DNA sensors, crucial receptors to resist pathogens, are deregulated in colorectal cancer and associated with initiation and progression of the disease Liangmei He 1 , Yuxia Liu 2 , Weiling Lai 3 , Hongbo Tian 3 , Lingxia Chen 4 , Lu Xie 4 , Zhiping Liu 2, 4 1 Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical University; 2 Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University 3 Gannan Medical University; 4 School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000 China. Corresponding Authors: Zhiping Liu, 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2
66
Embed
· Web viewThe onset of CRC is a multistep, multifactorial, and polygenic process, but chronic inflammation is well recognized as a risk factor for CRC. Clinically, inflammatory
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
DNA sensors, crucial receptors to resist pathogens, are
deregulated in colorectal cancer and associated with
Aberrant inflammatory response is an important risk factor of tumor formation, as
well as an important feature after tumor formation [50]. In the early stage of tumor
formation, inflammatory environment facilitates the activation of various signaling
pathways, and the differentiation from normal cell into hyperplasia toward tumor [50].
In the late stages of tumor formation, tumor cells require a variety of positive or
negative regulatory mechanisms to escape immune surveillance [51]. The
dysregulation of the immune system compromises the effective host barrier against
the formation and development of tumors.
DNA sensors are one of the major sub-family of innate immune receptors that
recognize DNA. They are mainly expressed in the cytoplasm of innate immune cells
and can be also expressed in some other cells, such as epithelial cells. The activation
of these receptors can lead to the elimination of invading pathogenic microorganisms
through recognizing exogenous DNA. Subsequent studies have shown that the DNA
sensors can also respond to abnormal accumulated endogenous DNA in cytoplasm
and is involved in the development of inflammatory diseases and autoimmune
diseases [52]. Notably, in recent years, more and more studies have shown that DNA
sensors also participate in the development of tumors, although their specific
functions and mechanisms are still unknown.
Recent studies suggest that DNA sensors such as AIM2, TLR9, DHX9, DHX36
and adaptor STING may have roles in CRC development, and the other DNA sensors
such as DDX41, DDX60, IFI16, and DAI participate in the development of other
types of cancers. Here, we firstly highlighted the notion that many DNA sensors may
have a regulatory role in the occurrence and development of CRC. However, there is
still a lack of systematic understanding on the expression profile, underlying
mechanisms and clinical significance of DNA sensors in CRC. Our present study
represents a comprehensive analysis of DNA sensor expression in CRC and its
16
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
3132
relationship with the tumor stages by combining with the clinical CRC samples,
mouse CRC samples, and Oncomine platform.
We found that DNA sensors and the downstream molecules, including AIM2,
DDX60, TLR9, ASC, MyD88, and IL-18 were down-regulated in CRC. The helicase
family members, including DDX41, DHX9, and DHX36, were up-regulated in CRC
tissues in comparison with controls. IFI16 and STING were the exception in that they
showed no significant change in CRC. Our results of STING and IFI16 were different
from some previous studies. Genetic and epigenetic difference may exist by regions,
racial or the quality of sample. Further analysis showed that the expression of AIM2,
DDX41, DHX9, DAI, and DDX60 showed significant differences between controls
and CRC samples. Among these DNA sensors, AIM2, DAI, and DDX60 showed
consistent change in our clinical CRC samples and TCGA database, and were worthy
of further investigation on their role in CRC development and clinical application.
In summary, our present work studied the expression profile of DNA sensors in
CRC, which broaden our horizons about the function of DNA sensors beyond
immunity against viral infection. Notably, although some agonists of DNA sensors
(e.g. TLR9 and STING) have been applied in clinical or pre-clinical studies and
achieved some encouraging outcomes, their effects in different tumors or different
stages are largely undefined. Therefore, further understanding on the expression and
the role of DNA sensors in different cell types in TME is necessary for rational design
of DNA sensor agonists in clinical trials. On the other hand, we noticed that although
DHX9, were up-regulated in CRC, they decreased in early stage of AOM/DSS treated
mouse. Therefore, the expression of DNA sensors may vary along with diseases
progression, and further investigations on their expression patterns in middle and late
stages of CRC formation may help to understand the full DNA sensors expression
patterns.
17
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
3334
Declarations
Authors’ contribution
Study design: Zhiping Liu; Experiment and statistical analysis: Liangmei He,
Yuxia Liu and Weilin Lai; Drafting and editing: Liangmei He, Hongbo Tian, Lingxia
Chen, and Lu Xie. All authors read and approved the final manuscript.
