DOI QR코드

DOI QR Code

Carcinogenic Role of Tumor Necrosis Factor-α Inducing Protein of Helicobacter pylori in Human Stomach

  • 투고 : 2005.12.14
  • 발행 : 2006.01.31

초록

Helicobacter pylori is the definitive carcinogen for stomach cancer and is known to induce proinflammatory cytokines, such as tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and interleukin-1(IL-1) in the stomach. Based on our findings that TNF-$\alpha$ is an endogenous tumor promoter, we identified the TNF-$\alpha$ inducing protein (Tip$\alpha$) gene family, and confirmed Tip$\alpha$ and HP-MP1 as new carcinogenic proteins of H. pylori. Tip$\alpha$ protein is unique to H. pylori, and this paper shows the strong tumor promoting activity of Tip$\alpha$ gene family, in cooperation with Ras protein and its mechanisms of action in relation to NF-${\kappa}B$ activation, and discusses the carcinogenic role of Tip$\alpha$ in stomach cancer. Our recent finding showing that penicillin-binding proteins of other bacteria are weak homologues of Tip$\alpha$ is also discussed.

키워드

참고문헌

  1. Alm, R. A., Ling, L.-S., Moir, D. T., King, B. L., Brown, E. D., Doig, P. C., Smith, D. R., Noonan, B., Guild, B. C., deJonge, B. L., Carmel, G., Tummino, P. J., Caruso, A., Uria-Nickelsen, M., Mills, D. M., Ives, C., Gibson, R., Merberg, D., Mills, S. D., Jiang, Q., Taylor, D. E., Vovis, G. F. and Trust, T. J. (1999) Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 397, 176-180 https://doi.org/10.1038/16495
  2. Atherton, J. C., Cao, P., Peek, Jr. R. M., Tummuru, M. K. R., Blaser, M. J. and Cover, T. L. (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. J. Biol. Chem. 270, 17771-17777 https://doi.org/10.1074/jbc.270.1.1
  3. Censini, S., Lange, C., Xiang, Z., Crabtree, J. E., Ghiara, P., Borodovsky, M., Rappuoli, R. and Covacci, A. (1996) cag, a pathogenicity island of Helicobacter pylori, encodes type Ispecific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA 93, 14648-14653 https://doi.org/10.1073/pnas.93.25.14648
  4. Correa, P. (2003) Helicobacter pylori infection and gastric cancer. Cancer Epidemiol. Biomarkers Prev. 12, 238-241
  5. Covacci, A., Telford, J. L., Giudice, G. D., Parsonnet, J. and Rappuoli, R. (1999) Helicobacter pylori virulence and genetic geography. Science 284, 1328-1333 https://doi.org/10.1126/science.284.5418.1328
  6. Crabtree, J. E., Shallcross, T. M., Heatley, R. V. and Wyatt, J. I. (1991) Mucosal tumour necrosis factor ${\alpha}$ and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 32, 1473-1477 https://doi.org/10.1136/gut.32.1.1
  7. Fujiki, H. and Suganuma, M. (1993) Tumor promotion by inhibitors of protein phosphatases 1 and 2A: The okadaic acid class of compounds. Adv. Cancer Res. 125, 143-194
  8. Fujiki, H., Suganuma, M., Okabe, S., Kurusu, M., Imai, K. and Nakachi, K. (2002) Involvement of TNF-${\alpha}$ changes in human cancer development, prevention and palliative care. Mech. Ageing Dev. 123, 55-1663
  9. Fujiki, H., Takeuchi, H., Nishitani, N., Yamanaka, H., Suzuki, K., Kurusu, M. and Suganuma, M. (2004) Carcinogenic potential of tabacco tar-resistant Staphylococcus aureus in buccal cavity. J. Cancer Res. Clin. Oncol. 130, 301-305 https://doi.org/10.1007/s00432-003-0498-7
  10. Fujiki, H. and Suganuma, M. (2005) Translational research on TNF-${\alpha}$ as an endogenous tumor promoter and green tea as cancer preventive in humans. J. Environ. Sci. Health 23, 3-30
  11. Greten, F. R., Eckmann, L., Greten T. F., Park, J. M., Li, Z.-W., Egan, L. J., Kagnoff, M. F. and Karin, M. (2004) IKK${\beta}$ links inflammation and tumorigenesis in a mouse model of colitisassociated cancer. Cell 118, 285-296 https://doi.org/10.1016/j.cell.2004.07.013
  12. Harris, P. R., Mobley, H. L. T., Perez-Perez, G. I., Blaser, M. J. and Smith, P. D. (1996) Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterology 111, 419-425 https://doi.org/10.1053/gast.1996.v111.pm8690207
  13. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994) IARC Monographs on The Evaluation of Carcinogenic Risks to Humans, vol 61 Schistosomes, Liver Flukes and Helicobacter pylori. pp. 177-220. IARC, France
  14. Ichinose, M., Nakanishi, H., Fujino, S. and Tatematsu, M. (1998) Establishment and characterization of two cell lines from Nmethyl- N-nitrosourea-induced mouse glandular stomach carcinomas. Jpn. J. Cancer Res. 89, 516-524 https://doi.org/10.1111/j.1349-7006.1998.tb03292.x
  15. Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K. L., Brown, D. and Slack, F. J. (2005) RAS is regulated by the let-7 microRNA family. Cell 120, 635-647 https://doi.org/10.1016/j.cell.2005.01.014
  16. Karin, M., Cao, Y., Grete, F. R. and Li, Z-W. (2002) NF-${\kappa}$B in cancer: From innocent bystander to major culprit. Nature Rev. Cancer 2, 301-310 https://doi.org/10.1038/nrc780
  17. Keates, S., Hitti, Y. S., Upton, M. and Kelly, C. P. (1997) Helicobacter plori infection activates NF-${\kappa}$B in gastric epithelial cells. Gastroentherology 113, 1099-1109 https://doi.org/10.1053/gast.1997.v113.pm9322504
  18. Komori, A., Yatsunami, J., Suganuma, M., Okabe, S., Abe, S., Sakai, A., Sasaki, K. and Fujiki H. (1993) Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation. Cancer Res. 53, 1982-1985
  19. Koonin, E. V., Makarova, K. S. and Aravind, L. (2001) Horizontal gene transfer in prokaryotes: quantificantion and classification. Annu. Rev. Microbiol. 55, 709-742 https://doi.org/10.1146/annurev.micro.55.1.709
  20. Kuzuhara, T., Suganuma, M., Tsuge, H. and Fujiki, H. (2005) Presence of a motif conserved between Helicobacter pylori TNF-${\alpha}$ inducing protein (Tip${\alpha}$) and penicillin-binding proteins. Biol. Pharm. Bull. 28, 2133-2137 https://doi.org/10.1248/bpb.28.2133
  21. Lee, I., Lee, H., Kim, M,. Fukumoto, M., Sawada, S., Jakate, S. and Gould, V. E. (2005) Ethnic difference of Helicobacter pylori gastritis: Korean and Japanese gastritis is characterized by male- and antrum-predominant acute foveolitis in comparison with American gastritis. World J. Gastroenterol. 11, 94-98 https://doi.org/10.3748/wjg.v11.i1.94
  22. Lim, D. and Strynadka, N. C. (2002) Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat. Struct. Biol. 9, 870-876
  23. Marshall, B. J. and Warren, J. R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311-1314
  24. Maeda, S., Yoshida, H., Ogura, K., Mitsuno, Y., Hirata, Y., Yamaji, Y., Akanuma, M., Shiratori, Y. and Omata, M. (2000) H. pylori activates NF-${\kappa}$B through a signaling pathway involving I${\kappa}$B kinases, NF-${\kappa}$B-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology 119, 97-108 https://doi.org/10.1053/gast.2000.8540
