胰臟癌是惡性腫瘤之一，五年內存活率只有5-6%，目前缺乏有效的治療。乙型轉化生長因子 (Transforming growth factor-β; TGF-β)為多功能性細胞激素。當TGF-β功能喪失或訊息傳遞異常突變，將導致細胞異常增生、誘導上皮間質轉化 (epithelial-mesenchymal transition; EMT) 及轉移。由流行病學、微生物相及本實驗室動物實驗的研究，牙周致病菌牙齦卟啉菌 (Porphyromonas gingivalis; P.gingivalis) 為胰臟癌的致病因子之一。在動物模式中，我們發現益生菌可抑制小鼠之胰臟癌惡化。本研究主要探討TGF-β訊息路徑是否參與益生菌減少胰臟癌惡化的機制。人類胰臟癌細胞株BxPC-3與P. gingivalis培養液共同作用，我們發現TGF-β訊息路徑相關分子包括TGF-β1, Smad2, Smad3, and Smad4顯著增加，其磷酸化的Smad2和Smad3也增加。而Smad7蛋白顯著降低。為了瞭解TGF-β訊息路徑在P. gingivalis促進胰臟癌進展所扮演的角色，利用LSL-KrasG12D; Pdx-1-Cre (KC) 基因轉殖胰臟癌小鼠口腔塗抹P. gingivalis。一個月後，我們發現TGF-β及其下游訊息分子Smad2，Smad3，Smad4在胰腺細胞的細胞質中明顯增加。另外也發現TGF-β訊息路徑活化之phospho-Smad2和phospho-Smad3則有入細胞核的情況，則Smad7的表現量降低。給予益生菌治療抑制P. gingivalis處理之胰腺細胞TGF-β訊息路徑的活化。已知Smad3會調控PD-1的表現，結果顯示口腔塗抹P. gingivalis使PD-1和PD-L1表現增加，而給予益生菌則抑制PD-1和PD-L1的表現。在BxPC-3與P. gingivalis培養液共同作用，也發現PD-1與PD-L1 (及SHP-2) 蛋白表現增加。綜合以上結果，我們在活體外及活體內的實驗均證實給予P. gingivalis活化TGF-β 與PD-1/PD-L1訊息路徑與胰臟癌的惡化程度呈正相關性。重要的是，益生菌會抑制胰臟癌進展之TGF-β訊息路徑的活化。未來我們將更進一步來了解P. gingivalis和益生菌透過何種機制來調控TGF-β/Smad與PD-1/PD-L1訊息路徑。

Pancreatic cancer is one of the malignant tumors which survival rate is only 5-6% in 5 years, and has no effective therapeutic strategy. Transforming growth factor-β(TGF-β) is a multifunctional cytokine that can inhibit cell growth. Loss of function or mutation of TGF-βwill cause the abnormal proliferation of cells. According the findings through epidemiological studies, microbiota analysis and our animal studies, the periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) may act as a risk factor of pancreatic cancer. We also found that oral administration of probiotics could inhibit pancreatic cancer progression in vivo. In this study, we analyzed whether downregulation of TGF-βsignal pathway play a role of probiotics in the pancreatic cancer suppression. We found that TGF-βsignaling pathway-associated molecules including TGF-β1, Smad2, Smad3, and Smad4 proteins were significantly increased, and phosphorylation levels of Smad2 and Smad3 were increased too. In addition, protein level of Smad7 protein decreased in P. gingivalis culture broth-treated human pancreatic cancer BxPC-3 cells than non-treated cells in vitro. To understand whether the TGF-βsignaling pathway play role in the pathogenesis of P. gingivalis–promoted pancreatic cancer progression, LSL-KrasG12D;Pdx-1-Cre (KC) transgenic pancreatic cancer mice were oral smear periodontal pathogens P. gingivalis. After one month, we found that TGF-βand its downstream signaling molecules Smad2, Smad3, Smad4 were significantly increased in the cytoplasm of pancreatic cells. In addition, nucleus translocation of phospho-Smad2 and phospho-Smad3 through TGF-βsignaling pathway activation were found too. Smad7 protein expression were decreased in pancreatic tissues from P. gingivalis-treated KC mice. On the other hand, probiotic treatment cold reverse the activation of TGF-βpathway by P. gingivalis-treatment. It has been known that Smad3 control immune check point PD-1 expression. Our results indicated that P. gingivalis treatment increased, but probiotics treatment suppressed, PD-1 and PD-L1 protein expressions. The enhancement of protein levels of PD-1 and PD-L1 (also SHP-2) by P. gingivalis treatment were found in P. gingivalis culture broth-treated BxPC-3 cells too. In conclusion, TGF-βand PD-1/PD-L1 pathway activation were observed after P. gingivalis-treatment in vivo and in vitro and it was correlated with the pancreatic cancer progression. More importantly, probiotics administration may reverse the activation of TGF-βpathway in the development process of pancreatic cancer. What are the mechanisms of P. gingivalis and probiotics for regulating TGF-βand PD-1/PD-L1 signal pathway should be clarified in more detail in the future.

