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Circulating MiR-16-5p and MiR-19b-3p as Two Novel Potential Biomarkers to Indicate Progression of Gastric Cancer.

Zhang J, Song Y, Zhang C, Zhi X, Fu H, Ma Y, Chen Y, Pan F, Wang K, Ni J, Jin W, He X, Su H, Cui D - Theranostics (2015)

Bottom Line: And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05).The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p).Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy.

View Article: PubMed Central - PubMed

Affiliation: 1. Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of the Ministry of Education, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.

ABSTRACT
Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P<0.05). And the two miRNAs were down-regulated in GC cases (FC<0.5). Especially, the down-regulation degree was correlated with the progression of the GC cases from the early stage to the advanced stage (0.2< r s<0.3, P<0.01). And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05). The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p). Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy. In conclusion, miR-19b-3p and miR-16-5p maybe prospective biomarkers to detect gastric cancer and indicate its progression, and thus may own great potential in applications such as early screening and progression evaluation of gastric cancer in the near future.

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Differentially expressed miRNAs from two sets of microarray profiling. Unsupervised hierarchical cluster analysis for differentially expressed miRNAs identified as significant by t-test (P<0.05) provided by microarray profiling: (A) Set 1 (No., BH13053) comprised of 7 GC cases and 8 normal controls and (B) Set 2 (No., BH13333) comprised of 9 GC cases and 10 normal controls. Samples are shown in columns and miRNAs in rows. The insets are color keys indicating the range of normalized log2-based signals and the histograms of the signals. (C) Two-way Venn diagram indicating the numbers of differentially expressed miRNAs (P<0.05) in Set 1 (a) and Set 2 (b).
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Figure 2: Differentially expressed miRNAs from two sets of microarray profiling. Unsupervised hierarchical cluster analysis for differentially expressed miRNAs identified as significant by t-test (P<0.05) provided by microarray profiling: (A) Set 1 (No., BH13053) comprised of 7 GC cases and 8 normal controls and (B) Set 2 (No., BH13333) comprised of 9 GC cases and 10 normal controls. Samples are shown in columns and miRNAs in rows. The insets are color keys indicating the range of normalized log2-based signals and the histograms of the signals. (C) Two-way Venn diagram indicating the numbers of differentially expressed miRNAs (P<0.05) in Set 1 (a) and Set 2 (b).

Mentions: To initially discover a group of miRNAs from genome-wide profiling of currently published human miRNAs, two batches of microarray assays were conducted with the rapid development of miRBase and the corresponding microarray chip. The hierarchical clusterings of the differentially expressed miRNAs (P<0.05) between GC and N groups from the two sets of microarray analysis were illustrated in Fig. 2. Both of the assays divided the cohorts into two groups, which was generally in consistency with the original GC and N groups. In the two assays 50 and 51 miRNAs were respectively identified with statistical significance at the level of P<0.05. And Venn diagram showed that merely 5 identical miRNAs were identified by both of the two sets (Supplementary Material: Table S2). We can see that the single hsa-miR-19b-3p was down-regulated in GC cases, and the other four miRNAs including hsa-miR-671-5p were up-regulated. To enlarge the candidate miRNAs for qRT-PCR validation, the differentially expressed miRNAs from the independent microarray assays at the level of P<0.01 and FC>2 or <0.5 were included. As shown in Supplementary Material: Table S3, 14 miRNAs were identified as differentially expressed miRNAs in the set of BH13053, while 7 miRNAs were explored in BH13333. Most of the differential miRNAs from BH13053 microarray were previously studied, particularly, let-7a and miR-106b have been identified by Tsujiura as biomarkers in plasma for GC diagnosis 18. However, a majority of the differentially expressed miRNAs from BH13333 microarray were sequenced as newly identified ones according to miRBase. Although miR-451 was shown to be decreased in gastric and colorectal cancer versus non-tumor tissues 29 and increased in plasma samples from GC patients 19, current reports showed little correlation of the rest of miRNAs discovered by BH13333 with GC or other diseases. Finally, considering the purpose to screen some novel biomarkers based on the steady expression levels of miRNAs in plasma, 6 miRNAs independently discovered by BH13053, and 1 down-regulated miRNA and 1 up-regulated miRNA collectively discovered by BH13053 and BH13333 were selected for the following quantification (Table 2).


