Skip to main content
SpringerLink
Log in

MicroRNA-3607 inhibits the tumorigenesis of colorectal cancer by targeting DDI2 and regulating the DNA damage repair pathway

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Mutations in the DNA damage repair (DDR) pathway are frequently detected in colorectal cancer (CRC). The dysregulation of miRNAs, such as oncogenes or tumor suppressors, participates in CRC tumorigenesis. A previous study showed that low miR-3607 expression correlated with poor survival in prostate cancer patients, but its role in CRC remains unclear. In this study, we analyzed miR-3607 expression Pan-Cancer data from the NCI’s Genomic Data Commons (GDC) and found that miR-3607 was downregulated in lymphatic invasion patients and in recurrent cancer and correlated with Pan-Cancer patient survival. Functional studies indicated that the overexpression of miR-3607 decreased CRC cell proliferation, migration and invasion. Additionally, we used gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and a protein–protein interaction network to demonstrate that miR-3607 affects the DDR pathway. Luciferase reporter and apoptosis assays confirmed that DNA damage inducible 1 homolog 2 (DDI2) is the functional target of miR-3607. Therefore, miR-3607 inhibits the tumorigenesis of CRC probably by suppressing the oncogene DDI2, and it might serve as a novel target for CRC prediction and therapy.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, Fan H, Shen H, Way GP, Greene CS (2018) Genomic and molecular landscape of DNA damage repair deficiency across The Cancer Genome Atlas. Cell Rep 23(1):239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Peltomäki P (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10(7):735–740

    Article  PubMed  Google Scholar 

  3. Jeggo PA, Pearl LH, Carr AM (2016) DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 16(1):35

    Article  CAS  PubMed  Google Scholar 

  4. Rich JN (2007) Cancer stem cells in radiation resistance. Can Res 67(19):8980–8984

    Article  CAS  Google Scholar 

  5. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Investig 119(6):1420–1428

    Article  CAS  Google Scholar 

  6. Chandy C, Maitra R (2017) Emerging role of transcription factors in epithelial mesenchymal transition attributing to metastasis of colorectal cancer. of 7:2

  7. Lee RC, Feinbaum RL, Ambros V (1993) The C elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854

    Article  CAS  Google Scholar 

  8. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  Google Scholar 

  9. Tokarz P, Blasiak J (2012) The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment. Acta Biochim Pol. https://doi.org/10.18388/abp.2012_2079

    Article  PubMed  Google Scholar 

  10. Saini S, Majid S, Shahryari V, Tabatabai ZL, Arora S, Yamamura S, Tanaka Y, Dahiya R, Deng G (2014) Regulation of SRC kinases by microRNA-3607 located in a frequently deleted locus in prostate cancer. Mol Cancer Ther 13(7):1652–1693

    Article  CAS  Google Scholar 

  11. Summy JM, Gallick GE (2003) Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 22(4):337–358

    Article  CAS  PubMed  Google Scholar 

  12. Allgayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE (2002) Activation of Src kinase in primary colorectal carcinoma. Cancer 94(2):344–351

    Article  CAS  Google Scholar 

  13. Su N, Peng L, Xia B, Zhao Y, Xu A, Wang J, Wang X, Jiang B (2012) Lyn is involved in CD24-induced ERK1/2 activation in colorectal cancer. Mol Cancer 11(1):43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ishizawar R, Parsons SJ (2004) c-Src and cooperating partners in human cancer. Cancer Cell 6(3):209–214

    Article  CAS  PubMed  Google Scholar 

  15. Chaudhry MA, Omaruddin RA, Brumbaugh CD, Tariq MA, Pourmand N (2013) Identification of radiation-induced microRNA transcriptome by next-generation massively parallel sequencing. J Rad Res 54(5):808–822

    Article  CAS  Google Scholar 

  16. McDermott N, Meunier A, Wong S, Buchete V, Marignol L (2017) Profiling of a panel of radioresistant prostate cancer cells identifies deregulation of key miRNAs. Clin Transl Radiat Oncol 2:63–68

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O (2006) ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med 203(2):297–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Murga M, Jaco I, Fan Y, Soria R, Martinez-Pastor B, Cuadrado M, Yang S-M, Blasco MA, Skoultchi AI, Fernandez-Capetillo O (2007) Global chromatin compaction limits the strength of the DNA damage response. J Cell Biol 178(7):1101–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. He H, Zhao X, Zhu Z, Du L, Chen E, Liu S, Li Q, Dong J, Yang J, Lei L (2019) MicroRNA-3191 promotes migration and invasion by downregulating TGFBR2 in colorectal cancer. J Biochem Mol Toxicol 4:4. https://doi.org/10.1002/jbt.22308

