Regulatory pathways of colorectal cancer and their synergistic cross-talk mechanism

Document Type : Review Article

Authors

1 Pharmacogenomics and CADD Laboratory, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi-630 003, Tamil Nadu, India

2 Basic Engineering Departments, Alagappa Polytechnic College, Karaikudi–630 004, Tamil Nadu, India

Abstract

Context: Cancer is the leading cause of death in the human population, ensuing from the accumulation of damage to genetic materials and affecting various parts of the organs. This review is focused on the cell signaling cross-talk mechanism of colorectal cancer (CRC) and its regulations. Genomic instability acts as the major driving force for CRC. The major CRC cascade mechanisms such as Wnt, Ras, TOPK, p53, and ubiquitin pathways were discussed. These interlinked signals cross-talk with one another in various regulatory mechanisms and play a unique role in CRC.
Evidence Acquisition: The major cross-talking signals of CRC are the most significant part of this review. Wnt is a resource and center of axis for cross-talk and interlinked signaling mechanism. Wnt/β-catenin signaling was regulated by frizzled receptor, co-factors, Ras, TOPK, and many other mechanisms; related literature of CRC were collected through a literature survey and categorized using the keywords. The pathways with high specificity interlinked with Wnt were identified and used as the major targets for this review.
Results and Conclusion: The interlinked signaling pathways and gene networks were explained with their specificity role in CRC. We highlighted the major regulatory signaling and interlinked pathways of CRC, as new multi targets approach. Furthermore, we discussed the potent targeted genes, bio-markers for a better prognosis, and therapies for CRC patients. Through highlighting the gene cross-talking signaling cascade; we have provided the source for gene network interaction and targeted therapy. This study paves the way for multi-targeting of interlinked pathways and suggesting these would be perfect for suppressing of CRC. The signaling pathways discussed in this review are not only focused on CRC but also the new potent targets and bio-markers for different types of cancers. Targeting multiple interlinked pathways could be useful for developing new potential bio-markers for treatment and diagnosis purposes.

Keywords


  1. Jemal A, Siegel R, Ward E, Hao Y, et al. Cancer statistics. CA Cancer J Clin. 2009;22;59(4): 225-49. doi: 10.3322/caac.20006. [Pub Med:19474385].
  2. Stryker SJ, Wolff BG, Culp CE, Libbe SD, et al. Natural history of untreated colonic polyps. Gastroenterology. 1987;93(5):1009-13. [Pub Med:3653628].
  3. Payne S. Not an equal opportunity disease–a sex and gender-based review of colorectal cancer in men and women: part I. Journal of Men's Health and Gender. 2007;4(2):131-9.
  4. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. cell. 1990;61(5):759-67. [Pub Med:2188735].
  5. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330 -7. doi: 10.1038/nature11252. [Pub Med:22810696].
  6. Spink KE, Fridman SG, Weis WI. Molecular mechanisms of β‐catenin recognition by adenomatous polyposis coli revealed by the structure of an APC–β‐catenin complex. The EMBO J. 2001;20(22):6203-12. doi: 10.1093/emboj/20.22.6203. [Pub Med:11707392].
  7. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059-72. doi: 10.1053/j.gastro.2009.12.065. [Pub Med:20420946].
  8. Cox AD, Fesik SW, Kimmelman AC, Luo J, et al. Drugging the undruggable RAS: mission possible?. Nat Rev Drug Discov. 2014;13(11):828-51. doi: 10.1038/nrd4389. [Pub Med:25323927].
  9. Nakamura T, Hamada F, Ishidate T, Anai KI, et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with β‐catenin, GSK‐3β and APC and reduces the β‐catenin level. Genes Cells. 1998;3(6):395-403. [Pub Med:9734785].
  10. Kirubakaran P, Arunkumar P, Premkumar K, Muthusamy K. Sighting of tankyrase inhibitors by structure-and ligand-based screening and in vitro approach. Mol Biosyst. 2014;10(10):2699-712. doi: 10.1039/c4mb00309h. [Pub Med:25091558].
  11. Loganathan L, Natarajan K, Muthusamy K. Computational study on cross-talking cancer signalling mechanism of ring finger protein 146, AXIN and Tankyrase protein complex. J Biomol Struct Dyn. 2019; 1-13. doi: 10.1080/07391102.2019.1696707. [Pub Med:31760854].
