次亞麻油酸對調控Twist1表現和 Twist1啟動Hs578T人類三陰性乳 腺癌細胞間質化和轉移之研究

Effect of alpha-linolenic acid on Twist1 expression and Twist1- mediated epithelial-mesencylmal transition and metastasis in Hs578T triple-negative human breast cancer cell.

劉淑惠

次亞麻油酸 ； Twist-1 ； 上皮細胞間質化 ； 轉移 ； Hs578T乳癌細胞 ； α-Linolenic acid ； Twist-1 ； EMT ； Metastasis ； Hs578T breast cancer cell

中山醫學大學營養學研究所學位論文

2016年

碩士

李健群

繁體中文

乳癌是全球女性最常見的惡性腫瘤，也是女性癌症死因的第一名。癌細胞轉移是導致乳癌患者死亡的主因。Twist-1屬於basic-helix-loop-helix (bHLH)家族轉錄因子，已被證實在啟動上皮細胞間質化(Epithelial-mesenchymal transition, EMT)，促進多種癌細胞移行和侵襲作用扮演關鍵角色。先前研究證實n-3 PUFAs對於抑制乳癌發展有顯著效果，然而對於抑制三陰性乳癌細胞轉移機制仍不清楚。本研究以Hs578T三陰性乳癌細胞實驗模式，探討次亞麻油酸(α-linolenic acid, 18:3, n-3; ALA)透過何種機制影響癌細胞EMT和轉移。結果顯示：預處理100 μM ALA顯著抑制Twist-1蛋白質表現。處理ALA或利用siRNA將Twist-1基因knockdown後皆可顯著抑制乳癌細胞移行能力。處理ALA 60 min後可顯著抑制p-STAT3α蛋白質表現。一旦將STAT3α基因knockdown後亦可抑制twist-1、N-cadherin蛋白質表現。預處理ALA或twist-1 siRNA可增加上皮標誌物E-cadherin蛋白質表現並顯著抑制twist-1、snail2、N-cadherin、vimentin、fibronection等間質標誌物蛋白質表現。綜合上述實驗結果，ALA可透過負向調控STAT3α表現及活性抑制twist-1表現，進而抑制乳癌細胞間質化並降低三陰性乳癌細胞移行。

Breast cancer is the commonly diagnosed cancer among women all over the world. Metastasis is leading cause of death from breast cancer. Twist-1 is a basic-helix-loop-helix (bHLH) transcription factor essential in embryological morphogenesis. Several studies showed that Twist-1 plays an important role in cancer cell epithelial-mesenchymal transition (EMT), migration and invasion. Previous studies showed thatn-3 PUFAs was observed to display anticancer activity on in breast cancer, however, the anti-metastatic mechanism of n-3 PUFAs for triple-negative breast cancer cells is still unclear. In this study, we investigated the effect of ALA on cell EMT and metastasis on Hs578T TNBC cells We found that 100 μM ALA significantly inhibited Twist-1 expression. Cell migration was suppressed by ALA or Twist-1 siRNA treatment. Treatment with ALA for 60 min significantly inhibited the phosphorylation of STAT3α. Upon STAT3α knockdown, the protein level of twist-1 and N-cadherin were decreased. Pretreatment with ALA or Twist-1 siRNA, increasedthe epithelial marker such as E-cadherin protein expression and decreased the mesenchymal markers including twist-1, snail2, N-cadherin, vimentin, fibronection protein expression. Taken together, our result indicate that ALA suppressed EMT and cell migration may through down-regulation of STAT3α expression and activity as well as twist-1 expression on Hs578T triple-negative breast cancer cells.

1. Abedi, E., and M. A. Sahari. 2014. 'Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties', Food Sci Nutr, 2: 443-63.
   連結：
2. Aittomäki, Saara, and Marko Pesu. 2014. 'Therapeutic targeting of the Jak/STAT pathway', Basic & clinical pharmacology & toxicology, 114: 18-23.
   連結：
3. Albert, Christine M, Kyungwon Oh, William Whang, JoAnn E Manson, Claudia U Chae, Meir J Stampfer, Walter C Willett, and Frank B Hu. 2005. 'Dietary α-linolenic acid intake and risk of sudden cardiac death and coronary heart disease', Circulation, 112: 3232-38.