    Article  CAS  Google Scholar 

  20. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P (2016) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucl Acids Res. https://doi.org/10.1093/nar/gkw937

    Article  PubMed  Google Scholar 

  21. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Muñoz P (2011) The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8(5):511–524

    Article  CAS  PubMed  Google Scholar 

  23. Whitfield ML, George LK, Grant GD, Perou CM (2006) Common markers of proliferation. Nat Rev Cancer 6(2):99

    Article  CAS  PubMed  Google Scholar 

  24. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532

    Article  CAS  PubMed  Google Scholar 

  25. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352–1355

    Article  CAS  PubMed  Google Scholar 

  26. Tessitore A, Cicciarelli G, Del Vecchio F, Gaggiano A, Verzella D, Fischietti M, Vecchiotti D, Capece D, Zazzeroni F, Alesse E (2014) MicroRNAs in the DNA damage/repair network and cancer. Int J Genom. https://doi.org/10.1155/2014/820248

    Article  Google Scholar 

  27. Wan G, Mathur R, Hu X, Zhang X, Lu X (2011) miRNA response to DNA damage. Trends Biochem Sci 36(9):478–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu H, Gatti RA (2010) MicroRNAs: new players in the DNA damage response. J Mol Cell Biol 3(3):151–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kottemann MC, Conti BA, Lach FP, Smogorzewska A (2018) Removal of RTF2 from stalled replisomes promotes maintenance of genome integrity. Mol Cell 69(1):24–35

    Article  CAS  PubMed  Google Scholar 

  30. Longley DB, Latif T, Boyer J, Allen WL, Maxwell PJ, Johnston PG (2003) The interaction of thymidylate synthase expression with p53-regulated signaling pathways in tumor cells. Semin Oncol 3:3–9

    Article  CAS  Google Scholar 

  31. Chowdhury AMA, Katoh H, Hatanaka A, Iwanari H, Nakamura N, Hamakubo T, Natsume T, Waku T, Kobayashi A (2017) Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation. Sci Rep 7(1):12494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Palma M, Lopez L, García M, de Roja N, Ruiz T, García J, Rosell E, Vela C, Rueda P, Rodriguez M-J (2012) Detection of collagen triple helix repeat containing-1 and nuclear factor (erythroid-derived 2)-like 3 in colorectal cancer. BMC Clin Pathol 12(1):2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. LaPointe LC, Pedersen SK, Dunne R, Brown GS, Pimlott L, Gaur S, McEvoy A, Thomas M, Wattchow D, Molloy PL (2012) Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing. PLoS ONE 7(1):e29059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 31401081) and the Natural Science Foundation of Shaanxi Provincial Department of Education (Grant No. 18JK0796).

Author information

Authors and Affiliations

  1. Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Taibai North Road 229, Xi’an, 710069, Shaanxi, China

    Lei Lei, Xiaojuan Zhao, Shuzhen Liu, Qing Cao, Bianbian Yan & Jin Yang

  2. Institute of Preventive Genomic Medicine, Xi’an, 710069, China

    Lei Lei, Xiaojuan Zhao, Shuzhen Liu, Qing Cao, Bianbian Yan & Jin Yang

Authors
  1. Lei Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaojuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuzhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bianbian Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Yang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10495_2019_1549_MOESM1_ESM.tif

Fig. S1 Expression analysis of epithelial-mesenchymal transition (EMT) markers in CRC from the TCGA database using the TNM staging system. Expression data of EMT markers were normalized to fragments per kilobase of transcript per million mapped reads (FPKM) and are shown as log2(FPKM +1). All data are shown as the mean ± SEM, *P < 0.05 and **P < 0.01. Supplementary material 1 (TIFF 2116 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lei, L., Zhao, X., Liu, S. et al. MicroRNA-3607 inhibits the tumorigenesis of colorectal cancer by targeting DDI2 and regulating the DNA damage repair pathway. Apoptosis 24, 662–672 (2019). https://doi.org/10.1007/s10495-019-01549-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-019-01549-5

Keywords

Search

Navigation