Tumor Biology

, Volume 37, Issue 5, pp 6637–6645 | Cite as

MTUS1 and its targeting miRNAs in colorectal carcinoma: significant associations

  • Onder Ozcan
  • Murat Kara
  • Onder Yumrutas
  • Esra Bozgeyik
  • Ibrahim Bozgeyik
  • Ozgur Ilhan Celik
Original Article

Abstract

Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 (MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic Array™ integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98-5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa-miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1.

Keywords

Colorectal cancer MTUS1 miRNA miR-135b-5p miR-373-3p miR-183-5p 

Notes

Acknowledgments

This study was funded by a project from the Scientific Research Projects Management Unit of Mugla Sitki Kocman University (grant number 13/152).

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Geyik E, Igci YZ, Pala E, Suner A, Borazan E, Bozgeyik I, Bayraktar E, Bayraktar R, Ergun S, Cakmak EA, Gokalp A, Arslan A: Investigation of the association between ATP2b4 and ATP5b genes with colorectal cancer. Gene. 2014;540:178-182Google Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: Cancer J Clin. 2012;62:10–29.Google Scholar
  3. 3.
    Centelles JJ: General aspects of colorectal cancer. ISRN oncology 2012;2012Google Scholar
  4. 4.
    Di Benedetto M, Bieche I, Deshayes F, Vacher S, Nouet S, Collura V, et al. Structural organization and expression of human mtus1, a candidate 8p22 tumor suppressor gene encoding a family of angiotensin ii at2 receptor-interacting proteins, atip. Gene. 2006;380:127–36.CrossRefPubMedGoogle Scholar
  5. 5.
    Ding X, Zhang N, Cai Y, Li S, Zheng C, Jin Y, et al. Down-regulation of tumor suppressor mtus1/atip is associated with enhanced proliferation, poor differentiation and poor prognosis in oral tongue squamous cell carcinoma. Mol Oncol. 2012;6:73–80.CrossRefPubMedGoogle Scholar
  6. 6.
    Frank B, Bermejo JL, Hemminki K, Sutter C, Wappenschmidt B, Meindl A, et al. Copy number variant in the candidate tumor suppressor gene mtus1 and familial breast cancer risk. Carcinogenesis. 2007;28:1442–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Pils D, Horak P, Gleiss A, Sax C, Fabjani G, Moebus VJ, et al. Five genes from chromosomal band 8p22 are significantly down-regulated in ovarian carcinoma. Cancer. 2005;104:2417–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Seibold S, Rudroff C, Weber M, Galle J, Wanner C, Marx M. Identification of a new tumor suppressor gene located at chromosome 8p21. 3-22. FASEB J. 2003;17:1180–2.PubMedGoogle Scholar
  9. 9.
    Ye H, Pungpravat N, Huang B-L, Muzio LL, Mariggio MA, Chen Z, et al. Genomic assessments of the frequent loss of heterozygosity region on 8p21. 3-p22 in head and neck squamous cell carcinoma. Cancer Genet Cytogenet. 2007;176:100–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Schetter AJ, Okayama H, Harris CC. The role of micrornas in colorectal cancer. Cancer J (Sudbury, Mass). 2012;18:244.CrossRefGoogle Scholar
  11. 11.
    Chen J, Wang W, Zhang Y, Hu T, Chen Y. The roles of mir-200c in colon cancer and associated molecular mechanisms. Tumor Biol. 2014;35:6475–83.CrossRefGoogle Scholar
  12. 12.
    Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, et al. Microrna-200c modulates epithelial-to-mesenchymal transition (emt) in human colorectal cancer metastasis. Gut. 2013;62:1315–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Song C, Liu LZ, Pei XQ, Liu X, Yang L, Ye F, Xie X, Chen J, Tang H: Mir-200c inhibits breast cancer proliferation by targeting kras. Oncotarget 2015Google Scholar
  14. 14.