   連結：
4. Alexander, Nelson R, Nhan L Tran, Harish Rekapally, Carol E Summers, Carlotta Glackin, and Ronald L Heimark. 2006. 'N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1', Cancer research, 66: 3365-69.
   連結：
5. Ansieau, Stéphane. 2013. 'EMT in breast cancer stem cell generation', Cancer letters, 338: 63-68.
   連結：
6. Ascherio, Alberto, Eric B Rimm, Edward L Giovannucci, Donna Spiegelman, Stampfer Meir, and Walter C Willett. 1996. 'Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States', Bmj, 313: 84-90.
   連結：
7. Attisano, Liliana, and Jeffrey L Wrana. 2002. 'Signal transduction by the TGF-β superfamily', Science, 296: 1646-47.
   連結：
8. Barceló-Coblijn, Gwendolyn, and Eric J Murphy. 2009. 'Alpha-linolenic acid and its conversion to longer chain n− 3 fatty acids: Benefits for human health and a role in maintaining tissue n− 3 fatty acid levels', Progress in lipid research, 48: 355-74.
   連結：
9. Barceló-Coblijn, Gwendolyn, Eric J Murphy, Rgia Othman, Mohammed H Moghadasian, Tarek Kashour, and James K Friel. 2008. 'Flaxseed oil and fish-oil capsule consumption alters human red blood cell n–3 fatty acid composition: a multiple-dosing trial comparing 2 sources of n–3 fatty acid', The American journal of clinical nutrition, 88: 801-09.
   連結：
10. Barrallo-Gimeno, Alejandro, and M Angela Nieto. 2005. 'The Snail genes as inducers of cell movement and survival: implications in development and cancer', Development, 132: 3151-61.
    連結：
11. Baylies, Mary K, and Michael Bate. 1996. 'twist: a myogenic switch in Drosophila', Science, 272: 1481.
    連結：
12. Blondeau, Nicolas, Robert H Lipsky, Miled Bourourou, Mark W Duncan, Philip B Gorelick, and Ann M Marini. 2015. 'Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties—Ready for use in the stroke clinic?', BioMed research international, 2015.
    連結：
13. Blondeau, Nicolas, Catherine Widmann, Michel Lazdunski, and Catherine Heurteaux. 2001. 'Activation of the nuclear factor-κB is a key event in brain tolerance', The Journal of Neuroscience, 21: 4668-77.
    連結：
14. Bonaventure, Jacky, and Vincent El Ghouzzi. 2003. 'Molecular and cellular bases of syndromic craniosynostoses', Expert reviews in molecular medicine, 2: 1-17.
    連結：
15. Burdge, G. C. 2006. 'Metabolism of alpha-linolenic acid in humans', Prostaglandins Leukot Essent Fatty Acids, 75: 161-8.
    連結：
16. Calò, Valentina, Manuela Migliavacca, Viviana Bazan, Marcella Macaluso, Maria Buscemi, Nicola Gebbia, and Antonio Russo. 2003. 'STAT proteins: from normal control of cellular events to tumorigenesis', Journal of cellular physiology, 197: 157-68.
    連結：
17. Campos, Hannia, Ana Baylin, and Walter C Willett. 2008. 'α-Linolenic acid and risk of nonfatal acute myocardial infarction', Circulation, 118: 339-45.
    連結：
18. Chang, Qing, Eirini Bournazou, Pasquale Sansone, Marjan Berishaj, Sizhi Paul Gao, Laura Daly, Jared Wels, Till Theilen, Selena Granitto, and Xinmin Zhang. 2013. 'The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis', Neoplasia, 15: 848-IN45.
    連結：
19. Chang, T. M., and W. C. Hung. 2012. 'Transcriptional repression of TWIST1 gene by Prospero-related homeobox 1 inhibits invasiveness of hepatocellular carcinoma cells', FEBS Lett, 586: 3746-52.
    連結：
20. Chen, W., Q. Gao, S. Han, F. Pan, and W. Fan. 2015. 'The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling', Tumour Biol, 36: 973-81.
