Skip to main content
SpringerLink
Log in

Study of apoptosis-related interactions in colorectal cancer

  • Review
  • Published:
Tumor Biology

Abstract

Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer. In this study, molecular interactions behind the apoptotic regulation have been explored. For this purpose, enrichment analysis was performed considering microRNAs (miRNAs) that putatively target TP53 and altered during colon cancer. This revealed gene associated with both TP53 and miRNAs. Further analysis showed that a significant molecular interaction between the shortlisted candidates (TP53, miR-143, KRAS, BCL2, and PLK1) exists. Mutation study was conducted to confirm the clinical relevance of candidates. It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets. Overall, we showed the importance of interactions between TP53, miR-143, KRAS, BCL2, and PLK1 with respect to colorectal cancer using bioinformatics approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cummings JH, Wiggins HS, Jenkins DJ, Houston H, Jivraj T, Drasar BS, Hill MJ. Influence of diets high and low in animal fat on bowel habit, gastrointestinal transit time, fecal microflora, bile acid, and fat excretion. J Clin Invest. 1978;61:953–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. De Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G, Bentzen CL, Niesor EJ, Dufour JF. The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci. 2004;49:982–9.

    Article  CAS  PubMed  Google Scholar 

  3. Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011;8:686–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yu J, Mallon MA, Zhang W, Freimuth RR, Marsh S, Watson MA, Goodfellow PJ, McLeod HL. DNA repair pathway profiling and microsatellite instability in colorectal cancer. Clin Cancer Res. 2006;12:5104–11.

    Article  CAS  PubMed  Google Scholar 

  6. Piche A, Rancourt C. Gene therapy to overcome drug resistance in cancer: targeting key regulators of the apoptotic pathway. Curr Gene Ther. 2001;1:317–24.

    Article  CAS  PubMed  Google Scholar 

  7. Mulcahy SP, Grundler K, Frias C, Wagner L, Prokop A, Meggers E. Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry. Dalton Trans. 2010;39:8177–82.

    Article  CAS  PubMed  Google Scholar 

  8. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bueno MJ, Malumbres M. MicroRNAs and the cell cycle. Biochim Biophys Acta. 2011;1812:592–601.

    Article  CAS  PubMed  Google Scholar 

  10. Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007;23:175–205.

    Article  CAS  PubMed  Google Scholar 

  11. Skaftnesmo KO, Prestegarden L, Micklem DR, Lorens JB. MicroRNAs in tumorigenesis. Curr Pharm Biotechnol. 2007;8:320–5.

    Article  CAS  PubMed  Google Scholar 

  12. Lynam-Lennon N, Reynolds JV, Pidgeon GP, Lysaght J, Marignol L, Maher SG. Alterations in DNA repair efficiency are involved in the radioresistance of esophageal adenocarcinoma. Radiat Res. 2010;174:703–11.

  13. Koturbash I, Zemp FJ, Pogribny I, Kovalchuk O. Small molecules with big effects: the role of the microRNAome in cancer and carcinogenesis. Mutat Res. 2011;722:94–105.

    Article  CAS  PubMed  Google Scholar 

  14. Wu W. MicroRNA: potential targets for the development of novel drugs? 2010;10:1–8.

  15. Li B, Song Y, Liu TJ, Cui YB, Jiang Y, Xie ZS, Xie SL. miRNA-22 suppresses colon cancer cell migration and invasion by inhibiting the expression of T-cell lymphoma invasion and metastasis 1 and matrix metalloproteinases 2 and 9. Oncol Rep. 2013;29:1932–8.

    CAS  PubMed  Google Scholar 

  16. Zhu R, Yang Y, Tian Y, Bai J, Zhang X, Li X, Peng Z, He Y, Chen L, Pan Q, Fang D, Chen W, Qian C, Bian X, Wang R. Ascl2 knockdown results in tumor growth arrest by miRNA-302b-related inhibition of colon cancer progenitor cells. PLoS One. 2012;7:e32170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Singh M, Singh A, Kundu S, Bansal S, Bajaj A. Deciphering the role of charge, hydration, and hydrophobicity for cytotoxic activities and membrane interactions of bile acid based facial amphiphiles. Biochim Biophys Acta. 2013;1828:1926–37.