  25. Moore, R. J., Owens, D. M., Stamp, G., Arnott, C., Burke, F., East, N., Holdsworth, H., Turner, L., Rollins, B., Pasparakis, M., Kollias, G. and Balkwill, F. (1999) Mice deficient in tumor necrosis factor-${\alpha}$ are resistant to skin carcinogenesis. Nature Med. 5, 828-831 https://doi.org/10.1038/10552
  26. Noach, L. A., Bosma, N. B., Jansen, J., Hoek, F. J., van Deventer, S. J. and Tytgat, G. N. (1994) Mucosal tumor necrosis factor-${\alpha}$, interleukin 1${\beta}$, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J. Gastroenterol. 29, 425- 429 https://doi.org/10.3109/00365529409091402
  27. Normark, S., Nilsson, C., Normark, B. H. and Hornef, M. W. (2003) Persistent infection with Helicobacter pylori and the development of gastric cancer. Adv. Cancer Res. 90, 63-89 https://doi.org/10.1016/S0065-230X(03)90002-9
  28. Odenbreit, S., Puls, J., Sedlmaier, B., Gerland, E., Fischer, W. and Haas, R. (2000) Translocation of Helicobacter pylori cagA into gastric epithelial cells by type IV secretion. Science 287, 1497- 1500 https://doi.org/10.1126/science.287.5457.1497
  29. Ohmori, K., Sasaki, K., Asada, S., Tanaka, N. and Umeda, M. (2004) An assay method for the prediction of tumor promoting potential of chemicals by use of Bhas 42 cells. Mutat Res. 557, 191-202 https://doi.org/10.1016/j.mrgentox.2003.10.014
  30. Ohuchi, N., Hand, P. H., Merlo, G., Fujita, J., Mariani-Costantini, R., Thor, A., Nose, M., Callahan, R. and Schlom, J. (1987) Enhanced expression of c-Ha-ras p21 in human stomach adenocarcinomas defined by immunoassays using monoclonal antibodies and in situ hybridization. Cancer Res. 47, 1413-1420
  31. Old, L. J. (1985) Tumor necrosis factor (TNF). Science 230, 630-632 https://doi.org/10.1126/science.2413547
  32. Park, S. M., Park, J., Kim, J. G., Cho, H. D., Cho, J. H., Lee, D. H. and Cha. Y. J. (1998) Infection with Helicobacter pylori expressing the cagA gene is not associated with an increased risk of developing peptic ulcer diseases in Korean patients. Scand J. Gastroenterol. 33, 923-927 https://doi.org/10.1080/003655298750026921
  33. Peek, Jr. R. M. and Blaser, M. J. (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Rev. Cancer 2, 28-37 https://doi.org/10.1038/nrc703
  34. Penta, R., De Falco, M., Iaquinto, G., and De Luca, A. (2005) Helicobacter pylori and gastric epithelial cells: from gastritis to cancer. J. Exp. Clin. Cancer Res. 24, 337-345
  35. Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and Ben-Neriah, Y. (2004) NF-${\kappa}$B functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466 https://doi.org/10.1038/nature02924
  36. Sasaki, K., Mizusawa, H., Ishidate, M. and Tanaka, N. (1990) Transformation of RAS transfected BALB 3T3 clone (Bhas 42) by promoters: Application for screening and specificity of promoters. Toxic in Vitro 4, 657-659 https://doi.org/10.1016/0887-2333(90)90137-I
  37. Shimizu, N., Inada, K., Nakanishi, H., Tsukamoto, T., Ikehara, Y., Kaminishi, M., Kuramoto, S., Sugiyama, A., Katsuyama, T. and Tatematsu, M. (1999) Helicobacter pylori infection enhances glandular stomach carcinogenesis in Mongolian gerbils treated with chemical carcinogens. Carcinogenesis 20, 669-676 https://doi.org/10.1093/carcin/20.4.669
  38. Shimoyama, T., Fukuda, S., Tanaka, M., Mikami, T., Saito, Y. and Munakata, A. (1997) High prevalence of the CagA-positive Helicobacter pylori strains in Japanese asymptomatic patients and gastric cancer patients. Scand J. Gastroenterol 32, 465-468 https://doi.org/10.3109/00365529709025082
  39. Sueoka, E., Sueoka, N., Okabe, S., Komori, A., Suganuma, M., Kozu, T. and Fujiki, H. (1998) Tumorigenicity of MTG8, a leukemia-related gene, in concert with v-Ha-ras gene in BALB/3T3 cells. Br. J. Haematol. 101, 737-742 https://doi.org/10.1046/j.1365-2141.1998.00696.x
  40. Suganuma, M., Okabe, S., Marino, M. W., Sakai, A., Sueoka, E. and Fujiki, H. (1999) Essential role of tumor necrosis factor ${\alpha}$ (TNF-${\alpha}$) in tumor promotion as revealed by TNF-${\alpha}$-deficient mice. Cancer Res. 59, 4516-4518
  41. Suganuma, M., Kurusu, M., Okabe, S., Sueoka, N., Yoshida, M., Wakatsuki, Y. and Fujiki, H. (2001) Helicobacter pylori membrane protein 1: A new carcinogenic factor of Helicobacter pylori. Cancer Res. 61, 6356-6359
  42. Suganuma, M., Okabe, S., Kurusu, M., Iida, N., Ohshima, S., Saeki, Y., Kishimoto, T. and Fujiki, H. (2002) Discrete roles of cytokines, TNF-${\alpha}$, IL-1, IL-6 in tumor promotion and cell transformation. Int. J. Oncol. 20, 131-136
  43. Suganuma, M., Kurusu, M., Suzuki, K., Nishizono, A., Murakami, K., Fujioka, T. and Fujiki, H. (2005) New tumor necrosis factor-${\alpha}$-inducing protein released from Helicobacter pylori for gastric cancer progression. J. Cancer Res. Clin. Oncol. 131, 305-313 https://doi.org/10.1007/s00432-004-0611-6
  44. Sugiyama, A., Maruta, F., Ikeno, T., Ishida, K., Kawasaki, S., Katsuyama, T., Shimizu, N. and Tatematsu, M. (1998) Helicobacter pylori infection enhances N-methyl-N-nitrosoureainduced stomach carcinogenesis in the Mongolian gerbil. Cancer Res, 58, 2067-2069
  45. Tomb, J.-F., White, O., Kerlavage, A. R., Clayton, R. A., Sutton, G. G., Fleischmann, R. D., Ketchum, K. A., Klenk, H. P., Gill, S., Dougherty, B. A., Nelson, K., Quackenbush, J., Zhou, L., Kirkness, E. F., Peterson, S., Loftus, B., Richardson, D., Dodson, R., Khalak, H. G., Glodek, A., McKenney, K., Fitzegerald, L. M., Lee, N., Adams, M. D., Hickey, E. K., Berg, D. E., Gocayne, J. D., Utterback, T. R., Peterson, J. D., Kelley, J. M., Cotton, M. D., Weidman, J. M., Fujii, C., Bowman, C., Watthey, L., Wallin, E., Hayes, W. S., Borodovsky, M., Karp, P. D., Smith, H. O., Fraser, C. M. and Venter, J. C. (1997) The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388, 539-547?⨀儙돐?⨀?⨀?⨀⤙댐#Ȁ https://doi.org/10.1038/41483
  46. Tsuchihara, K., Hijikata, M., Fukuda, K., Kuroki, T., Yamamoto, N. and Shimotohno, K. (1999) Hepatitis C virus core protein regulates cell growth and signal transduction pathway transmitting growth stimuli. Viology 258, 100-107 https://doi.org/10.1006/viro.1999.9694
  47. Yamaoka, Y., Kita, M., Kodama, T., Sawai, N., Kashima, K. and Imanishi, J. (1997) Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains. Gut 41, 442-451 https://doi.org/10.1136/gut.41.4.442
  48. Yoshida, M., Wakatsuki, Y., Kobayashi, Y., Itoh, T., Murakami, K., Mizoguchi, A., Usui, T., Chiba, T. and Kita, T. (1999) Cloning and characterization of a novel membrane-associated antigenic protein of Helicobacter pylori. Infect. Immun. 67, 286-293