    連結：
21. Cheng, George Z, Joseph Chan, Qi Wang, Weizhou Zhang, Calvin D Sun, and Lu-Hai Wang. 2007. 'Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel', Cancer research, 67: 1979-87.
    連結：
22. Cho, Kyung Hwa, Kang Jin Jeong, Shang Cheul Shin, Jaeku Kang, Chang Gyo Park, and Hoi Young Lee. 2013. 'STAT3 mediates TGF-β1-induced TWIST1 expression and prostate cancer invasion', Cancer letters, 336: 167-73.
    連結：
23. Christensen, J. H., M. S. Christensen, E. Toft, J. Dyerberg, and E. B. Schmidt. 2000. 'Alpha-linolenic acid and heart rate variability', Nutr Metab Cardiovasc Dis, 10: 57-61.
    連結：
24. Chua, HL1, P Bhat-Nakshatri, SE Clare, A Morimiya, Sunil Badve, and Harikrishna Nakshatri. 2007. 'NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2', Oncogene, 26: 711-24.
    連結：
25. Cobaleda, César, María Pérez-Caro, Carolina Vicente-Dueñas, and Isidro Sánchez-García. 2007. 'Function of the zinc-finger transcription factor SNAI2 in cancer and development', Annu. Rev. Genet., 41: 41-61.
    連結：
26. Comijn, Joke, Geert Berx, Petra Vermassen, Kristin Verschueren, Leo van Grunsven, Erik Bruyneel, Marc Mareel, Danny Huylebroeck, and Frans Van Roy. 2001. 'The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion', Molecular cell, 7: 1267-78.
    連結：
27. Darnell Jr, James E, Ian M Kerr, and George R Stark. 1994. 'Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins', Science-AAAS-weekly paper edition-including guide to scientific information, 264: 1415-20.
    連結：
28. Das, U. N. 2006. 'Essential Fatty acids - a review', Curr Pharm Biotechnol, 7: 467-82.
    連結：
29. Deshpande, R., P. Mansara, and R. Kaul-Ghanekar. 2016. 'Alpha-linolenic acid regulates Cox2/VEGF/MAP kinase pathway and decreases the expression of HPV oncoproteins E6/E7 through restoration of p53 and Rb expression in human cervical cancer cell lines', Tumour Biol, 37: 3295-305.
    連結：
30. Endres, S., R. Ghorbani, V. E. Kelley, K. Georgilis, G. Lonnemann, J. W. van der Meer, J. G. Cannon, T. S. Rogers, M. S. Klempner, P. C. Weber, and et al. 1989. 'The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells', N Engl J Med, 320: 265-71.
    連結：
31. Feldmann, Georg, Surajit Dhara, Volker Fendrich, Djahida Bedja, Robert Beaty, Michael Mullendore, Collins Karikari, Hector Alvarez, Christine Iacobuzio-Donahue, and Antonio Jimeno. 2007. 'Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers', Cancer research, 67: 2187-96.
    連結：
32. Foulkes, W. D., I. E. Smith, and J. S. Reis-Filho. 2010. 'Triple-negative breast cancer', N Engl J Med, 363: 1938-48.
    連結：
33. Gao, Wei, Catherine Sweeney, Mary Connolly, Aisling Kennedy, Chin Teck Ng, Jennifer McCormick, Douglas J Veale, and Ursula Fearon. 2012. 'Notch‐1 mediates hypoxia‐induced angiogenesis in rheumatoid arthritis', Arthritis & Rheumatism, 64: 2104-13.
    連結：
34. Garg, Minal. 2013. 'Epithelial-mesenchymal transition-activating transcription factors-multifunctional regulators in cancer', World J Stem Cells, 5: 188-95.
    連結：
35. Gordon, Michael D, and Roel Nusse. 2006. 'Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors', Journal of Biological Chemistry, 281: 22429-33.
    連結：
36. Gort, Eelke H, Karijn PM Suijkerbuijk, Suzan M Roothaan, Venu Raman, Marc Vooijs, Elsken van der Wall, and Paul J van Diest. 2008. 'Methylation of the TWIST1 promoter, TWIST1 mRNA levels, and immunohistochemical expression of TWIST1 in breast cancer', Cancer Epidemiology Biomarkers & Prevention, 17: 3325-30.
