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Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

Authors: Edita Baltruskeviciene, Diana Schveigert, Vaidotas Stankevicius, Ugnius Mickys, Tadas Zvirblis, Jaroslav Bublevic, Kestutis Suziedelis, Eduardas Aleknavicius

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

MiRNAs are often deregulated in colorectal cancer and might function as tumor suppressors or as oncogenes. They participate in controlling key signaling pathways involved in proliferation, invasion and apoptosis and may serve as prognostic and predictive markers. In this study we aimed to evaluate the role of miRNA-148a and miRNA-625-3p in metastatic colorectal cancer.

Methods

Fifty-four patients with a first-time diagnosed CRC receiving FOLFOX ± Bevacizumab were involved in the study. Tumor samples underwent routine pathology examination including evaluation for tumor budding and KRAS. MiRNA-148a and miRNA-625-3p expression analysis was done by RT-PCR. Associations between expression of both miRNAs and clinico-pathological factors, treatment outcomes and survival were analyzed.

Results

Both miRNA-148a and miRNA-625-3p were down-regulated in the tumors compared to normal colonic mucosa. Significantly lower expression of both miRNAs was noticed in tumors with budding phenomenon compared to tumors without it (median values of miRNA-148a were 0.314 and 0.753 respectively, p = 0.011, and 0.404 and 0.620 respectively for miRNA-625-3p, p = 0.036). Significantly lower expression of miRNA-625-3p was detected in rectal tumors, compared to tumors in the colon (median 0.390 and 0.665 respectively, p = 0.037). Progression free survival was significantly lower in patients with high miRNA-148a expression (6 and 9 months respectively, p = 0.033), but there were no significant differences in PFS for miRNA-625-3p and in overall survival for both miRNAs.