中文摘要 I
Abstract II
表目錄 V
圖目錄 VI
縮寫表 VIII
第一章、緒論 1
一、 胰臟癌 (Pancreatic cancer) 1
二、 牙周病 (Periodontal disease) 3
三、 轉化生長因子-β (Transforming growth factor beta，TGF-β) 5
四、 益生菌 6
第二章、研究動機 7
第三章、材料與方法 8
一、 實驗動物 8
二、 DNA電泳 8
三、 牙齦卟啉單孢菌 (Porphyromonas gingivalis, P. gingivalis) 培養 13
四、 P. gingivalis口腔感染 14
五、 小鼠器官處理 17
六、 小鼠胰臟石蠟包埋切片及紫木蘇與伊紅染色法 (委託力沛有限公司處理) 18
七、 免疫組織化學染色 (委託力沛有限公司處理) 20
八、 細胞培養 22
九、 西方墨點法 25
第四章、 實驗結果 33
第五章、 討論 37
第六章、 參考文獻 41
 
表目錄

附表 一、 Primer sequence 11
附表 二、 PCR reaction mixture for Kras 12
附表 三、 PCR reaction mixture for Cre 12
附表 四、 作用時間及溫度 12

1.Craig D. Logsdon & Baoan Ji. The role of protein synthesis and digestive enzymes in acinar cell injury. Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):362-70
2.Dhiraj Yadav, Albert B. Lowenfels. The Epidemiology of Pancreatitis and Pancreatic Cancer. Gastroenterology. 2013 Jun; 144(6): 1252-1261.
3.Huang J, Roosaar A, Axéll T, Ye W. A prospective cohort study on poor oral hygiene and pancreatic cancer risk. Int J Cancer. 2016 Jan 15;138(2):340-347.
4.Manuel Hidalgo and Daniel D. Von Hoff. Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. Clin Cancer Res. 2012 Aug 15;18(16):4249-4256.
5.Dominique S. Michaud and Jacques Izard. Microbiota, Oral Microbiome, and Pancreatic Cancer. Cancer J 2014 May-Jun;20(3):203-206.
6.Lola Rahib, Benjamin D. Smith, Rhonda Aizenberg, Allison B. Rosenzweig, Julie M. Fleshman and Lynn M. Matrisian. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res; 74(11); 2913-2921.
7.Abul Azad, Su Yin Lim, Zenobia D''Costa, Keaton Jones, Angela Diana, Owen J Sansom, Philipp Kruger, Stanley Liu, W Gillies McKenna, Omer Dushek, Ruth J Muschel, Emmanouil Fokas. PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017 Feb;9(2):167-180.
8.Junjie Li, Fengyong Liu, Sanjay Gupta, Chun Li. Interventional Nanotheranostics of Pancreatic Ductal Adenocarcinoma. Theranostics. 2016; 6(9): 1393-1402.
9.Siu Wai Tsang, Yi-Fu Guan, Juan Wang, Zhao-Xiang Bian, and Hong-Jie Zhang. Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis. Sci Rep. 2016; 6: 22859.
10.Ahmed Bettaieb, Yannan Xi, Ellen Hosein, Nicole Coggins, Santana Bachaalany, Florian Wiede, Salvador Perez, Stephen M Griffey, Juan Sastre, Tony Tiganis, and Fawaz G Haj. Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis. Cell Commun Signal. 2014; 12: 13.