    連結：
37. Greenburg, Gary, and Elizabeth D Hay. 1982. 'Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells', The Journal of cell biology, 95: 333-39.
    連結：
38. Harper, Charles R, and Terry A Jacobson. 2005. 'Usefulness of omega-3 fatty acids and the prevention of coronary heart disease', The American journal of cardiology, 96: 1521-29.
    連結：
39. Hong, J., J. Zhou, J. Fu, T. He, J. Qin, L. Wang, L. Liao, and J. Xu. 2011. 'Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness', Cancer Res, 71: 3980-90.
    連結：
40. Hosono, S, H Kajiyama, M Terauchi, K Shibata, K Ino, A Nawa, and F Kikkawa. 2007. 'Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients', British journal of cancer, 96: 314-20.
    連結：
41. Johnston, Paul A, and Jennifer R Grandis. 2011. 'STAT3 signaling: anticancer strategies and challenges', Molecular interventions, 11: 18.
    連結：
42. Kalluri, Raghu, and Robert A Weinberg. 2009. 'The basics of epithelial-mesenchymal transition', The Journal of clinical investigation, 119: 1420-28.
    連結：
43. Karvonen, Henna M, Antti Aro, Niina S Tapola, Irma Salminen, Matti IJ Uusitupa, and Essi S Sarkkinen. 2002. 'Effect of [alpha]-linolenic acid [ndash] rich Camelina sativa oil on serum fatty acid composition and serum lipids in hypercholesterolemic subjects', Metabolism, 51: 1253-60.
    連結：
44. Kim, Eun Soo, Sung Yi Hong, Hye Kyung Lee, Seung Won Kim, Min Ji An, Tae Il Kim, Kyoung Ryul Lee, Won Ho Kim, and Jae Hee Cheon. 2008. 'Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells', Oncology reports, 20: 1321.
    連結：
45. Kim, Ji‐Yoon, Han Deuk Park, Eunju Park, Jeong‐Woo Chon, and Yoo Kyoung Park. 2009. 'Growth‐inhibitory and proapoptotic effects of alpha‐linolenic acid on estrogen‐positive breast cancer cells', Annals of the New York Academy of Sciences, 1171: 190-95.
    連結：
46. Kim, Kyu-Bong, Yoon A Nam, Hyung Sik Kim, A Wallace Hayes, and Byung-Mu Lee. 2014. 'α-Linolenic acid: nutraceutical, pharmacological and toxicological evaluation', Food and Chemical Toxicology, 70: 163-78.
    連結：
47. Lang-Lazdunski, Loïc, Nicolas Blondeau, Gisèle Jarretou, Michel Lazdunski, and Catherine Heurteaux. 2003. 'Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats', Journal of vascular surgery, 38: 564-75.
    連結：
48. Leaf, A. 2007. 'Omega-3 fatty acids and prevention of arrhythmias', Curr Opin Lipidol, 18: 31-4.
    連結：
49. Lin, Li, Aiguo Liu, Zhengang Peng, Huey-Jen Lin, Pui-Kai Li, Chenglong Li, and Jiayuh Lin. 2011. 'STAT3 is necessary for proliferation and survival in colon cancer–initiating cells', Cancer research, 71: 7226-37.
    連結：
50. Ling, Xiaoyang, and Ralph B Arlinghaus. 2005. 'Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice', Cancer research, 65: 2532-36.
    連結：
51. Liu, Jiajie, and David WL Ma. 2014. 'The role of n-3 polyunsaturated fatty acids in the prevention and treatment of breast cancer', Nutrients, 6: 5184-223.
    連結：
52. Lo, Hui-Wen, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L Abbruzzese, Gabriel N Hortobagyi, and Mien-Chie Hung. 2007. 'Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression', Cancer research, 67: 9066-76.
    連結：
53. Lombaerts, M, T Van Wezel, K Philippo, JWF Dierssen, RME Zimmerman, J Oosting, R Van Eijk, PH Eilers, B van De Water, and CJ Cornelisse. 2006. 'E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines', British journal of cancer, 94: 661-71.
    連結：
54. Marusyk, A., and K. Polyak. 2010. 'Tumor heterogeneity: causes and consequences', Biochim Biophys Acta, 1805: 105-17.