    Gattolliat C-H, Uguen A, Pesson M, Trillet K, Simon B, Doucet L, et al. MicroRNA and targeted mRNA expression profiling analysis in human colorectal adenomas and adenocarcinomas. Eur J Cancer. 2015;51:409–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Paraskevopoulou MD, Georgakilas G, Kostoulas N, Vlachos IS, Vergoulis T, Reczko M, et al. Diana-microt web server v5. 0: Service integration into mirna functional analysis workflows. Nucleic Acids Res. 2013;41:W169–73.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Reczko M, Maragkakis M, Alexiou P, Grosse I, Hatzigeorgiou AG. Functional microRNA targets in protein coding sequences. Bioinformatics. 2012;28:771–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Li J-H, Liu S, Zhou H, Qu L-H, Yang J-H: Starbase v2. 0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale clip-seq data. Nucleic acids research 2013:gkt1248.Google Scholar
  19. 19.
    Yang J-H, Li J-H, Shao P, Zhou H, Chen Y-Q, Qu L-H. Starbase: a database for exploring microRNA-mRNA interaction maps from argonaute clip-seq and degradome-seq data. Nucleic Acids Res. 2011;39:D202–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang X. Mirdb: a microRNA target prediction and functional annotation database with a wiki interface. RNA. 2008;14:1012–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang X, El Naqa IM. Prediction of both conserved and nonconserved microRNA targets in animals. Bioinformatics. 2008;24:325–32.CrossRefPubMedGoogle Scholar
  23. 23.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  24. 24.
    Kara M, Yumrutas O, Ozcan O, Celik OI, Bozgeyik E, Bozgeyik I, Tasdemir S: Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma. Gene 2015Google Scholar
  25. 25.
    Rehmsmeier M, Steffen P, Höchsmann M, Giegerich R. Fast and effective prediction of microRNA/target duplexes. RNA. 2004;10:1507–17.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chan KL, Man-Fong Lee J, Guan XY, Fan ST, Oi-Lin Ng I. High-density allelotyping of chromosome 8p in hepatocellular carcinoma and clinicopathologic correlation. Cancer. 2002;94:3179–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Zuern C, Heimrich J, Kaufmann R, Richter KK, Settmacher U, Wanner C, et al. Down-regulation of mtus1 in human colon tumors. Oncol Rep. 2010;23:183–9.PubMedGoogle Scholar
  28. 28.
    Nouet S, Amzallag N, Li J-M, Louis S, Seitz I, Cui T-X, et al. Trans-inactivation of receptor tyrosine kinases by novel angiotensin ii at2 receptor-interacting protein, atip. J Biol Chem. 2004;279:28989–97.CrossRefPubMedGoogle Scholar
  29. 29.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes mir15 and mir16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci. 2002;99:15524–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bandres E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, et al. Identification by real-time pcr of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Nagel R, le Sage C, Diosdado B, van der Waal M, Vrielink JAFO, Bolijn A, et al. Regulation of the adenomatous polyposis coli gene by the mir-135 family in colorectal cancer. Cancer Res. 2008;68:5795–802.CrossRefPubMedGoogle Scholar
  32. 32.
    Syring I, Bartels J, Holdenrieder S, Kristiansen G, Müller SC, Ellinger J. Circulating serum miRNA (mir-367-3p, mir-371a-3p, mir-372-3p and mir-373-3p) as biomarkers in patients with testicular germ cell cancer. J Urol. 2015;193:331–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Wu A, Li J, Wu K, Mo Y, Luo Y, Ye H, et al. Mir-373-3p promotes invasion and metastasis of lung adenocarcinoma cells. Zhongguo fei ai za zhi=. Chinese J lung Cancer. 2014;18:427–35.Google Scholar
  34. 34.
    Sarver AL, Li L, Subramanian S. MicroRNA mir-183 functions as an oncogene by targeting the transcription factor egr1 and promoting tumor cell migration. Cancer Res. 2010;70:9570–80.CrossRefPubMedGoogle Scholar
  35. 35.
    Tang J-F, Yu Z-H, Liu T, Lin Z-Y, Wang Y-H, Yang L-W, et al. Five miRNAs as novel diagnostic biomarker candidates for primary nasopharyngeal carcinoma. Asian Pacific J Cancer Prevention: APJCP. 2013;15:7575–81.CrossRefGoogle Scholar
  36. 36.
    Chang C-W, Wu H-C, Terry MB, Santella RM. MicroRNA expression in prospectively collected blood as a potential biomarker of breast cancer risk in the BCFR. Anticancer Res. 2015;35:3969–77.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Wang L, Zhu M-J, Ren A-M, Wu H-F, Han W-M, Tan R-Y, Tu R-Q: A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer. 2014Google Scholar
