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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

An overview of the study designs.For microRNA expression analysis, we used 3 sample cohort, technical validation set (n = 8), training set (n = 18) and independent tumor set (n = 114). For SNP analysis, we used 119 NSCLC cohorts that contain majority of samples we used for microRNA analysis. Integration of deregulated microRNAs and allelic imbalance results were performed in a subset of sample.
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f3: An overview of the study designs.For microRNA expression analysis, we used 3 sample cohort, technical validation set (n = 8), training set (n = 18) and independent tumor set (n = 114). For SNP analysis, we used 119 NSCLC cohorts that contain majority of samples we used for microRNA analysis. Integration of deregulated microRNAs and allelic imbalance results were performed in a subset of sample.

Mentions: Subsequently we tested additional 10 tumor and normal paired samples by Q-RT-PCR that results in matched 18 tumor-normal cohort as a training set (n = 18). An overview of experimental design is shown in Fig. 3. Expression patterns of the training set (18 paired tumor-normal) are available in Supplementary Table S6, and scatter plots of tested miRNA by Q-RT-PCR are shown in Fig. 4. An optimal cut-off point with maximal sensitivity and specificity was determined by generating ROC curve for individual microRNA marker (solid line in Fig. 4). Using the cut-off value, the frequency of each deregulated microRNA in the tumor was as follows: 44% (8/18) overexpressed for miR-205 (P = 0.018), 56% (10/18) overexpressed for miR-296 (P = 0.035), 89% (16/18) overexpressed for miR-21 (P < 0.001), 22% (4/18) overexpressed for miR-23b (P = 0.104), 89% (16/18) under expressed for miR-126 (P < 0.001), 78% (14/18) under expressed for miR-145 (P < 0.001), 33% (6/18) overexpressed for miR-150 (P = 0.229) and 83% (15/18) overexpressed for miR-31 (P < 0.001). A detailed summary of Q-RT-PCR analysis in training set is available in Table 1.


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)

An overview of the study designs.For microRNA expression analysis, we used 3 sample cohort, technical validation set (n = 8), training set (n = 18) and independent tumor set (n = 114). For SNP analysis, we used 119 NSCLC cohorts that contain majority of samples we used for microRNA analysis. Integration of deregulated microRNAs and allelic imbalance results were performed in a subset of sample.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: An overview of the study designs.For microRNA expression analysis, we used 3 sample cohort, technical validation set (n = 8), training set (n = 18) and independent tumor set (n = 114). For SNP analysis, we used 119 NSCLC cohorts that contain majority of samples we used for microRNA analysis. Integration of deregulated microRNAs and allelic imbalance results were performed in a subset of sample.
Mentions: Subsequently we tested additional 10 tumor and normal paired samples by Q-RT-PCR that results in matched 18 tumor-normal cohort as a training set (n = 18). An overview of experimental design is shown in Fig. 3. Expression patterns of the training set (18 paired tumor-normal) are available in Supplementary Table S6, and scatter plots of tested miRNA by Q-RT-PCR are shown in Fig. 4. An optimal cut-off point with maximal sensitivity and specificity was determined by generating ROC curve for individual microRNA marker (solid line in Fig. 4). Using the cut-off value, the frequency of each deregulated microRNA in the tumor was as follows: 44% (8/18) overexpressed for miR-205 (P = 0.018), 56% (10/18) overexpressed for miR-296 (P = 0.035), 89% (16/18) overexpressed for miR-21 (P < 0.001), 22% (4/18) overexpressed for miR-23b (P = 0.104), 89% (16/18) under expressed for miR-126 (P < 0.001), 78% (14/18) under expressed for miR-145 (P < 0.001), 33% (6/18) overexpressed for miR-150 (P = 0.229) and 83% (15/18) overexpressed for miR-31 (P < 0.001). A detailed summary of Q-RT-PCR analysis in training set is available in Table 1.

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