TY - JOUR
T1 - Genome-Wide miRNA analysis identifies miR- 188-3p as a novel prognostic markerandmolecular factor involved in colorectal carcinogenesis
AU - Pichler, Martin
AU - Stiegelbauer, Verena
AU - Vychytilova-Faltejskova, Petra
AU - Ivan, Cristina
AU - Ling, Hui
AU - Winter, Elke
AU - Zhang, Xinna
AU - Goblirsch, Matthew
AU - Wulf-Goldenberg, Annika
AU - Ohtsuka, Masahisa
AU - Haybaeck, Johannes
AU - Svoboda, Marek
AU - Okugawa, Yoshinaga
AU - Gerger, Armin
AU - Hoefler, Gerald
AU - Goel, Ajay
AU - Slaby, Ondrej
AU - Calin, George Adrian
N1 - Funding Information:
G.A. Calin is supported by the CLL Global Research Foundation. The work in G.A. Calin's laboratory is supported in part by the NIH/NCI grants 1UH2TR00943-01 and T32CA009599, Developmental Research Awards in Prostate Cancer, Multiple Myeloma, Leukemia (P50 CA100632), and Head and Neck (P50 CA097007) SPOREs, a SINF MDACC-DKFZ grant in CLL, a SINF grant in colon cancer, the Laura and John Arnold Foundation, the RGK Foundation, and the Estate of C. G. Johnson Jr. M. Pichler is supported by an Erwin-Schroedinger Scholarship of the Austrian Science Funds (project no. J3389-B23). This study was also supported in part by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number: 15400; to A. Gerger). The work in A. Goel's laboratory was supported by the grants R01 CA72851 and CA 181572 from the NCI, NIH, and funds from the Baylor Research Institute. This work was also supported by grant IGA NT/13860-4/ 2012 of the Czech Ministry of Health, by the project "CEITEC-Central European Institute of Technology" (CZ.1.05/1.1.00/02.0068) and the project BBMRI CZ (LM2010004).
Publisher Copyright:
© 2016 AACR.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Purpose: Characterization of colorectal cancer transcriptome by high-Throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: SixmiRNAs (miR-92b-3p,miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR- 188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells.
AB - Purpose: Characterization of colorectal cancer transcriptome by high-Throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting. Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs. Results: SixmiRNAs (miR-92b-3p,miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR- 188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration. Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells.
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U2 - 10.1158/1078-0432.CCR-16-0497
DO - 10.1158/1078-0432.CCR-16-0497
M3 - Article
C2 - 27601590
AN - SCOPUS:85014729382
SN - 1078-0432
VL - 23
SP - 1323
EP - 1333
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -