/pnas.211430998.
Thiery JP, Acloque H, Huang RY, Nieto MA. 2009. Epithelial-mesenchymal transitions in development and disease. Cell. 139(5):871-890. doi: 10.1016/j.cell.2009.11.007.
Wang Q, Li Z, Wu Y, Huang R, Zhu Y, Zhang W, Wang Y, Cheng J. 2017. Pharmacological inhibition of Bmi1 by PTC-209 impaired tumor growth in head neck squamous cell carcinoma. Cancer Cell Int. 17:107. doi: 10.1186/s12935-017-0481-z.
Warnakulasuriya S. 2009. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45(4-5):309-316. doi: 10.1016/j.oraloncology.2008.06.002.
Warnakulasuriya S, Trivedy C, Peters TJ. 2002. Areca nut use: an independent risk factor for oral cancer. BMJ. 324(7341):799-800. doi: 10.1016/j.oraloncology.2008.06.002.
Way TD, Huang JT, Chou CH, Huang CH, Yang MH, Ho CT. 2014. Emodin represses TWIST1-induced epithelial-mesenchymal transitions in head and neck squamous cell carcinoma cells by inhibiting the beta-catenin and Akt pathways. Eur J Cancer. 50(2):366-378. doi: 10.1016/j.ejca.2013.09.025.
Wu ST, Sun GH, Cha TL, Kao CC, Chang SY, Kuo SC, Way TD. 2016. CSC-3436 switched tamoxifen-induced autophagy to apoptosis through the inhibition of AMPK/mTOR pathway. J Biomed Sci. 23(1):60. doi: 10.1186/s12929-016-0275-y.
Wu Z, Min L, Chen D, Hao D, Duan Y, Qiu G, Wang Y. 2011. Overexpression of Bmi1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. PLoS One. 6(2):e14648. doi: 10.1371/journal.pone.0014648.
Yang CX, Sedhom W, Song J, Lu SL. 2019. The role of microRNAs in recurrence and metastasis of head and neck squamous cell carcinoma. Cancers (Basel). 11(3). pii: E395. doi: 10.3390/cancers11030395.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. 2004. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117(7):927-939. doi: 10.1016/j.cell.2004.06.006.
Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, Chang SY, Lee OK, Wu KJ. 2010. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 12(10):982-992. doi: 10.1038/ncb2099.
Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ. 2008. Direct regulation of Twist by HIF-1alpha promotes metastasis. Nat Cell Biol. 10(3):295-305. doi: 10.1038/ncb1691.
Yao C, Xi C, Hu K, Gao W, Cai X, Qin J, Lv S, Du C, Wei Y. 2018. Inhibition of enterovirus 71 replication and viral 3C protease by quercetin. Virol J. 15(1):116. doi: 10.1186/s12985-018-1023-6.
Yu SS, Cirillo N. 2019. The molecular markers of cancer stem cells in head and neck tumors. J Cell Physiol. doi: 10.1002/jcp.28963. [Epub ahead of print].
Yuan B, Zhao H, Xue X, Zhou J, Wang X, Han Y, Zhang L, Guo X, Zhi Q. 2016. Prognostic value and clinicopathological differences of Bmi1 in gastric cancer: a meta-analysis. Anticancer Agents Med Chem. 16(4):407-413. PMID: 25968877.
Zhang Q, Shi S, Yen Y, Brown J, Ta JQ, Le AD. 2010. A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett. 289(2):151-160. doi: 10.1016/j.canlet.2009.08.010.

簡易檢索 / 詳目顯示

相關論文