Fund
This work was supported by funds from Talents' Start-up Fund of Gannan
Medical University (QD201404), Natural Science Foundation of Jiangxi Province
(20151BAB205061, 20171ACB20024, and 20181BAB205032), National Natural
Science Foundation of China (31560260, 31960163), and Science and Technology
Foundation of Jiangxi Provincial Department of Education (Gjj150937) (All to
Zhiping Liu).
Competing interest
All authors have no conflict of interest in this paper.
Availability of data and materials
In this study, the TCGA database in the Oncomine platform was chosen to study
the expression profile of the DNA sensors (Analysis Type: Cancer vs. Normal
Analysis;Cancer Type:Colorectal Cancer; Data Type:mRNA;Sample Type:
Clinical Specimen , Genes : every one DNA sensors; Dataset name : TCGA
Colorectal, Threshold fold change ≥ 1.5,p value ≥ IE-4,Gene Rank in the top 10).
All data generated or analyzed during this study are included in this published article.
18
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
3536
Ethics approval and consent to participate
All the animal experiments were approved by the Animal Ethical and Welfare
Committee of Gannan Medical University.
Consent for publication
We all consent for publication.
Acknowledgement
Not applicable
19
462
463
464
465
466
467
468
469
470
471
3738
References
1. Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424.
2. Arnold, M., et al., Global patterns and trends in colorectal cancer incidence and mortality. Gut, 2017. 66(4): p. 683-691.
3. Jess, T., C. Rungoe, and L. Peyrin-Biroulet, Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol, 2012. 10(6): p. 639-45.
4. Wang, K. and M. Karin, Tumor-Elicited Inflammation and Colorectal Cancer. Adv Cancer Res, 2015. 128: p. 173-96.
5. Takeuchi, O. and S. Akira, Pattern recognition receptors and inflammation. Cell, 2010. 140(6): p. 805-20.
6. Parlato, M. and G. Yeretssian, NOD-like receptors in intestinal homeostasis and epithelial tissue repair. Int J Mol Sci, 2014. 15(6): p. 9594-627.
7. Meylan, E., J. Tschopp, and M. Karin, Intracellular pattern recognition receptors in the host response. Nature, 2006. 442(7098): p. 39-44.
8. He, L., et al., Nucleic acid sensing pattern recognition receptors in the development of colorectal cancer and colitis. Cell Mol Life Sci, 2017. 74(13): p. 2395-2411.
9. Paludan, S.R. and A.G. Bowie, Immune sensing of DNA. Immunity, 2013. 38(5): p. 870-80.10. Dempsey, A. and A.G. Bowie, Innate immune recognition of DNA: A recent history. Virology,
2015. 479-480: p. 146-52.11. Gurtler, C. and A.G. Bowie, Innate immune detection of microbial nucleic acids. Trends
Microbiol, 2013. 21(8): p. 413-20.12. Li, T.T., S. Ogino, and Z.R. Qian, Toll-like receptor signaling in colorectal cancer: carcinogenesis
to cancer therapy. World J Gastroenterol, 2014. 20(47): p. 17699-708.13. Sipos, F., et al., Contribution of TLR signaling to the pathogenesis of colitis-associated cancer
in inflammatory bowel disease. World J Gastroenterol, 2014. 20(36): p. 12713-21.14. Chen, G.Y., Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. Eur J
Immunol, 2014. 44(2): p. 321-7.15. Hornung, V., et al., AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating
inflammasome with ASC. Nature, 2009. 458(7237): p. 514-8.16. Wilson, J.E., et al., Inflammasome-independent role of AIM2 in suppressing colon
tumorigenesis via DNA-PK and Akt. Nat Med, 2015. 21(8): p. 906-13.17. Man, S.M., et al., Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.
Cell, 2015. 162(1): p. 45-58.18. Chen, J., Z. Wang, and S. Yu, AIM2 regulates viability and apoptosis in human colorectal
cancer cells via the PI3K/Akt pathway. Onco Targets Ther, 2017. 10: p. 811-817.19. Ishikawa, H., Z. Ma, and G.N. Barber, STING regulates intracellular DNA-mediated, type I
interferon-dependent innate immunity. Nature, 2009. 461(7265): p. 788-92.20. Zhang, Z., et al., The helicase DDX41 senses intracellular DNA mediated by the adaptor STING
in dendritic cells. Nat Immunol, 2011. 12(10): p. 959-65.