Circulating MiR-16-5p and MiR-19b-3p as Two Novel Potential Biomarkers to Indicate Progression of Gastric Cancer.

Zhang J, Song Y, Zhang C, Zhi X, Fu H, Ma Y, Chen Y, Pan F, Wang K, Ni J, Jin W, He X, Su H, Cui D - Theranostics (2015)

Differentially expressed miRNAs from two sets of microarray profiling. Unsupervised hierarchical cluster analysis for differentially expressed miRNAs identified as significant by t-test (P<0.05) provided by microarray profiling: (A) Set 1 (No., BH13053) comprised of 7 GC cases and 8 normal controls and (B) Set 2 (No., BH13333) comprised of 9 GC cases and 10 normal controls. Samples are shown in columns and miRNAs in rows. The insets are color keys indicating the range of normalized log2-based signals and the histograms of the signals. (C) Two-way Venn diagram indicating the numbers of differentially expressed miRNAs (P<0.05) in Set 1 (a) and Set 2 (b).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4402497&req=5

Figure 2: Differentially expressed miRNAs from two sets of microarray profiling. Unsupervised hierarchical cluster analysis for differentially expressed miRNAs identified as significant by t-test (P<0.05) provided by microarray profiling: (A) Set 1 (No., BH13053) comprised of 7 GC cases and 8 normal controls and (B) Set 2 (No., BH13333) comprised of 9 GC cases and 10 normal controls. Samples are shown in columns and miRNAs in rows. The insets are color keys indicating the range of normalized log2-based signals and the histograms of the signals. (C) Two-way Venn diagram indicating the numbers of differentially expressed miRNAs (P<0.05) in Set 1 (a) and Set 2 (b).
Mentions: To initially discover a group of miRNAs from genome-wide profiling of currently published human miRNAs, two batches of microarray assays were conducted with the rapid development of miRBase and the corresponding microarray chip. The hierarchical clusterings of the differentially expressed miRNAs (P<0.05) between GC and N groups from the two sets of microarray analysis were illustrated in Fig. 2. Both of the assays divided the cohorts into two groups, which was generally in consistency with the original GC and N groups. In the two assays 50 and 51 miRNAs were respectively identified with statistical significance at the level of P<0.05. And Venn diagram showed that merely 5 identical miRNAs were identified by both of the two sets (Supplementary Material: Table S2). We can see that the single hsa-miR-19b-3p was down-regulated in GC cases, and the other four miRNAs including hsa-miR-671-5p were up-regulated. To enlarge the candidate miRNAs for qRT-PCR validation, the differentially expressed miRNAs from the independent microarray assays at the level of P<0.01 and FC>2 or <0.5 were included. As shown in Supplementary Material: Table S3, 14 miRNAs were identified as differentially expressed miRNAs in the set of BH13053, while 7 miRNAs were explored in BH13333. Most of the differential miRNAs from BH13053 microarray were previously studied, particularly, let-7a and miR-106b have been identified by Tsujiura as biomarkers in plasma for GC diagnosis 18. However, a majority of the differentially expressed miRNAs from BH13333 microarray were sequenced as newly identified ones according to miRBase. Although miR-451 was shown to be decreased in gastric and colorectal cancer versus non-tumor tissues 29 and increased in plasma samples from GC patients 19, current reports showed little correlation of the rest of miRNAs discovered by BH13333 with GC or other diseases. Finally, considering the purpose to screen some novel biomarkers based on the steady expression levels of miRNAs in plasma, 6 miRNAs independently discovered by BH13053, and 1 down-regulated miRNA and 1 up-regulated miRNA collectively discovered by BH13053 and BH13333 were selected for the following quantification (Table 2).

Bottom Line: And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05).The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p).Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy.

View Article: PubMed Central - PubMed

Affiliation: 1. Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication of the Ministry of Education, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.

ABSTRACT
Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P<0.05). And the two miRNAs were down-regulated in GC cases (FC<0.5). Especially, the down-regulation degree was correlated with the progression of the GC cases from the early stage to the advanced stage (0.2< r s<0.3, P<0.01). And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05). The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p). Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy. In conclusion, miR-19b-3p and miR-16-5p maybe prospective biomarkers to detect gastric cancer and indicate its progression, and thus may own great potential in applications such as early screening and progression evaluation of gastric cancer in the near future.

Show MeSH
Related in: MedlinePlus