  12. Spink KE, Fridman SG, Weis WI. Molecular mechanisms of β‐catenin recognition by adenomatous polyposis coli revealed by the structure of an APC–β‐catenin complex. The EMBO J. 2001;20(22):6203-12. doi: 10.1093/emboj/20.22.6203. [Pub Med:11707392].
  13. Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017;16;8(20):33972. doi: 10.18632/oncotarget.15687. [Pub Med:28430641]. 
  14. Chen Z, He X, Jia M, Liu Y, et al. β-catenin overexpression in the nucleus predicts progress disease and unfavourable survival in colorectal cancer: a meta-analysis. PLoS One. 2013;8(5):e63854. doi: 10.1371/journal. pone.0063854. [Pub Med:23717499].
  15. Mann B, Gelos M, Siedow A, Hanski ML, et al. Target genes of β-catenin–T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A. 1999;96(4):1603-8. [Pub Med:9990071]. 
  16. Loganathan L, Muthusamy K. Current Scenario in Structure and Ligand-Based Drug Design on Anti-colon Cancer Drugs. Curr Pharm Design. 2018;24(32):3829- 3841. doi: 10.2174/1381612824666181114114513.  [Pub Med:30426891]. 
  17. Elbadawy M, Usui T, Yamawaki H, Sasaki K. Emerging roles of C-Myc in Cancer stem cell-related signaling and resistance to cancer chemotherapy: a potential therapeutic target against colorectal cancer. Int J Mol Sci. 2019;20(9):  pii: E2340. doi: 10.3390/ijms20092340. [Pub Med:31083525].
  18. Kirubakaran P, Karthikeyan M. Pharmacophore modeling, 3D-QSAR and DFT studies of IWR small-molecule inhibitors of Wnt response. J Recept Signal Transduct Res. 2013;33(5):276-85. doi: 10.3109/10799893.2013.822888. [Pub Med:23914783].
  19. Wangefjord S, Manjer J, Gaber A, Nodin B, et al. Cyclin D1 expression in colorectal cancer is a favorable prognostic factor in men but not in women in a prospective, population-based cohort study. Biol Sex Differ. 2011;2:10. doi: 10.1186/2042-6410-2-10.[Pub Med:21888663].
  20. Zhang X, Sukamporn P, Zhang S, Min KW, et al. 3, 3'-diindolylmethane downregulates cyclin D1 through triggering endoplasmic reticulum stress in colorectal cancer cells. Oncol Reports. 2017;38(1):569-574. doi: 10.3892/or.2017.5693. [Pub Med:28586058].
  21. Kirubakaran P, Muthusamy K, Singh KH, Nagamani S. Ligand-based pharmacophore modeling; atom-based 3D-QSAR analysis and molecular docking studies of phosphoinositide-dependent kinase-1 inhibitors. Indian J Pharm Sci. 2012;74(2):141-51. doi: 10.4103/0250-474X.103846. [Pub Med:23325995].
  22. Jain S, Ghanghas P, Rana C, Sanyal SN. Role of GSK-3β in regulation of canonical Wnt/β-catenin signaling and PI3-K/Akt oncogenic pathway in colon cancer. Cancer invest. 2017;35(7):473-483. doi: 10.1080/07357907.2017.1337783. [Pub Med:28718684].
  23. Thorne CA, Hanson AJ, Schneider J, Tahinci E, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Bio. 2010;6(11):829-36. doi: 10.1038/nchembio.453. [Pub Med:20890287].
  24. Yang J, Wu J, Tan C, Klein PS. PP2A: B56ϵ is required for Wnt/β-catenin signaling during embryonic development. Development. 2003;130(23):5569-78. [Pub Med: 14522869].
  25. Novellasdemunt L, Antas P, Li VS. Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am J Physiol. 2015;309(8):C511-21. doi: 10.1152/ajpcell.00117.2015. [Pub Med:26289750].
  26. Yan W, Guo M. Epigenetics of colorectal cancer. Methods Mol Biol. 2015;1238:405-24. doi: 10.1007/978-1-4939-1804-1_22. [Pub Med:25421673]. 