11.Hannah M. Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A. Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C. Ostrowski, Phil A. Hart, Darwin L. Conwell, and Gregory B. Lesinski. Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo. Sci Rep. 2017; 7: 1787.
12.Haoqiang Ying, Prasenjit Dey, Wantong Yao, Alec C. Kimmelman, Giulio F. Draetta, Anirban Maitra, and Ronald A. DePinho. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016 Feb 15; 30(4): 355-385.
13.T-L Kuo, C-C Weng, K-K Kuo, C-Y Chen, D-C Wu, W-C Hung and K-H Cheng. APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice. Oncogene (2016) 35, 2223-2234.
14.C Loncle, M I Molejon, S Lac, J I Tellechea, G Lomberk, L Gramatica, M F Fernandez Zapico, N Dusetti, R Urrutia, and J L Iovanna. The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes KrasG12D-mediated pancreatic cancer initiation. Cell Death Dis. 2016 Jul; 7(7): e2295.
15.Meredith A. Collins, Filip Bednar, Yaqing Zhang, Jean-Christophe Brisset, Stefanie Galbán, Craig J. Galbán, Sabita Rakshit, Karen S. Flannagan, N. Volkan Adsay, and Marina Pasca di Magliano. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012 Feb 1; 122(2): 639-653.
16.Jonas Cicenas, Kotryna Kvederaviciute, Ingrida Meskinyte, Edita Meskinyte-Kausiliene, Aiste Skeberdyte, and Jonas Cicenas, Jr. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers (Basel). 2017 May; 9(5): 42.
17.R Hill, M Rabb, P A Madureira, D Clements, S A Gujar, D M Waisman, C A Giacomantonio, and P W K Lee. Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy Cell Death Dis. 2013 Sep; 4(9): e791.
18.Steffen Ormanns, Michael Haas, Anna Remold, Stephan Kruger, Stefan Holdenrieder, Thomas Kirchner, Volker Heinemann, and Stefan Boeck. The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy. Int J Mol Sci. 2017 May; 18(5): 1094.
19.John P. Morris, IV, Sam C. Wang, and Matthias Hebrok. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010 Oct; 10(10): 683-695.
20.Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015 Jan;15(1):30-44
21.Paster BJ, Olsen I, Aas JA, Dewhirst FE. The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontol 2000. 2006;42:80-87.
22.Yan Li, Jinzhi He, Zhili He, Yuan Zhou, Mengting Yuan, Xin Xu, Feifei Sun, Chengcheng Liu, Jiyao Li, Wenbo Xie, Ye Deng, Yujia Qin, Joy D VanNostrand, Liying Xiao, Liyou Wu, Jizhong Zhou, Wenyuan Shi and Xuedong Zhou. Phylogenetic and functional gene structure shifts of the oral microbiomes in periodontitis patients. The ISME Journal (2014) 8, 1879-1891.
23.T. L. Cerajewska, M. Davies & N. X. West. Periodontitis: a potential risk factor for Alzheimer''s disease. British Dental Journal 218, 29-34 (2015).
24.Olsen I, Progulske-Fox A. Invasion of Porphyromonas gingivalis strains into vascular cells and tissue. J Oral Microbiol. 2015 Aug 31;7:28788.
25.Dominique S Michaud, Jacques Izard, Charlotte S Wilhelm-Benartzi, Doo-Ho You, Verena A Grote, Anne Tjnneland, Christina C Dahm, Kim Overvad, Mazda Jenab, Veronika Fedirko, Marie Christine Boutron-Ruault, Françoise Clavel-Chapelon, Antoine Racine, Rudolf Kaaks, Heiner Boeing, Jana Foerster, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Carlotta Sacerdote, Sabina Sieri, Domenico Palli, Rosario Tumino, Salvatore Panico, Peter D Siersema, Petra HM Peeters, Eiliv Lund, Aurelio Barricarte, José-María Huerta, Esther Molina-Montes, Miren Dorronsoro, J Ramón Quirós, Eric J Duell, Weimin Ye, Malin Sund, Björn Lindkvist, Dorthe Johansen, Kay-Tee Khaw, Nick Wareham, Ruth C Travis, Paolo Vineis, H Bas Bueno-de-Mesquita, Elio Riboli. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2013 Dec;62(12):1764-70.