Conclusions

There was a significant relationship between low miRNA-148a and miRNA-625-3p expression and tumor budding, which is thought to represent epithelial-mesenchymal transition. Both studied miRNAs may be associated with a more aggressive phenotype and could be the potential prognostic and predictive biomarkers in CRC. Further investigation is needed to confirm miRNAs involvement in EMT, and their prognostic and predictive value.
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Literature
2.
go back to reference Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chien CRC, Makhson A, et al. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer. New England Journal of Medicine. 2009;360(14):1408–17. doi:10.1056/Nejmoa0805019.CrossRefPubMed Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chien CRC, Makhson A, et al. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer. New England Journal of Medicine. 2009;360(14):1408–17. doi:10.​1056/​Nejmoa0805019.CrossRefPubMed
3.
go back to reference Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandala M, Cervantes A, et al. Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:64–72. doi:10.1093/annonc/mdt354.CrossRef Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandala M, Cervantes A, et al. Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:64–72. doi:10.​1093/​annonc/​mdt354.CrossRef
7.
16.
go back to reference Hur K, Toiyama Y, Schetter AJ, Okugawa Y, Harris CC, Boland CR, et al. Identification of a Metastasis-Specific MicroRNA Signature in Human Colorectal Cancer. J Natl Cancer Inst. 2015;107(3) doi:10.1093/jnci/dju492. Hur K, Toiyama Y, Schetter AJ, Okugawa Y, Harris CC, Boland CR, et al. Identification of a Metastasis-Specific MicroRNA Signature in Human Colorectal Cancer. J Natl Cancer Inst. 2015;107(3) doi:10.​1093/​jnci/​dju492.
17.
18.
go back to reference Takahashi M, Cuatrecasas M, Balaguer F, Hur K, Toiyama Y, Castells A et al. The Clinical Significance of MiR-148a as a Predictive Biomarker in Patients with Advanced Colorectal Cancer. Plos One. 2012;7(10). doi:ARTN e46684. doi:10.1371/journal.pone.0046684. Takahashi M, Cuatrecasas M, Balaguer F, Hur K, Toiyama Y, Castells A et al. The Clinical Significance of MiR-148a as a Predictive Biomarker in Patients with Advanced Colorectal Cancer. Plos One. 2012;7(10). doi:ARTN e46684. doi:10.​1371/​journal.​pone.​0046684.
21.
go back to reference Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting met/Snail signaling. Oncogene. 2014;33(31):4069–76. doi:10.1038/onc.2013.369.CrossRefPubMed Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting met/Snail signaling. Oncogene. 2014;33(31):4069–76. doi:10.​1038/​onc.​2013.​369.CrossRefPubMed
22.
go back to reference Qin Z, He W, Tang J, Ye Q, Dang W, Lu Y, et al. MicroRNAs provide feedback regulation of epithelial-Mesenchymal transition induced by growth factors. J Cell Physiol. 2016;231(1):120–9. doi:10.1002/jcp.25060.CrossRefPubMed Qin Z, He W, Tang J, Ye Q, Dang W, Lu Y, et al. MicroRNAs provide feedback regulation of epithelial-Mesenchymal transition induced by growth factors. J Cell Physiol. 2016;231(1):120–9. doi:10.​1002/​jcp.​25060.CrossRefPubMed
23.
go back to reference Horcic M, Koelzer VH, Karamitopoulou E, Terracciano L, Puppa G, Zlobec I, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44(5):697–705. doi:10.1016/j.humpath.2012.07.026.CrossRefPubMed Horcic M, Koelzer VH, Karamitopoulou E, Terracciano L, Puppa G, Zlobec I, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44(5):697–705. doi:10.​1016/​j.​humpath.​2012.​07.​026.CrossRefPubMed
24.
go back to reference 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 Research. 2013;41(Web Server issue):W169-WW73. doi:10.1093/nar/gkt393. 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 Research. 2013;41(Web Server issue):W169-WW73. doi:10.​1093/​nar/​gkt393.
25.
go back to reference Chou C-H, Chang N-W, Shrestha S, Hsu S-D, Lin Y-L, Lee W-H, et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 2016;44(Database issue):D239–D47. doi:10.1093/nar/gkv1258.CrossRefPubMed Chou C-H, Chang N-W, Shrestha S, Hsu S-D, Lin Y-L, Lee W-H, et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 2016;44(Database issue):D239–D47. doi:10.​1093/​nar/​gkv1258.CrossRefPubMed
28.
go back to reference Hausser J, Zavolan M. Identification and consequences of miRNA-target interactions-beyond repression of gene expression. Nature Reviews Genetics. 2014;vol 15:pg 599. 2014;15(10):702. Hausser J, Zavolan M. Identification and consequences of miRNA-target interactions-beyond repression of gene expression. Nature Reviews Genetics. 2014;vol 15:pg 599. 2014;15(10):702.
31.
go back to reference Hibino Y, Sakamoto N, Naito Y, Goto K, Oo HZ, Sentani K, et al. Significance of miR-148a in colorectal Neoplasia: Downregulation of miR-148a contributes to the carcinogenesis and cell invasion of colorectal cancer. Pathobiology. 2015;82(5):233–41. doi:10.1159/000438826.CrossRefPubMed Hibino Y, Sakamoto N, Naito Y, Goto K, Oo HZ, Sentani K, et al. Significance of miR-148a in colorectal Neoplasia: Downregulation of miR-148a contributes to the carcinogenesis and cell invasion of colorectal cancer. Pathobiology. 2015;82(5):233–41. doi:10.​1159/​000438826.CrossRefPubMed
32.
33.
34.
go back to reference Huang Y, Yu HJ, Lei H, Xie CH, Zhong YH. Matrix metalloproteinase 7 is a useful marker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. Medical Oncology. 2014;31(3) doi:10.1007/S12032-013-0824-0. Huang Y, Yu HJ, Lei H, Xie CH, Zhong YH. Matrix metalloproteinase 7 is a useful marker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. Medical Oncology. 2014;31(3) doi:10.​1007/​S12032-013-0824-0.
38.
go back to reference Liffers ST, Munding JB, Vogt M, Kuhlmann JD, Verdoodt B, Nambiar S, et al. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab Investig. 2011;91(10):1472–9. doi:10.1038/labinvest.2011.99.CrossRefPubMed Liffers ST, Munding JB, Vogt M, Kuhlmann JD, Verdoodt B, Nambiar S, et al. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab Investig. 2011;91(10):1472–9. doi:10.​1038/​labinvest.​2011.​99.CrossRefPubMed
41.
go back to reference Bronsert P, Enderle-Ammour K, Bader M, Timme S, Kuehs M, Csanadi A, et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol. 2014;234(3):410–22. doi:10.1002/path.4416.CrossRefPubMed Bronsert P, Enderle-Ammour K, Bader M, Timme S, Kuehs M, Csanadi A, et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol. 2014;234(3):410–22. doi:10.​1002/​path.​4416.CrossRefPubMed
43.
go back to reference Jensen DH, Dabelsteen E, Specht L, Fiehn AMK, Therkildsen MH, Jonson L, et al. Molecular profiling of tumour budding implicates TGF-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. J Pathol. 2015;236(4):505–16. doi:10.1002/path.4550.CrossRefPubMed Jensen DH, Dabelsteen E, Specht L, Fiehn AMK, Therkildsen MH, Jonson L, et al. Molecular profiling of tumour budding implicates TGF-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. J Pathol. 2015;236(4):505–16. doi:10.​1002/​path.​4550.CrossRefPubMed
46.
go back to reference Lou XL, Qi XL, Zhang Y, Long HD, Yang JJ. Decreased expression of microRNA-625 is associated with tumor metastasis and poor prognosis in patients with colorectal cancer. J Surg Oncol. 2013;108(4):230–5. doi:10.1002/jso.23380.CrossRefPubMed Lou XL, Qi XL, Zhang Y, Long HD, Yang JJ. Decreased expression of microRNA-625 is associated with tumor metastasis and poor prognosis in patients with colorectal cancer. J Surg Oncol. 2013;108(4):230–5. doi:10.​1002/​jso.​23380.CrossRefPubMed
47.
go back to reference Li C, Li DC, Che SS, Ma K, Wang YJ, Xia LH, et al. The decreased expression of miR-625 predicts poor prognosis of esophageal squamous cell carcinoma. Int J Clin Exp Med. 2015;8(6):9560–4.PubMedPubMedCentral Li C, Li DC, Che SS, Ma K, Wang YJ, Xia LH, et al. The decreased expression of miR-625 predicts poor prognosis of esophageal squamous cell carcinoma. Int J Clin Exp Med. 2015;8(6):9560–4.PubMedPubMedCentral
49.
go back to reference Lavarino C, Pilotti S, Oggionni M, Gatti L, Perego P, Bresciani G, et al. p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J Clin Oncol. 2000;18(23):3936–45.CrossRefPubMed Lavarino C, Pilotti S, Oggionni M, Gatti L, Perego P, Bresciani G, et al. p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J Clin Oncol. 2000;18(23):3936–45.CrossRefPubMed
Metadata
Title
Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding
Authors
Edita Baltruskeviciene
Diana Schveigert
Vaidotas Stankevicius
Ugnius Mickys
Tadas Zvirblis
Jaroslav Bublevic
Kestutis Suziedelis
Eduardas Aleknavicius
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3575-z

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