    Article  CAS  PubMed  Google Scholar 

  18. Shi XB, Tepper CG, de Vere White RW. Cancerous miRNAs and their regulation. Cell Cycle. 2008;7:1529–38.

    Article  CAS  PubMed  Google Scholar 

  19. Salim H, Akbar NS, Zong D, Vaculova AH, Lewensohn R, Moshfegh A, Viktorsson K, Zhivotovsky B. miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence. Br J Cancer. 2012;107:1361–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Luo X, Burwinkel B, Tao S, Brenner H. MicroRNA signatures: novel biomarker for colorectal cancer? Cancer Epidemiol Biomark Prev. 2011;20:1272–86.

    Article  CAS  Google Scholar 

  21. Vishnubalaji R, Hamam R, Abdulla MH, Mohammed MA, Kassem M, Al-Obeed O, Aldahmash A, Alajez NM. Genome-wide mRNA and miRNA expression profiling reveal multiple regulatory networks in colorectal cancer. Cell Death Dis. 2015;6:e1614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Piepoli A, Tavano F, Copetti M, Mazza T, Palumbo O, Panza A, di Mola FF, Pazienza V, Mazzoccoli G, Biscaglia G, Gentile A, Mastrodonato N, Carella M, Pellegrini F, di Sebastiano P, Andriulli A. Mirna expression profiles identify drivers in colorectal and pancreatic cancers. PLoS One. 2012;7:e33663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pfister TD, Reinhold WC, Agama K, Gupta S, Khin SA, Kinders RJ, Parchment RE, Tomaszewski JE, Doroshow JH, Pommier Y. Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity. Mol Cancer Ther. 2009;8:1878–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kohn KW, Zeeberg BM, Reinhold WC, Pommier Y. Gene expression correlations in human cancer cell lines define molecular interaction networks for epithelial phenotype. PLoS One. 2014;9:e99269.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sanchez Y, Segura V, Marin-Bejar O, Athie A, Marchese FP, Gonzalez J, Bujanda L, Guo S, Matheu A, Huarte M. Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. Nat Commun. 2014;5:5812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pereira H, Silva S, Juliao R, Garcia P, Perpetua F. Prognostic markers for colorectal cancer: expression of P53 and BCL2. World J Surg. 1997;21:210–3.

    Article  CAS  PubMed  Google Scholar 

  27. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nelson HD, Huffman LH, Fu R, Harris EL, U.S.P.S.T. Force. Genetic risk assessment and BRCA mutation testing for breast and ov arian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2005;143:362–79.

    Article  CAS  PubMed  Google Scholar 

  29. Bonadona V, Dussart-Moser S, Voirin N, Sinilnikova OM, Mignotte H, Mathevet P, Bremond A, Treilleux I, Martin A, Romestaing P, Raudrant D, Rudigoz RC, Lenoir GM, Lasset C. Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat. 2007;101:233–45.

    Article  CAS  PubMed  Google Scholar 

  30. Stulp RP, Herkert JC, Karrenbeld A, Mol B, Vos YJ, Sijmons RH. Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum. Hered Cancer Clin Pract. 2008;6:15–21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  32. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Morrow JK, Tian L, Zhang S. Molecular networks in drug discovery. Crit Rev Biomed Eng. 2010;38:143–56.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Torsello A, Garufi C, Cosimelli M, Diodoro MG, Zeuli M, Vanni B, Campanella C, D’Angelo C, Sperduti I, Perrone Donnorso R, Cognetti F, Terzoli E, Mottolese M, R.E.C.I.R.I. Colorectal Disease Management Team. P53 and bcl-2 in colorectal cancer arising in patients under 40 years of age: distribution and prognostic relevance. Eur J Cancer. 2008;44:1217–22.

    Article  CAS  PubMed  Google Scholar 

  35. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Bjorling L, Ponten F. Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 2010;28:1248–50.

    Article  CAS  PubMed  Google Scholar 

  36. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Escandell JM, Kaler P, Recio MC, Sasazuki T, Shirasawa S, Augenlicht L, Rios JL, Klampfer L. Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: the role of p53 and p21. Biochem Pharmacol. 2008;76:198–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blanchard P, Quero L, Pacault V, Schlageter MH, Baruch-Hennequin V, Hennequin C. Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy. BMC Cancer. 2012;12:119.

    Article  PubMed  PubMed Central  Google Scholar 

  39. De Bruijn MT, Raats DA, Tol J, Hinrichs J, Teerenstra S, Punt CJ, Rinkes IH, Kranenburg O. Combined KRAS and TP53 mutation status is not predictive in CAPOX-treated metastatic colorectal cancer. Anticancer Res. 2011;31:1379–85.

    PubMed  Google Scholar 

  40. Takahashi T, Sano B, Nagata T, Kato H, Sugiyama Y, Kunieda K, Kimura M, Okano Y, Saji S. Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci. 2003;94:148–52.

    Article  CAS  PubMed  Google Scholar 

  41. Wolf G, Hildenbrand R, Schwar C, Grobholz R, Kaufmann M, Stutte HJ, Strebhardt K, Bleyl U. Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer. Pathol Res Pract. 2000;196:753–9.

    CAS  PubMed  Google Scholar 

  42. Takai N, Miyazaki T, Fujisawa K, Nasu K, Hamanaka R, Miyakawa I. Polo-like kinase (PLK) expression in endometrial carcinoma. Cancer Lett. 2001;169:41–9.

    Article  CAS  PubMed  Google Scholar 

  43. Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, Rubsamen-Waigmann H, Strebhardt K. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 1997;14:543–9.

    Article  CAS  PubMed  Google Scholar 

  44. Knecht R, Elez R, Oechler M, Solbach C, von Ilberg C, Strebhardt K. Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:2794–7.

    CAS  PubMed  Google Scholar 

  45. Takai N, Miyazaki T, Fujisawa K, Nasu K, Hamanaka R, Miyakawa I. Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage. Cancer Lett. 2001;164:41–9.

    Article  CAS  PubMed  Google Scholar 

  46. Gray Jr PJ, Bearss DJ, Han H, Nagle R, Tsao MS, Dean N, Von Hoff DD. Identification of human polo-like kinase 1 as a potential therapeutic target in pancreatic cancer. Mol Cancer Ther. 2004;3:641–6.

    Article  CAS  PubMed  Google Scholar 

  47. Degenhardt Y, Greshock J, Laquerre S, Gilmartin AG, Jing J, Richter M, Zhang X, Bleam M, Halsey W, Hughes A, Moy C, Liu-Sullivan N, Powers S, Bachman K, Jackson J, Weber B, Wooster R. Sensitivity of cancer cells to Plk1 inhibitor GSK461364A is associated with loss of p53 function and chromosome instability. Mol Cancer Ther. 2010;9:2079–89.

    Article  CAS  PubMed  Google Scholar 

  48. Gilmartin AG, Bleam MR, Richter MC, Erskine SG, Kruger RG, Madden L, Hassler DF, Smith GK, Gontarek RR, Courtney MP, Sutton D, Diamond MA, Jackson JR, Laquerre SG. Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res. 2009;69:6969–77.

    Article  CAS  PubMed  Google Scholar 

  49. Steckel M, Molina-Arcas M, Weigelt B, Marani M, Warne PH, Kuznetsov H, Kelly G, Saunders B, Howell M, Downward J, Hancock DC. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 2012;22:1227–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137:835–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Feng YB, Lin DC, Shi ZZ, Wang XC, Shen XM, Zhang Y, Du XL, Luo ML, Xu X, Han YL, Cai Y, Zhang ZQ, Zhan QM, Wang MR. Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int J Cancer. 2009;124:578–88.

    Article  CAS  PubMed  Google Scholar 

  52. Yang F, Xie YQ, Tang SQ, Wu XB, Zhu HY. miR-143 regulates proliferation and apoptosis of colorectal cancer cells and exhibits altered expression in colorectal cancer tissue. Int J Clin Exp Med. 2015;8:15308–12.

    PubMed  PubMed Central  Google Scholar 

  53. Su J, Liang H, Yao W, Wang N, Zhang S, Yan X, Feng H, Pang W, Wang Y, Wang X, Fu Z, Liu Y, Zhao C, Zhang J, Zhang CY, Zen K, Chen X, Wang Y. MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer. PLoS One. 2014;9:e114420.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Pagliuca A, Valvo C, Fabrizi E, di Martino S, Biffoni M, Runci D, Forte S, De Maria R, Ricci-Vitiani L. Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression. Oncogene. 2013;32:4806–13.