  49. Wang, J., Chi, D. S., Kalin, G. B., Sosinski, C., Miller, L. E., Burja, I. and Thomas, E. (2002) Helicobacter pylori infection and oncogene expressions in gastric carcinoma and its precursor lesions. Digestive Diseases Sci. 47, 107-113 https://doi.org/10.1023/A:1013223722331

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  1. TNFR1 Signaling and IFN-γ Signaling Determine whether T Cells Induce Tumor Dormancy or Promote Multistage Carcinogenesis vol.13, pp.6, 2008, https://doi.org/10.1016/j.ccr.2008.04.001
  2. Helicobacter pylori-derived extracellular vesicles increased in the gastric juices of gastric adenocarcinoma patients and induced inflammation mainly via specific targeting of gastric epithelial cells vol.49, pp.5, 2017, https://doi.org/10.1038/emm.2017.47
  3. Crystal Structure of the TNF-α-Inducing Protein (Tipα) from Helicobacter pylori: Insights into Its DNA-Binding Activity vol.392, pp.1, 2009, https://doi.org/10.1016/j.jmb.2009.07.010
  4. Stable isotope labeling by amino acids in cell culture based proteomics reveals differences in protein abundances between spiral and coccoid forms of the gastric pathogen Helicobacter pylori vol.126, 2015, https://doi.org/10.1016/j.jprot.2015.05.011
  5. Helicobacter and Digestive Malignancies vol.11, pp.s1, 2006, https://doi.org/10.1111/j.1478-405X.2006.00431.x
  6. TNF-α-inducing protein, a carcinogenic factor secreted fromH. pylori, enters gastric cancer cells vol.123, pp.1, 2008, https://doi.org/10.1002/ijc.23484
  7. In-vitro gastric cancer prevention by a polyphenol-rich extract from olives through induction of apoptosis vol.18, pp.1, 2009, https://doi.org/10.1097/CEJ.0b013e3282fb75f7
  8. Molecular and histological evaluation of tumor necrosis factor-alpha expression in Helicobacter pylori-mediated gastric carcinogenesis vol.137, pp.4, 2011, https://doi.org/10.1007/s00432-010-0921-9
  9. Caffeic Acid Phenethyl Ester (CAPE) May be a Promising Adjuvant Treatment in Gastric Cancer vol.41, pp.10, 2007, https://doi.org/10.1097/MCG.0b013e31806b5938
  10. Helicobacter pyloriin Human Stomach: Can It Be Called Mutualism or a Disease? vol.59, pp.5, 2012, https://doi.org/10.4166/kjg.2012.59.5.329
  11. The role of viral and bacterial pathogens in gastrointestinal cancer vol.216, pp.2, 2008, https://doi.org/10.1002/jcp.21427
  12. How the Discovery of TNF-α Has Advanced Gastrointestinal Diseases and Treatment Regimes vol.59, pp.4, 2014, https://doi.org/10.1007/s10620-014-3042-5
  13. Tumour necrosis factor and cancer vol.9, pp.5, 2009, https://doi.org/10.1038/nrc2628
  14. E-cadherin Gene Promoter Hypermethylation in H. pylori-Induced Enlarged Fold Gastritis vol.12, pp.5, 2007, https://doi.org/10.1111/j.1523-5378.2007.00519.x
  15. Structures of the tumor necrosis factor α inducing protein Tipα: A novel virulence factor fromHelicobacter pylori vol.583, pp.10, 2009, https://doi.org/10.1016/j.febslet.2009.04.033
  16. β-catenin protein utilized by Tumour necrosis factor-α in porcine preadipocytes to suppress differentiation vol.42, pp.6, 2009, https://doi.org/10.5483/BMBRep.2009.42.6.338
  17. Muc1 LimitsHelicobacter felisBinding to Gastric Epithelial Cells But Does not Limit Colonization and Gastric Pathology Following Infection vol.13, pp.6, 2008, https://doi.org/10.1111/j.1523-5378.2008.00644.x
  18. Some fibrocystic breast change may be caused by sexually transmitted H. pylori during oral nipple contact: Supporting literature and case report of resolution after gut H. pylori eradication treatment vol.68, pp.5, 2007, https://doi.org/10.1016/j.mehy.2006.09.050