  27. Caldwell GM, Jones CE, Soon Y, Warrack R, et al. Reorganisation of Wnt-response pathways in colorectal tumorigenesis. Br J of Cancer. 2008;98(8):1437-42. doi: 10.1038/sj.bjc.6604327.  [Pub Med:18414471].
  28. Bafico A, Gazit A, Pramila T, Finch PW, et al. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem. 1999      ;274(23):16180-7. [Pub Med:10347172].
  29. Vincan E, Barker N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin Exp Metastasis. 2008 ;25(6):657-63.  doi: 10.1007/s10585-008-9156-4. [Pub Med:18350253].
  30. Wong SC, He CW, Chan CM, Chan AK, et al. Clinical significance of frizzled homolog 3 protein in colorectal cancer patients. PLoS One. 2013;8(11). doi: 10.1371/journal.pone.0079481. [Pub Med:24255701].
  31. Kim BK, Yoo HI, Kim I, Park J, et al. FZD6 expression is negatively regulated by miR-199a-5p in human colorectal cancer. BMB Rep. 2015;48(6):360-6. [Pub Med;25772759].
  32. Ueno K, Hazama S, Mitomori S, Nishioka M,et al. Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells. Br J cancer. 2009;101(8):1374-81. doi: 10.1038/sj.bjc.6605307. [Pub Med;19773752].
  33. Ueno K, Hiura M, Suehiro Y, Hazama S, et al. Frizzled-7 as a potential therapeutic target in colorectal cancer.Neoplasia. 2008;10(7):697-705. [Pub Med;18592008].
  34. Terasaki H, Saitoh T, Shiokawa K, Katoh M. Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT-β-catenin-TCF signaling pathway. Int J Mol Med. 2002;9(2):107-12. [Pub Med;11786918].
  35. Nagayama S, Yamada E, Kohno Y, Aoyama T, et al. Inverse correlation of the up‐regulation of FZD10 expression and the activation of β‐catenin in synchronous colorectal tumors. Cancer science. 2009;100(3):405-12. doi: 10.1111/j.1349-7006.2008.01052.x. [Pub Med:19134005].
  36. Sebio A, Kahn M, Lenz HJ. The potential of targeting Wnt/β-catenin in colon cancer. Expert Opin The Targets. 2014;18(6):611-5. doi: 10.1517/14728222.2014.906580. [Pub Med: 24702624].
  37. Lammi L, Arte S, Somer M, Järvinen H, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet. 2004;74(5):1043-50. [Pub Med:15042511]
  38. Liu W, Dong X, Mai M, Seelan RS, et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling. Nat Genet. 2000;26(2):146-7. [Pub Med:11017067].
  39. Chen HY, Lin YM, Chung HC, Lang YD, et al. miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. Cancer Res. 2012;72(14):3631-41. doi: 10.1158/0008-5472.CAN-12-0667. [Pub Med:22593189].
  40. Jiang Z, Wang Z, Xu Y, Wang B, et al. Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer. Biosci Rep. 2010;30(6):383-90. doi: 10.1042/BSR20090129. [Pub Med:20001967}
  41. Cristóbal I, Manso R, Rincón R, Caramés C, et al. Phosphorylated protein phosphatase 2A determines poor outcome in patients with metastatic colorectal cancer. Br J Cancer. 2014;111(4):756-62. doi: 10.1038/bjc.2014.376. [Pub Med:25003662].
  42. Gay B, Suarez S, Caravatti G, Furet P, et al. Selective GRB2 SH2 inhibitors as anti‐Ras therapy. International journal of cancer. 1999;83(2):235-41. [Pub Med:10471533].
  43. Fixman ED, Fournier TM, Kamikura DM, Naujokas MA, et al. Pathways downstream of Shc and Grb2 are required for cell transformation by the tpr-Met oncoprotein. Biol Chem. 1996;271(22):13116-22. [Pub Med:8662733].
  44. He F, Chen H, Yang P, Wu Q, et al. Gankyrin sustains PI3K/GSK-3β/β-catenin signal activation and promotes colorectal cancer aggressiveness and progression. Oncotarget. 2016;7(49):81156- -81171. doi: 10.18632/oncotarget.13215. [Pub Med:27835604].
  45. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncology. 1999;17(11):3631-52. [Pub Med:10550163]. 
  46. Long IS, Han K, Li M, Shirasawa S, et al. Met Receptor Overexpression and Oncogenic Ki-ras Mutation Cooperate to Enhance Tumorigenicity of Colon Cancer Cells in Vivo. Mol Cancer Res. 2003;1(5):393-401. [Pub Med:12651912].
  47. Juárez M, Egoavil C, Rodríguez-Soler M, Hernández-Illán E, et al. KRAS and BRAF somatic mutations in colonic polyps and the risk of metachronous neoplasia. PloS one. 2017;12(9). doi: 10.1371/journal.pone.0184937. [Pub Med:8953955].
  48. Ates O, Yalcin S. Concomitant RAS and BRAF mutation in colorectal cancer-A report of 7 cases. Indian J C. 2019;56(2):176-179. doi: 10.4103/ijc.IJC_430_18. [Pub Med:31062740].
  49. Takeda T, Banno K, Okawa R, Yanokura M, et al. ARID1A gene mutation in ovarian and endometrial cancers. Oncol Rep. 2016;35(2):607-13. doi: 10.3892/or.2015.4421. [Pub Med:26572704].
  50. Thompson H. US National Cancer Institute's new Ras project targets an old foe. Nat Med. 2013;19(8):949-50. doi: 10.1038/nm0813-949. [Pub Med:23921727].
  51. Kirubakaran P, Karthikeyan M, Singh KD, Nagamani S, et al. In silico structural and functional analysis of the human TOPK protein by structure modeling and molecular dynamics studies. J Mol Model. 2013;19(1):407-19. doi: 10.1007/s00894-012-1566-1. [Pub Med:22940854].
  52. Langlois B, Perrot G, Schneider C, Henriet P, et al. LRP-1 promotes cancer cell invasion by supporting ERK and inhibiting JNK signaling pathways. PLoS One. 2010;5(7). doi: 10.1371/journal.pone.0011584. [Pub Med:20644732].
  53. Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death  Diff. 2009;16(3):368-77. doi: 10.1038/cdd.2008.148. Epub 2008 Oct 10. [Pub Med:18846109].
  54. Yang JY, Zong CS, Xia W, Yamaguchi H, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10(2):138-48. doi: 10.1038/ncb1676. [Pub Med:18204439].
  55. Bolesta E, Pfannenstiel LW, Demelash A, Lesniewski ML, et al. Inhibition of Mcl-1 promotes senescence in cancer cells: implications for preventing tumor growth and chemotherapy resistance. Mol Cell Biol. 2012;32(10):1879-92. doi: 10.1128/MCB.06214-11. [Pub Med:22451485].
  56. Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem. 2016;109:314-41. doi: 10.1016/j.ejmech.2016.01.012. [Pub Med:26807863]..
  57. Xiao YC, Yang ZB, Cheng XS, Fang XB, et al. CXCL8, overexpressed in colorectal cancer, enhances the resistance of colorectal cancer cells to anoikis. Cancer lett. 2015;361(1):22-32.  doi: 10.1016/j.canlet.2015.02.021. [Pub Med: 25687885].
  58. Khalili H, Gong J, Brenner H, Austin TR, et al. Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer. Carcinogenesis. 2015;36(9):999-1007. doi: 10.1093/carcin/bgv086. [Pub Med:26071399].
  59. Ratner M. First multi-gene NGS diagnostic kit approved. Nat Biotechnol. 2017;35(8):699. doi: 10.1038/nbt0817-699. [Pub Med:28787405].
  60. Brand S, Olszak T, Beigel F, Diebold J, et al. Cell differentiation dependent expressed CCR6 mediates ERK‐1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. J Cell Biochem. 2006;97(4):709-23. [Pub Med:16215992].
  61. Cheng XS, Li YF, Tan J, Sun B, et al. CCL20 and CXCL8 synergize to promote progression and poor survival outcome in patients with colorectal cancer by collaborative induction of the epithelial–mesenchymal transition. Cancer Lett. 2014;348(1-2):77-87. doi: 10.1016/j.canlet.2014.03.008. [Pub Med:24657657].
  62. Deora AA, Win T, Vanhaesebroeck B, Lander HM. A Redox-triggered Ras-Effector Interaction Recruitment of phosphatidylinositol 3′-kinase to ras by redox stress. J Biol Chem. 1998;273(45):29923-8. [Pub Med:9792710].