26.Maja Sochalska,and Jan Potempa. Manipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis. Front Cell Infect Microbiol. 2017; 7: 197.
27.Nagihan Bostanci, Georgios N. Belibasakis. Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen. FEMS Microbiol Lett 333 (2012) 1-9.
28.Young-Jung Jung , Hye-Kyoung Jun & Bong-Kyu Choi. Porphyromonas gingivalis suppresses invasion of Fusobacterium nucleatum into gingival epithelial cells. 2017 Vol. 9, 1320193.
29.Sowmya A Castro, Russell Collighan, Peter A Lambert, Irundika HK Dias, Parbata Chauhan, Charlotte E Bland, Ivana Milic, Michael R Milward, Paul R Cooper, and Andrew Devitt. Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils. Cell Death Dis. 2017 Mar; 8(3): e2644.
30.Inaki de Diego, Florian Veillard, Maryta N. Sztukowska, Tibisay Guevara, Barbara Potempa, Anja Pomowski, James A. Huntington, Jan Potempa and F. Xavier Gomis-Ruth. Structure and Mechanism of Cysteine Peptidase Gingipain K (Kgp), a Major Virulence Factor of Porphyromonas gingivalis in Periodontitis. J Biol Chem. 2014 Nov 14; 289(46): 32291–32302.
31.Zhu XQ, Lu W, Chen Y, Cheng XF, Qiu JY, Xu Y, Sun Y. Effects of Porphyromonas gingivalis Lipopolysaccharide Tolerized Monocytes on Inflammatory Responses in Neutrophils. PLoS One. 2016 Aug 18;11(8):e0161482.
32.Tania Kllgaard, Christian Enevold, Klaus Bendtzen, Peter R. Hansen, Michael Givskov, Palle Holmstrup, and Claus H. Nielsen. Cholesterol crystals enhance TLR2- and TLR4-mediated pro-inflammatory cytokine responses of monocytes to the proatherogenic oral bacterium Porphyromonas gingivalis. PLoS One. 2017; 12(2): e0172773.
33.Jorg Brunner, Nina Scheres, Nawal B El Idrissi, Dong M Deng, Marja L Laine, Arie J van Winkelhoff and Wim Crielaard. The capsule of Porphyromonas gingivalis reduces the immune response of human gingival fibroblasts. BMC Microbiol. 2010; 10: 5.
34.Alberti-Segui C1, Arndt A, Cugini C, Priyadarshini R, Davey ME. HU protein affects transcription of surface polysaccharide synthesis genes in Porphyromonas gingivalis. J Bacteriol. 2010 Dec;192(23):6217-6229.
35.Nozoe K, Sanui T, Takeshita M, Fukuda T, Haraguchi A, Aida Y, Nishimura F. Innate immune-stimulatory activity of Porphyromonas gingivalis fimbriae is eliminated by phase separation using Triton X-114. J Immunol Methods. 2017 Feb;441:31-38.
36.Daniel R. Principe, Jennifer A. Doll, Jessica Bauer, Barbara Jung, Hidayatullah G. Munshi, Laurent Bartholin, Boris Pasche, Chung Lee and Paul J. Grippo. TGF-β: Duality of Function Between Tumor Prevention and Carcinogenesis. J Natl Cancer Inst. 2014 Feb; 106(2): djt369.
37.Daniel R. Principe, Brian DeCant, Emman Mascariñas, Elizabeth A. Wayne, Andrew M. Diaz, Naomi Diaz, Rosa Hwang, Boris Pasche, David W. Dawson, Deyu Fang, David J. Bentrem, Hidayatullah G. Munshi, Barbara Jung and Paul J. Grippo. TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016 May 1; 76(9): 2525–2539.
38.Glazer ES, Welsh E, Pimiento JM, Teer JK, Malafa MP. TGFβ1 overexpression is associated with improved survival and low tumor cell proliferation in patients with early-stage pancreatic ductal adenocarcinoma. Oncotarget. 2017 Jan 3;8(1):999-1006.