  19. Helicobacter pylori-secreting protein Tipα is a potent inducer of chemokine gene expressions in stomach cancer cells vol.133, pp.5, 2007, https://doi.org/10.1007/s00432-006-0169-6
  20. Nucleolin as cell surface receptor for tumor necrosis factor-α inducing protein: a carcinogenic factor of Helicobacter pylori vol.136, pp.6, 2010, https://doi.org/10.1007/s00432-009-0733-y
  21. DNA-binding activity of TNF-α inducing protein from Helicobacter pylori vol.362, pp.4, 2007, https://doi.org/10.1016/j.bbrc.2007.08.058
  22. Crystallization and Preliminary Crystallographic Studies of Active TNF-α-Inducing Protein From Helicobacter Pylori* vol.39, pp.12, 2013, https://doi.org/10.3724/SP.J.1206.2012.00125
  23. Gene trapping identifies a putative tumor suppressor and a new inducer of cell migration vol.376, pp.4, 2008, https://doi.org/10.1016/j.bbrc.2008.09.070
  24. Tip-α (hp0596 Gene Product) Is a Highly Immunogenic Helicobacter pylori Protein Involved in Colonization of Mouse Gastric Mucosa vol.56, pp.3, 2008, https://doi.org/10.1007/s00284-007-9083-7
  25. Structural basis for the Helicobacter pylori-carcinogenic TNF-α-inducing protein vol.388, pp.2, 2009, https://doi.org/10.1016/j.bbrc.2009.07.121
  26. Involvement of tumor necrosis factor-α in the upregulation of CXCR4 expression in gastric cancer induced by Helicobacter pylori vol.10, pp.1, 2010, https://doi.org/10.1186/1471-2407-10-419
  27. Pathogenesis of Helicobacter pylori Infection vol.11, pp.s1, 2006, https://doi.org/10.1111/j.1478-405X.2006.00424.x
  28. Epigenetic modifications induced by Helicobacter pylori infection through a direct microbe–gastric epithelial cells cross-talk vol.202, pp.5, 2013, https://doi.org/10.1007/s00430-013-0301-6
  29. Ectopic EBP2 expression enhances cyclin E1 expression and induces chromosome instability in HEK293 stable clones vol.41, pp.10, 2008, https://doi.org/10.5483/BMBRep.2008.41.10.716
  30. Helicobacter pylori infection might have a potential role in hepatocyte ballooning in nonalcoholic fatty liver disease vol.50, pp.9, 2015, https://doi.org/10.1007/s00535-015-1039-2
  31. Effect of Greek Raisins (Vitis Vinifera L.) From Different Origins on Gastric Cancer Cell Growth vol.60, pp.6, 2008, https://doi.org/10.1080/01635580802295776
  32. Infrequent COX-2 expression due to promoter hypermethylation in gastric cancers in Dalian, China vol.37, pp.12, 2006, https://doi.org/10.1016/j.humpath.2006.05.015
  33. Development of human tumor necrosis factor-α muteins with improved therapeutic potential vol.42, pp.5, 2009, https://doi.org/10.5483/BMBRep.2009.42.5.260
  34. Human gastric cancer development with TNF-α-inducing protein secreted from Helicobacter pylori vol.322, pp.2, 2012, https://doi.org/10.1016/j.canlet.2012.03.027
  35. Integrin-linked Kinase Modulates Lipopolysaccharide- andHelicobacter pylori-induced Nuclear Factor κB-activated Tumor Necrosis Factor-α Production via Regulation of p65 Serine 536 Phosphorylation vol.289, pp.40, 2014, https://doi.org/10.1074/jbc.M114.574541
  36. Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk vol.31, pp.3, 2015, https://doi.org/10.1185/03007995.2015.1011778
  37. vol.200, pp.3, 2015, https://doi.org/10.1534/genetics.115.176404