  63. Bellmann K, Martel J, Poirier DJ, Labrie MM, et al. Downregulation of the PI3K/Akt survival pathway in cells with deregulated expression of c-Myc. Apoptosis. 2006;11(8):1311-9. [Pub Med:16788862].
  64. Dasari A, Messersmith WA. New strategies in colorectal cancer: biomarkers of response to epidermal growth factor receptor monoclonal antibodies and potential therapeutic targets in phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. Clin Cancer Res. 2010;16(15):3811-8. doi: 10.1158/1078-0432.CCR-09-2283.  [Pub Med:20554751].
  65. Li XL, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015;21(1):84-93. doi: 10.3748/wjg.v21.i1.84. [Pub Med:25574081].
  66. Yu H, Yue X, Zhao Y, Li X, et al. LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat Commun. 2014;5 :5218. doi: 10.1038/ncomms6218. [Pub Med:25323535].
  67. Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death  Differ. 2018;25(1):65-80. doi: 10.1038/cdd.2017.186. [Pub Med:29149100].
  68. Yang J, Nie J, Ma X, Wei Y, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18(1):26. doi: 10.1186/s12943-019-0954-x. [Pub Med:30782187]
  69. Fang Y, Liang X, Jiang W, Li J, et al. Cyclin b1 suppresses colorectal cancer invasion and metastasis by regulating e-cadherin. PLoS One. 2015;10(5) :e0126875. doi: 10.1371/journal.pone.0126875. [Pub Med:25962181].
  70. Beasley WD, Beynon J, Jenkins GJ, Parry JM. Reprimo 824 G> C and p53R2 4696 C> G single nucleotide polymorphisms and colorectal cancer: a case–control disease association study. Int J Colorectal Dis. 2008;23(4):375-81. doi: 10.1007/s00384-007-0435-3. [Pub Med:18197409].
  71. Snoeren N, Emmink BL, Koerkamp MJ, van Hooff SR, et al. Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer. Br J Cancer. 2013;109(6):1636-47. doi: 10.1038/bjc.2013.489. [Pub Med:24002600].
  72. Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol. 2006;8(8):877-84. [Pub Med:16862142].
  73. Chen J, Wei Y, Feng Q, Ren L, et al. Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway. Int J Oncol. 2016;48(4):1628-38. doi: 10.3892/ijo.2016.3366. [Pub Med: 26847263]..
  74. Clark PA, Llanos S, Peters G. Multiple interacting domains contribute to p14 ARF mediated inhibition of MDM2. Oncogene. 2002;21(29):4498-507. doi: 10.1038/sj.onc.1205558. [Pub Med:12085228].
  75. Ling X, Xu C, Fan C, Zhong K, et al. FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX. Cancer Res. 2014;74(24):7487-97. doi: 10.1158/0008-5472.CAN-14-0683. [Pub Med:25512388].
  76. Kirubakaran P, Kothandan G, Cho SJ, Muthusamy K. Molecular insights on TNKS1/TNKS2 and inhibitor-IWR1 interactions. Mol Biosyst. 2014;10(2):281-93. doi: 10.1039/c3mb70305c. [Pub Med:24291818].
  77. Loganathan L, Muthusamy K, Jayaraj JM, Kajamaideen A, et al. In silico insights on tankyrase protein: A potential target for colorectal cancer. J Biomol Struct Dyn. 2019;37(14):3637- 3648. doi: 10.1080/07391102.2018.1521748.  [Pub Med:30204055 ].
  78. Rathinavelu A, Levy A. Key Genes in Prostate Cancer Progression: Role of MDM2, PTEN, and TMPRSS2-ERG Fusions. Prostate Cancer: Leading-edge Diagnostic Procedures and Treatments. 2016:179.
  79. Wang W, Li N, Li X, Tran MK, et al. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep. 2015;13(3):524-532. doi: 10.1016/j.celrep.2015.09.014. [Pub Med:26456820].
  80. Callow MG, Tran H, Phu L, Lau T, et al. Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling. PloS one. 2011;6(7):e22595. doi: 10.1371/journal.pone.0022595. [Pub Med: 21799911].