39.Inman GJ. Switching TGFβ from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev. 2011 Feb;21(1):93-99.
40.Stephen L. Shiao, A. Preethi Ganesan, Hope S. Rugo and Lisa M. Coussens. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 2011 Dec 15; 25(24): 2559-2572.
41.Huibin Yang, Gangyong Li, Jing-Jiang Wu, Lidong Wang, Michael Uhler and Diane M. Simeone. Protein Kinase A Modulates Transforming Growth Factor-β Signaling through a Direct Interaction with Smad4 Protein. J Biol Chem. 2013 Mar 22; 288(12): 8737-8749.
42.Juan Zhang, Xiaofei Zhang, Feng Xie, Zhengkui Zhang, Hans van Dam, Long Zhang and Fangfang Zhou. The regulation of TGF-β/SMAD signaling by protein deubiquitination. Protein Cell. 2014 Jul; 5(7): 503-517.
43.Wang X, Juan QF, He YW, Zhuang L, Fang YY, Wang YH. Multiple effects of probiotics on different types of diabetes: a systematic review and meta-analysis of randomized, placebo-controlled trials. J Pediatr Endocrinol Metab. 2017 May 24;30(6):611-622.
44.Julio Plaza-Diaz, Carolina Gomez-Llorente, Luis Fontana and Angel Gil. Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics. World J Gastroenterol. 2014 Nov 14; 20(42): 15632–15649.
45.Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010 Sep;7(9):503-14.
46.Matthias F. Kramer and Matthew D. Heath. Probiotics in the Treatment of Chronic Rhinoconjunctivitis and Chronic Rhinosinusitis. J Allergy (Cairo). 2014; 2014: 983635.
47.Goldstein EJ, Tyrrell KL, Citron DM. Lactobacillus species: taxonomic complexity and controversial susceptibilities. Clin Infect Dis. 2015 May 15;60 Suppl 2:S98-107.
48.Ashraf R, Shah NP. Selective and differential enumerations of Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium spp. in yoghurt--a review. Int J Food Microbiol. 2011 Oct 3;149(3):194-208.
49.Francesca Turroni, Sabrina Duranti, Francesca Bottacini, Simone Guglielmetti, Douwe Van Sinderen and Marco Ventura. Bifidobacterium bifidum as an example of a specialized human gut commensal. Front Microbiol. 2014; 5: 437.
50.Wang IJ, Wang JY. Children with atopic dermatitis show clinical improvement after Lactobacillus exposure. Clin Exp Allergy. 2015 Apr;45(4):779-787.
51.Hsu TC, Huang CY, Liu CH, Hsu KC, Chen YH, Tzang BS. Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89 and L. reuteri GMNL-263 ameliorate hepatic injuries in lupus-prone mice. Br J Nutr. 2017 Apr;117(8): 1066-1074.
52.Kan Gao, Li Liu, Xiaoxiao Dou, Chong Wang, Jianxin Liu, Wenming Zhang and Haifeng Wang. Doses Lactobacillus reuteri depend on adhesive ability to modulate the intestinal immune response and metabolism in mice challenged with lipopolysaccharide. Sci Rep. 2016; 6: 28332.
53.Han H. Wong & Nicholas R. Lemoine. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nature Reviews Gastroenterology and Hepatology 6, 412-422 (2009).
54.Tran DQ. TGF-β: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol. 2012 Feb;4(1):29-37.
55.Vegard Tjomsland, Dagny Sandnes, Ewa Pomianowska, Smiljana Torbica Cizmovic, Monica Aasrum, Ingvild Johnsen Brusevold, Thoralf Christoffersen, and Ivar P. Gladhaug. The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration. J Exp Clin Cancer Res. 2016; 35: 122.
56.Benjamin V. Park, Zachary T. Freeman, Ali Ghasemzadeh, Michael A. Chattergoon, Alleluiah Rutebemberwa, Jordana Steigner, Matthew E. Winter, Thanh V. Huynh, Suzanne M. Sebald, Se-Jin Lee, Fan Pan, Drew M. Pardoll and Andrea L. Cox. TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in CancerTGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer. Cancer Discov. 2016 Dec; 6(12): 1366–1381.