    連結：
55. Marventano, S., P. Kolacz, S. Castellano, F. Galvano, S. Buscemi, A. Mistretta, and G. Grosso. 2015. 'A review of recent evidence in human studies of n-3 and n-6 PUFA intake on cardiovascular disease, cancer, and depressive disorders: does the ratio really matter?', Int J Food Sci Nutr, 66: 611-22.
    連結：
56. Marx, Nikolaus, Bettina Kehrle, Klaus Kohlhammer, Miriam Grüb, Wolfgang Koenig, Vinzenz Hombach, Peter Libby, and Jorge Plutzky. 2002. 'PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis', Circulation research, 90: 703-10.
    連結：
57. Marx, Nikolaus, Uwe Schönbeck, Mitchell A Lazar, Peter Libby, and Jorge Plutzky. 1998. 'Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells', Circulation research, 83: 1097-103.
    連結：
58. Matsuo, Noriyuki, Hidenori Shiraha, Tatsuya Fujikawa, Nobuyuki Takaoka, Naoki Ueda, Shigetomi Tanaka, Shinichi Nishina, Yutaka Nakanishi, Masayuki Uemura, and Akinobu Takaki. 2009. 'Twist expression promotes migration and invasion in hepatocellular carcinoma', BMC cancer, 9: 1.
    連結：
59. Micalizzi, Douglas S, Susan M Farabaugh, and Heide L Ford. 2010. 'Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression', Journal of mammary gland biology and neoplasia, 15: 117-34.
    連結：
60. Mohan, Chakrabhavi Dhananjaya, Hanumantharayappa Bharathkumar, Krishna C Bulusu, Vijay Pandey, Shobith Rangappa, Julian E Fuchs, Muthu K Shanmugam, Xiaoyun Dai, Feng Li, and Amudha Deivasigamani. 2014. 'Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo', Journal of Biological Chemistry, 289: 34296-307.
    連結：
61. Moody, Susan E, Denise Perez, Tien-chi Pan, Christopher J Sarkisian, Carla P Portocarrero, Christopher J Sterner, Kathleen L Notorfrancesco, Robert D Cardiff, and Lewis A Chodosh. 2005. 'The transcriptional repressor Snail promotes mammary tumor recurrence', Cancer cell, 8: 197-209.
    連結：
62. Murone, Maximilien, Arnon Rosenthal, and Frederic J de Sauvage. 1999. 'Sonic hedgehog signaling by the patched–smoothened receptor complex', Current Biology, 9: 76-84.
    連結：
63. Peinado, Héctor, David Olmeda, and Amparo Cano. 2007. 'Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?', Nature Reviews Cancer, 7: 415-28.
    連結：
64. Polyak, Kornelia, and Robert A Weinberg. 2009. 'Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits', Nature Reviews Cancer, 9: 265-73.
    連結：
65. Puisieux, A, S Valsesia-Wittmann, and S Ansieau. 2006. 'A twist for survival and cancer progression', British journal of cancer, 94: 13-17.
    連結：
66. Ricote, Mercedes, Annabel F Valledor, and Christopher K Glass. 2004. 'Decoding Transcriptional Programs Regulated by PPARs and LXRs in the Macrophage Effects on Lipid Homeostasis, Inflammation, and Atherosclerosis', Arteriosclerosis, thrombosis, and vascular biology, 24: 230-39.
    連結：
67. Rosivatz, Erika, Ingrid Becker, Katja Specht, Elena Fricke, Birgit Luber, Raymonde Busch, Heinz Höfler, and Karl-Friedrich Becker. 2002. 'Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer', The American journal of pathology, 161: 1881-91.
    連結：
68. Sánchez-Tilló, Ester, Yongqing Liu, Oriol de Barrios, Laura Siles, Lucia Fanlo, Miriam Cuatrecasas, Douglas S Darling, Douglas C Dean, Antoni Castells, and Antonio Postigo. 2012. 'EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness', Cellular and molecular life sciences, 69: 3429-56.
    連結：
69. Sandri, Jacqueline, and Jacques Viala. 1995. 'Direct preparation of (Z, Z)-1, 4-dienic units with a new C6 homologating agent: Synthesis of α-linolenic acid', Synthesis, 1995: 271-75.
