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An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation.

Begum S, Hayashi M, Ogawa T, Jabboure FJ, Brait M, Izumchenko E, Tabak S, Ahrendt SA, Westra WH, Koch W, Sidransky D, Hoque MO - Sci Rep (2015)

Bottom Line: Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis.In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time.Further biological studies of miR-23b are warranted for the potential development of targeted therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231 USA.

ABSTRACT
In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy.

No MeSH data available.


Related in: MedlinePlus

MicroRNA expression array results:(A). MicroRNA expression array results of representative 4 tumor-normal paired samples. Significantly differential expression between tumors and adjacent normal samples were found in some of microRNAs (red dots). (B). Scatter plots of promising microRNA that differentially expressed between tumors and normal by array analysis are shown: (a) Average microRNA expression ratios between tumor and adjacent normal tissue of all 8 cases (y axis) are plotted according to the mean expression (x axis). Differentially expressed microRNAs are expected to deviate from the bulk population (red dots). (b) Sub-group analyses scatter plot of mean tumor expression levels (y axis) and adjacent normal expression levels (x axis) of individual microRNAs for 3 Adenocarcinoma cases and (c) same for 5 squamous cell carcinoma cases. Probes with a large differential expression are identified as red dots.
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f2: MicroRNA expression array results:(A). MicroRNA expression array results of representative 4 tumor-normal paired samples. Significantly differential expression between tumors and adjacent normal samples were found in some of microRNAs (red dots). (B). Scatter plots of promising microRNA that differentially expressed between tumors and normal by array analysis are shown: (a) Average microRNA expression ratios between tumor and adjacent normal tissue of all 8 cases (y axis) are plotted according to the mean expression (x axis). Differentially expressed microRNAs are expected to deviate from the bulk population (red dots). (b) Sub-group analyses scatter plot of mean tumor expression levels (y axis) and adjacent normal expression levels (x axis) of individual microRNAs for 3 Adenocarcinoma cases and (c) same for 5 squamous cell carcinoma cases. Probes with a large differential expression are identified as red dots.

Mentions: Primary NSCLC and corresponding normal tissues were analyzed in 8 pairs of samples. Supplementary Table S3 summarized the clinicopathological information of all the 8 cases. The microRNA array we used here contained 688 mature microRNAs. Two types of analysis were carried out to identify probes which showed differential expression between tumor and adjacent normal tissues. Firstly, the expression ratios of individual microRNA between tumor and adjacent normal tissue were compared. Representative scatter plots are shown in Fig. 2A for 4 cases. Secondly, mean expression ratio profile across all patients was compared to the mean adjacent normal expression profile, and the differentially expressed microRNAs are shown in Fig. 2B a. In both analyses, differentially expressed microRNAs were expected to deviate from the bulk population. Four overexpressed (miR-21, miR-193b, miR-205, miR-296) and 4 under expressed microRNAs (miR-126, miR-23b, miR-145 and let-7b) in tumor samples were identified by comparing mean expression values between tumors and normal (Fig. 2B a). Differential expression patterns were also observed in ADC or SCC specific manner (Fig. 2B b,c). Both ADCs and SCCs showed up-regulation of miR-205 and down-regulation of miR-126 and miR-145 in tumors. Up-regulations of miR-21, miR-150 and miR-296 were only found in ADCs, whereas up-regulation of miR-31 and down-regulation of let-7b were only seen in SCCs. In summary, considering mean expression values in all the 8 NSCLCs samples and group of ADC and SCC, 5 over-expressed (miR-21, miR-31, miR-150, miR-205, miR-296) and 3 under expressed microRNAs (miR-126, miR-23b, miR-145) in tumor samples were determined for technical validation.


An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation.

Begum S, Hayashi M, Ogawa T, Jabboure FJ, Brait M, Izumchenko E, Tabak S, Ahrendt SA, Westra WH, Koch W, Sidransky D, Hoque MO - Sci Rep (2015)

MicroRNA expression array results:(A). MicroRNA expression array results of representative 4 tumor-normal paired samples. Significantly differential expression between tumors and adjacent normal samples were found in some of microRNAs (red dots). (B). Scatter plots of promising microRNA that differentially expressed between tumors and normal by array analysis are shown: (a) Average microRNA expression ratios between tumor and adjacent normal tissue of all 8 cases (y axis) are plotted according to the mean expression (x axis). Differentially expressed microRNAs are expected to deviate from the bulk population (red dots). (b) Sub-group analyses scatter plot of mean tumor expression levels (y axis) and adjacent normal expression levels (x axis) of individual microRNAs for 3 Adenocarcinoma cases and (c) same for 5 squamous cell carcinoma cases. Probes with a large differential expression are identified as red dots.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4551983&req=5

f2: MicroRNA expression array results:(A). MicroRNA expression array results of representative 4 tumor-normal paired samples. Significantly differential expression between tumors and adjacent normal samples were found in some of microRNAs (red dots). (B). Scatter plots of promising microRNA that differentially expressed between tumors and normal by array analysis are shown: (a) Average microRNA expression ratios between tumor and adjacent normal tissue of all 8 cases (y axis) are plotted according to the mean expression (x axis). Differentially expressed microRNAs are expected to deviate from the bulk population (red dots). (b) Sub-group analyses scatter plot of mean tumor expression levels (y axis) and adjacent normal expression levels (x axis) of individual microRNAs for 3 Adenocarcinoma cases and (c) same for 5 squamous cell carcinoma cases. Probes with a large differential expression are identified as red dots.
Mentions: Primary NSCLC and corresponding normal tissues were analyzed in 8 pairs of samples. Supplementary Table S3 summarized the clinicopathological information of all the 8 cases. The microRNA array we used here contained 688 mature microRNAs. Two types of analysis were carried out to identify probes which showed differential expression between tumor and adjacent normal tissues. Firstly, the expression ratios of individual microRNA between tumor and adjacent normal tissue were compared. Representative scatter plots are shown in Fig. 2A for 4 cases. Secondly, mean expression ratio profile across all patients was compared to the mean adjacent normal expression profile, and the differentially expressed microRNAs are shown in Fig. 2B a. In both analyses, differentially expressed microRNAs were expected to deviate from the bulk population. Four overexpressed (miR-21, miR-193b, miR-205, miR-296) and 4 under expressed microRNAs (miR-126, miR-23b, miR-145 and let-7b) in tumor samples were identified by comparing mean expression values between tumors and normal (Fig. 2B a). Differential expression patterns were also observed in ADC or SCC specific manner (Fig. 2B b,c). Both ADCs and SCCs showed up-regulation of miR-205 and down-regulation of miR-126 and miR-145 in tumors. Up-regulations of miR-21, miR-150 and miR-296 were only found in ADCs, whereas up-regulation of miR-31 and down-regulation of let-7b were only seen in SCCs. In summary, considering mean expression values in all the 8 NSCLCs samples and group of ADC and SCC, 5 over-expressed (miR-21, miR-31, miR-150, miR-205, miR-296) and 3 under expressed microRNAs (miR-126, miR-23b, miR-145) in tumor samples were determined for technical validation.

Bottom Line: Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis.In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time.Further biological studies of miR-23b are warranted for the potential development of targeted therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231 USA.

ABSTRACT
In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy.

No MeSH data available.


Related in: MedlinePlus