  38. 38.
    Bandras E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29.CrossRefGoogle Scholar
  39. 39.
    Zhang X, Yan Z, Zhang J, Gong L, Li W, Cui J, Liu Y, Gao Z, Li J, Shen L: Combination of hsa-mir-375 and hsa-mir-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection. Annals of oncology 2011:mdq758.Google Scholar
  40. 40.
    Jo DH, Kim JH, Park W-Y, Kim K-W, Yu YS, Kim JH. Differential profiles of microRNAs in retinoblastoma cell lines of different proliferation and adherence patterns. J Pediatr Hematol Oncol. 2011;33:529–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Saito Y, Suzuki H, Tsugawa H, Imaeda H, Matsuzaki J, Hirata K, Hosoe N, Nakamura M, Mukai M, Saito H: Overexpression of mir-142-5p and mir-155 in gastric mucosa-associated lymphoid tissue (malt) lymphoma resistant to helicobacter pylori eradication. 2012Google Scholar
  42. 42.
    Balci S, Ayaz L, Gorur A, Yildirim Yaroglu H, Akbayir S, Dogruer Unal N, Bulut B, Tursen U, Tamer L: MicroRNA profiling for early detection of nonmelanoma skin cancer. Clinical and experimental dermatology 2015Google Scholar
  43. 43.
    Ibarrola-Villava M, Llorca-Cardenosa MJ, Tarazona N, Mongort C, Fleitas T, Perez-Fidalgo JA, Rosello S, Navarro S, Ribas G, Cervantes A: Deregulation of arid1a, cdh1, cmet and pik3ca and target-related microRNA expression in gastric cancer. Oncotarget 2015Google Scholar
  44. 44.
    Zhi F, Shao N, Wang R, Deng D, Xue L, Wang Q, Zhang Y, Shi Y, Xia X, Wang S: Identification of 9 serum microRNAs as potential noninvasive biomarkers of human astrocytoma. Neuro-oncology 2014:nou169.Google Scholar
  45. 45.
    Wen Y, Han J, Chen J, Dong J, Xia Y, Liu J, Jiang Y, Dai J, Lu J, Jin G: Plasma mirnas as early biomarkers for detecting hepatocellular carcinoma. International journal of cancer 2015Google Scholar
  46. 46.
    Ye S-B, Li Z-L, Luo D-h, Huang B-j, Chen Y-S, Zhang X-S, et al. Tumor-derived exosomes promote tumor progression and t-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget. 2014;5:5439.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Calvano Filho CMC, Calvano-Mendes DC, Carvalho KC, Maciel GA, Ricci MD, Torres AP, et al. Triple-negative and luminal a breast tumors: differential expression of mir-18a-5p, mir-17-5p, and mir-20a-5p. Tumor Biol. 2014;35:7733–41.CrossRefGoogle Scholar
  48. 48.
    Chen X, Shi K, Wang Y, Song M, Zhou W, Tu H, Lin Z: Clinical value of integrated-signature miRNAs in colorectal cancer: miRNA expression profiling analysis and experimental validation. Oncotarget 2015Google Scholar
  49. 49.
    Li Y, Kuscu C, Banach A, Zhang Q, Pulkoski-Gross A, Kim D, Liu J, Roth E, Li E, Shroyer KR: MicroRNA-181a-5p inhibits cancer cell migration and angiogenesis via downregulation of matrix metalloproteinase-14. Cancer research 2015:canres. 2875.2014.Google Scholar
  50. 50.
    Ma Z, Qiu X, Wang D, Li Y, Zhang B, Yuan T, et al. Mir-181a-5p inhibits cell proliferation and migration by targeting kras in non-small cell lung cancer a549 cells. Acta Biochim Biophys Sin. 2015;47:630–8.CrossRefPubMedGoogle Scholar
  51. 51.
    He S, Zeng S, Zhou Z-W, He Z-X, Zhou S-F. Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication. Drug Des Devel and Ther. 2015;9:1103.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Onder Ozcan
    • 1
  • Murat Kara
    • 2
  • Onder Yumrutas
    • 3
  • Esra Bozgeyik
    • 4
  • Ibrahim Bozgeyik
    • 3
  • Ozgur Ilhan Celik
    • 5
  1. 1.Faculty of Medicine, Department of General SurgeryMugla Sitki Kocman UniversityMuglaTurkey
  2. 2.Faculty of Medicine, Department of Medical GeneticsMugla Sitki Kocman UniversityMuglaTurkey
  3. 3.Faculty of Medicine, Department of Medical BiologyAdiyaman UniversityAdiyamanTurkey
  4. 4.Faculty of Medicine, Department of Medical Biology and GeneticsUniversity of GaziantepGaziantepTurkey
  5. 5.Faculty of Medicine, Department of PathologyMugla Sitki Kocman UniversityMuglaTurkey

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