    連結：
70. Serini, S., E. Fasano, E. Piccioni, G. Monego, A. R. Cittadini, L. Celleno, F. O. Ranelletti, and G. Calviello. 2012. 'DHA induces apoptosis and differentiation in human melanoma cells in vitro: involvement of HuR-mediated COX-2 mRNA stabilization and beta-catenin nuclear translocation', Carcinogenesis, 33: 164-73.
    連結：
71. Simons, Kai, and Derek Toomre. 2000. 'Lipid rafts and signal transduction', Nature reviews Molecular cell biology, 1: 31-39.
    連結：
72. Simopoulos, A. P. 2006. 'Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases', Biomed Pharmacother, 60: 502-7.
    連結：
73. Siveen, Kodappully Sivaraman, Sakshi Sikka, Rohit Surana, Xiaoyun Dai, Jingwen Zhang, Alan Prem Kumar, Benny KH Tan, Gautam Sethi, and Anupam Bishayee. 2014. 'Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors', Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1845: 136-54.
    連結：
74. Song, Li-Bing, Wen-Ting Liao, Hai-Qiang Mai, Hui-Zhong Zhang, Ling Zhang, Man-Zhi Li, Jing-Hui Hou, Li-Wu Fu, Wen-Lin Huang, and Yi-Xin Zeng. 2006. 'The clinical significance of twist expression in nasopharyngeal carcinoma', Cancer letters, 242: 258-65.
    連結：
75. Stasinopoulos, Ioannis A, Yelena Mironchik, Ana Raman, Flonne Wildes, Paul Winnard, and Venu Raman. 2005. 'HOXA5-twist interaction alters p53 homeostasis in breast cancer cells', Journal of Biological Chemistry, 280: 2294-99.
    連結：
76. Subramaniam, Aruljothi, Muthu K Shanmugam, Ekambaram Perumal, Feng Li, Alamelu Nachiyappan, Xiaoyun Dai, Shivananju Nanjunda Swamy, Kwang Seok Ahn, Alan Prem Kumar, and Benny KH Tan. 2013. 'Potential role of signal transducer and activator of transcription (STAT) 3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma', Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1835: 46-60.
    連結：
77. Sun, Haiguo, Yunping Hu, Zhennan Gu, Rick T Owens, Yong Q Chen, and Iris J Edwards. 2011. 'Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway', Carcinogenesis, 32: 1518-24.
    連結：
78. Takeda, Kiyoshi, Koichi Noguchi, Wei Shi, Takashi Tanaka, Makoto Matsumoto, Nobuaki Yoshida, Tadamitsu Kishimoto, and Shizuo Akira. 1997. 'Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality', Proceedings of the National Academy of Sciences, 94: 3801-04.
    連結：
79. Tang, Y., Y. Wang, M. F. Kiani, and B. Wang. 2016. 'Classification, Treatment Strategy, and Associated Drug Resistance in Breast Cancer', Clin Breast Cancer.
    連結：
80. Thiery, Jean Paul. 2002. 'Epithelial–mesenchymal transitions in tumour progression', Nature Reviews Cancer, 2: 442-54.
    連結：
81. Thiery, Jean Paul, and Jonathan P Sleeman. 2006. 'Complex networks orchestrate epithelial–mesenchymal transitions', Nature reviews Molecular cell biology, 7: 131-42.
    連結：
82. Truan, Jennifer S, Jian‐Min Chen, and Lilian U Thompson. 2010. 'Flaxseed oil reduces the growth of human breast tumors (MCF‐7) at high levels of circulating estrogen', Molecular nutrition & food research, 54: 1414-21.
    連結：
83. Tsai, Jeff H, and Jing Yang. 2013. 'Epithelial–mesenchymal plasticity in carcinoma metastasis', Genes & development, 27: 2192-206.
    連結：
84. Tvrzicka, Eva, Lefkothea-Stella Kremmyda, Barbora Stankova, and Ales Zak. 2011. 'Fatty acids as biocompounds: their role in human metabolism, health and disease–a review. Part 1: classification, dietary sources and biological functions', Biomedical Papers, 155: 117-30.