21. Sun, L., et al., Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 2013. 339(6121): p. 786-91.
22. Unterholzner, L., et al., IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol, 2010. 11(11): p. 997-1004.
23. Zhu, Q., et al., Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol, 2014. 193(10): p. 4779-82.
24. Ahn, J., H. Konno, and G.N. Barber, Diverse roles of STING-dependent signaling on the development of cancer. Oncogene, 2015. 34(41): p. 5302-8.
25. He, L., et al., STING signaling in tumorigenesis and cancer therapy: A friend or foe? Cancer Lett, 2017. 402: p. 203-212.
26. Albrethsen, J., et al., Subnuclear proteomics in colorectal cancer: identification of proteins enriched in the nuclear matrix fraction and regulation in adenoma to carcinoma progression. Mol Cell Proteomics, 2010. 9(5): p. 988-1005.
27. Jiang, Y., et al., The emerging roles of the DDX41 protein in immunity and diseases. Protein Cell, 2017. 8(2): p. 83-89.
28. Fu, T.Y., et al., Subsite-specific association of DEAD box RNA helicase DDX60 with the development and prognosis of oral squamous cell carcinoma. Oncotarget, 2016. 7(51): p. 85097-85108.
29. Rhodes, D.R., et al., Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia, 2007. 9(2): p. 166-80.
30. Snider, A.J., et al., Murine Model for Colitis-Associated Cancer of the Colon. Methods Mol Biol, 2016. 1438: p. 245-54.
31. Sharma, D., et al., Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis. Gastroenterology, 2018. 154(4): p. 948-964 e8.
32. Karki, R., et al., NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. Nature, 2016.33. Zaki, M.H., et al., The NOD-like receptor NLRP12 attenuates colon inflammation and
tumorigenesis. Cancer Cell, 2011. 20(5): p. 649-60.34. Dihlmann, S., et al., Lack of Absent in Melanoma 2 (AIM2) expression in tumor cells is closely
associated with poor survival in colorectal cancer patients. Int J Cancer, 2014. 135(10): p. 2387-96.
35. Becker, C. and D. Weigel, Epigenetic variation: origin and transgenerational inheritance. Curr Opin Plant Biol, 2012. 15(5): p. 562-7.
36. Liu, R., et al., Expression profile of innate immune receptors, NLRs and AIM2, in human colorectal cancer: correlation with cancer stages and inflammasome components. Oncotarget, 2015. 6(32): p. 33456-69.
37. HE, L., et al., Expression profle of Toll-like receptors 9 in colorectal cancer. Journal of Gannan Medical University, 2017. 37(1): p. 32-37.
38. Woo, S.R., et al., STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity, 2014. 41(5): p. 830-42.
39. Deng, L., et al., STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity, 2014. 41(5): p. 843-52.
40. Burdette, D.L., et al., STING is a direct innate immune sensor of cyclic di-GMP. Nature, 2011. 478(7370): p. 515-8.
41. Xia, T., et al., Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis. Cell Rep, 2016. 14(2): p. 282-97.
42. Yang, C.A., et al., DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression. Oncology, 2017. 92(2): p. 115-124.
43. Fullam, A. and M. Schroder, DExD/H-box RNA helicases as mediators of anti-viral innate immunity and essential host factors for viral replication. Biochim Biophys Acta, 2013. 1829(8): p. 854-65.
44. Jain, A., et al., DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells. Nucleic Acids Res, 2013. 41(22): p. 10345-57.
45. Fidaleo, M., et al., Genotoxic stress inhibits Ewing sarcoma cell growth by modulating alternative pre-mRNA processing of the RNA helicase DHX9. Oncotarget, 2015. 6(31): p. 31740-57.
46. Lee, T., et al., Tumor cell survival dependence on the DHX9 DExH-box helicase. Oncogene, 2016. 35(39): p. 5093-105.
47. Matsumura, K., et al., The novel G-quadruplex-containing long non-coding RNA GSEC antagonizes DHX36 and modulates colon cancer cell migration. Oncogene, 2017. 36(9): p. 1191-1199.
48. Hornung, V., SnapShot: Nucleic acid immune sensors, part 2. Immunity, 2014. 41(6): p. 1066-1066 e1.
49. Zhang, Z., et al., DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity, 2011. 34(6): p. 866-78.
50. Kundu, J.K. and Y.J. Surh, Inflammation: gearing the journey to cancer. Mutat Res, 2008. 659(1-2): p. 15-30.
51. Ribatti, D., The concept of immune surveillance against tumors. The first theories. Oncotarget, 2017. 8(4): p. 7175-7180.
52. Kawasaki, T., T. Kawai, and S. Akira, Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol Rev, 2011. 243(1): p. 61-73.