    Article  CAS  PubMed  Google Scholar 

  55. Li L, Pan X, Li Z, Bai P, Jin H, Wang T, Song C, Zhang L, Gao L. Association between polymorphisms in the promoter region of miR-143/145 and risk of colorectal cancer. Hum Immunol. 2013;74:993–7.

    Article  CAS  PubMed  Google Scholar 

  56. Kent OA, Fox-Talbot K, Halushka MK. RREB1 repressed miR-143/145 modulates KRAS signaling through downregulation of multiple targets. Oncogene. 2013;32:2576–85.

    Article  CAS  PubMed  Google Scholar 

  57. Zhuang M, Shi Q, Zhang X, Ding Y, Shan L, Shan X, Qian J, Zhou X, Huang Z, Zhu W, Ding Y, Cheng W, Liu P, Shu Y. Involvement of miR-143 in cisplatin resistance of gastric cancer cells via targeting IGF1R and BCL2. Tumour Biol. 2015;36:2737–45.

    Article  CAS  PubMed  Google Scholar 

  58. Xu B, Niu X, Zhang X, Tao J, Wu D, Wang Z, Li P, Zhang W, Wu H, Feng N, Wang Z, Hua L, Wang X. miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS. Mol Cell Biochem. 2011;350:207–13.

    Article  CAS  PubMed  Google Scholar 

  59. Manikandan M, Deva Magendhra Rao AK, Arunkumar G, Rajkumar KS, Rajaraman R, Munirajan AK. Down regulation of miR-34a and miR-143 may indirectly inhibit p53 in oral squamous cell carcinoma: a pilot study. Asian Pac J Cancer Prev. 2015;16:7619–25.

    Article  PubMed  Google Scholar 

  60. Bionaz M, Periasamy K, Rodriguez-Zas SL, Hurley WL, Loor JJ. A novel dynamic impact approach (DIA) for functional analysis of time-course omics studies: validation using the bovine mammary transcriptome. PLoS One. 2012;7:e32455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by School of Studies in Zoology and Biotechnology, Vikram University, Ujjain, MP India.

Dr. Rehana Qureshi was supported by the UGC—Dr. D.S. Kothari post-doctoral fellowship, Government of India.

Author information

Authors and Affiliations

  1. School of Studies in Zoology and Biotechnology, Vikram University, Ujjain, MP, India

    Himanshu Arora, Sharad Shrivastava & Mordhwaj S. Parihar

  2. Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, India

    Rehana Qureshi & MA Rizvi

Authors
  1. Himanshu Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rehana Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. MA Rizvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sharad Shrivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mordhwaj S. Parihar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Himanshu Arora.

Ethics declarations

Conflicts of interests

The authors declare that they have no competing interests.

Additional information

Himanshu Arora and Rehana Qureshi contributed equally to this work.

Electronic supplementary material

Supplementary Figure 1

Expression of miRNAs in hyperplastic polyp or normal mucosa (HPNM) (n = 23), high grade adenoma (n = 40), sessile serrate adenoma (SSA) (n = 13), traditional serrate adenoma (TSA) (n = 11), and tubular adenoma (TA) (n = 26) samples. (GIF 59 kb)

High resolution image (TIFF 543 kb)

Supplementary Table S1

Table showing miRNAs that could putatively bind toTP53 and significantly expressed during colon cancer using publically available datasets and targetscan, (XLSX 58 kb)

Supplementary Table S2

Lists the expression profile of miRNAs in hyperplastic polyp or normal mucosa (HPNM) (n = 23), high grade adenoma (n = 40), sessile serrate adenoma (SSA) (n = 13), traditional serrate adenoma (TSA) (n = 11), and tubular adenoma (TA) (n = 26) samples. (XLSX 66 kb)

Supplementary Table S3

Lists the results of functional analysis, showing all the functions with which miR-143 related candidates are involved in. This was done by Ingenuity pathway analysis. (XLSX 63 kb)

Supplementary Table S4

Lists the correlation between considered candidate genes and miRNA in NCI60 cells using publically available GEO repositories. (XLSX 42 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arora, H., Qureshi, R., Rizvi, M. et al. Study of apoptosis-related interactions in colorectal cancer. Tumor Biol. 37, 14415–14425 (2016). https://doi.org/10.1007/s13277-016-5363-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5363-9

Keywords

Search

Navigation