    連結：
85. Vandewalle, Cindy, Frans Van Roy, and Geert Berx. 2009. 'The role of the ZEB family of transcription factors in development and disease', Cellular and molecular life sciences, 66: 773-87.
    連結：
86. Vecchini, A, V Ceccarelli, F Susta, P Caligiana, P Orvietani, L Binaglia, G Nocentini, C Riccardi, G Calviello, and P Palozza. 2004. 'Dietary α-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells', Journal of lipid research, 45: 308-16.
    連結：
87. Vesuna, Farhad, and Venu Raman. 2010. 'Mus musculus twist homolog 1 (Drosophila)'.
    連結：
88. Vesuna, Farhad, Paul Winnard Jr, Venu Raman, and Carlotta Glackin. 2006. 'Twist overexpression promotes chromosomal instability in the breast cancer cell line MCF-7', Cancer genetics and cytogenetics, 167: 189.
    連結：
89. Wake, Matthew S, and Christine J Watson. 2015. 'STAT3 the oncogene–still eluding therapy?', FEBS journal, 282: 2600-11.
    連結：
90. Wang, Chenchen, William S Harris, Mei Chung, Alice H Lichtenstein, Ethan M Balk, Bruce Kupelnick, Harmon S Jordan, and Joseph Lau. 2006. 'n− 3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary-and secondary-prevention studies: a systematic review', The American journal of clinical nutrition, 84: 5-17.
    連結：
91. Wang, Zhiwei, Yiwei Li, Dejuan Kong, and Fazlul H Sarkar. 2010. 'The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness', Current drug targets, 11: 745-51.
    連結：
92. Wiggins, Ashleigh KA, Julie K Mason, and Lilian U Thompson. 2015. 'Growth and gene expression differ over time in alpha-linolenic acid treated breast cancer cells', Experimental cell research, 333: 147-54.
    連結：
93. Wushou, Alimujiang, Jing Hou, Ya-Jun Zhao, and Zhi-Ming Shao. 2014. 'Twist-1 up-regulation in carcinoma correlates to poor survival', International journal of molecular sciences, 15: 21621-30.
    連結：
94. Xie, Nianlin, Wei Zhang, Jia Li, Hongliang Liang, Huasong Zhou, Weixun Duan, Xuezeng Xu, Shiqiang Yu, Haifeng Zhang, and Dinghua Yi. 2011. 'α-Linolenic acid intake attenuates myocardial ischemia/reperfusion injury through anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats', Archives of medical research, 42: 171-81.
    連結：
95. Yap, Alpha S, William M Brieher, and Barry M Gumbiner. 1997. 'Molecular and functional analysis of cadherin-based adherens junctions', Annual review of cell and developmental biology, 13: 119-46.
    連結：
96. Zajac, M., J. Law, D. D. Cvetkovic, M. Pampillo, L. McColl, C. Pape, G. M. Di Guglielmo, L. M. Postovit, A. V. Babwah, and M. Bhattacharya. 2011. 'GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness', PLoS One, 6: e21599.
    連結：
97. Zeisberg, Michael, and Eric G Neilson. 2009. 'Biomarkers for epithelial-mesenchymal transitions', The Journal of clinical investigation, 119: 1429-37.
    連結：
98. Zhang, Chuanhai, Fenglin Guo, Geliang Xu, Jie Ma, and Feng Shao. 2015. 'STAT3 cooperates with Twist to mediate epithelial-mesenchymal transition in human hepatocellular carcinoma cells', Oncology reports, 33: 1872-82.
    連結：
99. Zheng, H, and Y Kang. 2014. 'Multilayer control of the EMT master regulators', Oncogene, 33.
    連結：
100. Zhou, Binhua P, Jiong Deng, Weiya Xia, Jihong Xu, Yan M Li, Mehmet Gunduz, and Mien-Chie Hung. 2004. 'Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition', Nature cell biology, 6: 931-40.
     連結：
101. 衛生福利部國民健康署 (2015) :中華民國101年癌症登記報告。衛生福利部國民健康署編印。
102. Bialek, Peter, Britt Kern, Xiangli Yang, Marijke Schrock, Drazen Sosic, Nancy Hong, Hua Wu, Kai Yu, David M Ornitz, and Eric N Olson. 2004. 'A twist code determines the onset of osteoblast differentiation', Developmental cell, 6: 423-35.