57.Chenzhong Kuang, Yan Xiao, Xubao Liu, Teresa M. Stringfield, Shaobo Zhang, Zhenzhen Wang and Yan Chen. In vivo disruption of TGF-β signaling by Smad7 leads to premalignant ductal lesions in the pancreas. Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1858-63.
58.Puneet Singh, Radhika Srinivasan, Jai Dev Wig and Bishan Das Radotra. A study of Smad4, Smad6 and Smad7 in Surgically Resected Samples of Pancreatic Ductal Adenocarcinoma and Their Correlation with Clinicopathological Parameters and Patient Survival. BMC Res Notes. 2011; 4: 560.
59.Natalie Ertz-Archambault, Paul Keim, and Daniel Von Hoff. Microbiome and pancreatic cancer: A comprehensive topic review of literature. World J Gastroenterol. 2017 Mar 14; 23(10): 1899–1908.
60.Shiheido Y, Maejima Y, Suzuki JI, Aoyama N, Kaneko M, Watanabe R, Sakamaki Y, Wakayama K, Ikeda Y, Akazawa H, Ichinose S, Komuro I, Izumi Y, Isobe M. Porphyromonas gingivalis, a periodontal pathogen, enhances myocardial vulnerability, thereby promoting post-infarct cardiac rupture. J Mol Cell Cardiol. 2016 Oct;99:123-137.
61.Eleonor Palm, Hazem Khalaf and Torbjörn Bengtsson. Porphyromonas gingivalis downregulates the immune response of fibroblasts. BMC Microbiology201313:155.
62.Brian Bierie, Harold L.Moses. Transforming growth factor beta (TGF-β) and inflammation in cancer. Cytokine & Growth Factor Reviews Volume 21, Issue 1, February 2010, Pages 49-59
63.Chen XF, Zhang HJ, Wang HB, Zhu J, Zhou WY, Zhang H, Zhao MC, Su JM, Gao W, Zhang L, Fei K, Zhang HT, Wang HY. Transforming growth factor-β1 induces epithelial-to-mesenchymal transition in human lung cancer cells via PI3K/Akt and MEK/Erk1/2 signaling pathways. Mol Biol Rep. 2012 Apr;39(4):3549-3556.
64.Aomatsu K, Arao T, Sugioka K, Matsumoto K, Tamura D, Kudo K, Kaneda H, Tanaka K, Fujita Y, Shimomura Y, Nishio K. TGF-β induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways in a human corneal epithelial cell line. Invest Ophthalmol Vis Sci. 2011 Apr 14;52(5):2437-2443.
65.Freudlsperger C, Bian Y, Contag Wise S, Burnett J, Coupar J, Yang X, Chen Z, Van Waes C. TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Oncogene. 2013 Mar 21;32(12):1549-1559.
66.Helena Tlaskalova-Hogenova, Renata Stepankova, Hana Kozakova, Tomas Hudcovic, Luca Vannucci, Ludmila Tuckova, Pavel Rossmann, Tomas Hrncir, Miloslav Kverka, Zuzana Zakostelska, Klara Klimesova, Jaroslava Pribylova, Jirina Bartova, Daniel Sanchez, Petra Fundova, Dana Borovska, Dagmar Srutkova, Zdenek Zídek, Martin Schwarzer, Pavel Drastich and David P Funda. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cellular & Molecular Immunology (2011) 8, 110–120.
67.Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. 2014 Jan;44(1):1-8.
68.Maroof H, Hassan ZM, Mobarez AM, Mohamadabadi MA. Lactobacillus acidophilus could modulate the immune response against breast cancer in murine model. J Clin Immunol. 2012 Dec;32(6):1353-1359.
69.Azad A, Yin Lim S, D''Costa Z, Jones K, Diana A, Sansom OJ, Kruger P, Liu S, McKenna WG, Dushek O, Muschel RJ, Fokas E. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017 Feb;9(2):167-180.
70.Mohania D, Kansal VK, Kumar M, Nagpal R, Yamashiro Y, Marotta F. Modulation of expression of Programmed Death-1 by administration of probiotic Dahi in DMH-induced colorectal carcinogenesis in rats. Acta Biomed. 2013 Sep 1;84(2):102-109.