103. Bromberg, Jacqueline F, Melissa H Wrzeszczynska, Geeta Devgan, Yanxiang Zhao, Richard G Pestell, Chris Albanese, and James E Darnell. 1999. 'Stat3 as an oncogene', Cell, 98: 295-303.
104. Côme, Christophe, Fabrice Magnino, Frédéric Bibeau, Pascal De Santa Barbara, Karl Friedrich Becker, Charles Theillet, and Pierre Savagner. 2006. 'Snail and slug play distinct roles during breast carcinoma progression', Clinical cancer research, 12: 5395-402.
105. Castanon, Irinka, Stephen Von Stetina, Jason Kass, and Mary K Baylies. 2001. 'Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development', Development, 128: 3145-59.
106. Chai, Edna Zhi Pei, Muthu K Shanmugam, Frank Arfuso, Arunasalam Dharmarajan, Chao Wang, Alan Prem Kumar, Ramar Perumal Samy, Lina HK Lim, Lingzhi Wang, and Boon Cher Goh. 2016. 'Targeting transcription factor STAT3 for cancer prevention and therapy', Pharmacology & therapeutics, 162: 86-97.
107. Chen, LH, S Xi, DA Cohen, and S Barve. 2000. "Dietary fish oil suppressed cytokines and nuclear factor-kappa B induced by murine AIDS virus infection." In FASEB JOURNAL, A238-A38. FEDERATION AMER SOC EXP BIOL 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA.
108. Cheng, George Z, WeiZhou Zhang, Mei Sun, Qi Wang, Domenico Coppola, Mena Mansour, LiMei Xu, Carliann Costanzo, Jin Q Cheng, and Lu-Hai Wang. 2008. 'Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function', Journal of Biological Chemistry, 283: 14665-73.
109. Deshpande, Rashmi, Prakash Mansara, Snehal Suryavanshi, and Ruchika Kaul-Ghanekar. 2013. 'Alpha-linolenic acid regulates the growth of breast and cervical cancer cell lines through regulation of NO release and induction of lipid peroxidation', Journal of Molecular Biochemistry, 2.
110. El Ghouzzi, Vincent, Laurence Legeai-Mallet, Sandra Aresta, Catherine Benoist, Arnold Munnich, Jean de Gunzburg, and Jacky Bonaventure. 2000. 'Saethre–Chotzen mutations cause TWIST protein degradation or impaired nuclear location', Human molecular genetics, 9: 813-19.
111. Hassan, Aktham, Ayman Ibrahim, Khaly Mbodji, Moïse Coëffier, Frédéric Ziegler, Frédéric Bounoure, Jean‐Michel Chardigny, Mohamed Skiba, Guillaume Savoye, and Pierre Déchelotte. 2010. 'An α-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-κB in rats with TNBS-induced colitis', The Journal of nutrition, 140: 1714-21.
112. Olive, Kenneth P, Michael A Jacobetz, Christian J Davidson, Aarthi Gopinathan, Dominick McIntyre, Davina Honess, Basetti Madhu, Mae A Goldgraben, Meredith E Caldwell, and David Allard. 2009. 'Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer', Science, 324: 1457-61.
113. Ren, Zhiyong, Xiang Mao, Claudia Mertens, Ravi Krishnaraj, Jie Qin, Pijus K Mandal, Michael J Romanowski, John S McMurray, and Xiaomin Chen. 2008. 'Crystal structure of unphosphorylated STAT3 core fragment', Biochemical and biophysical research communications, 374: 1-5.
114. Sahlgren, Cecilia, Maria V Gustafsson, Shaobo Jin, Lorenz Poellinger, and Urban Lendahl. 2008. 'Notch signaling mediates hypoxia-induced tumor cell migration and invasion', Proceedings of the National Academy of Sciences, 105: 6392-97.
115. Yang, Jing, Sendurai A Mani, Joana Liu Donaher, Sridhar Ramaswamy, Raphael A Itzykson, Christophe Come, Pierre Savagner, Inna Gitelman, Andrea Richardson, and Robert A Weinberg. 2004. 'Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis', Cell, 117: 927-39.