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Pan-cancer analysis reveals cooperativity of both strands of microRNA that regulate tumorigenesis and patient survival

Mitra, Ramkrishna, Adams, Clare M., Jiang, Wei, Greenawalt, Evan, Eischen, Christine M.·2020·Nature Communications
DOI 10.1038/s41467-020-14713-2PMC PMC7033124
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Abstract

Recently, both 5p and 3p miRNA strands are being recognized as functional instead of only one, leaving many miRNA strands uninvestigated. To determine whether both miRNA strands, which have different mRNA-targeting sequences, cooperate to regulate pathways/functions across cancer types, we evaluate genomic, epigenetic, and molecular profiles of >5200 patient samples from 14 different cancers, and RNA interference and CRISPR screens in 290 cancer cell lines. We identify concordantly dysregulated miRNA 5p/3p pairs that coordinately modulate oncogenic pathways and/or cell survival/growth across cancers. Down-regulation of both strands of miR-30a and miR-145 recurrently increased cell cycle pathway genes and significantly reduced patient survival in multiple cancers. Forced expression of all four strands show cooperativity, reducing cell cycle pathways and inhibiting lung cancer cell proliferation and migration. Therefore, we identify miRNA whose 5p/3p strands function together to regulate core tumorigenic processes/pathways and reveal a previously unknown pan-cancer miRNA signature with patient prognostic power.

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Fig. 1 Associations between miRNA 5p/3p concordant expression changes and cancer cell viability/growth. a Density plots showing distribution of 5p/3p expression correlations (green) compared to the background miRNA pairs (red). P-values determined by two-tailed Wilcoxon rank-sum test. b Number of TCGA normal (N) and tumor (T) samples by cancer type used for analysis. c Scatterplot with regression line, Spearman correlation test score (ρ) and P-value (two-tailed) indicates degree of global concordance observed in expression fold-changes of 5p/3p pairs across 14 cancer types compared with the corresponding normal samples. Each dot represents fold-change of one 5p/3p pair in one cancer type. Significant differential expressions of both, one, and no strands denoted by orange, blue, and gray dots, respectively. d Integrative approach to predict whether individual miRNA target set is enriched with cell survival/growth-associated genes. e Density plots showing distribution of survival/growth-associated miRNA and gene expression changes in the tumor tissues compared with the respective normal tissues. Schematic diagram indicates potential association between miRNA downregulation and induced cell survival/growth. f Pan-cancer (≥5 cancer types) dysregulated miRNA (n = 70) were plotted. Blue and red dots indicate a trend of consistent down and upregulation, respectively, across the cancer types. Gray dots indicate random up- or downregulation. The proportion of down- or upregulations was indicated on the x- and y-axis, respectively. Size of individual dots correlates with number of miRNA. g List of miRNA (blue and orange circles) that were predicted to be associated with cancer cell viability/growth from RNAi or CRISPR screening data. y-axis indicates percentage of the cell lines with which these miRNA had association. Orange dots represent the 5p and 3p strands of a miRNA that both modulate cancer cell survival/growth. h Empirical cumulative distribution of cell lines (y-axis) whose survival/growth might be coordinately regulated by the indicated miRNA 5p/3p pairs, as determined by the GSEA with 10% FDR (x-axis). i Distribution of cancer cells of indicated cancer type whose survival/growth may be regulated by both miR-30a-5p and 3p (left) or both miR-145-5p and 3p (right) as determined from RNAi (top) and CRISPR (bottom) screening data. Dots represent cancer cell lines.
Fig. 1 Associations between miRNA 5p/3p concordant expression changes and cancer cell viability/growth. a Density plots showing distribution of 5p/3p expression correlations (green) compared to the background miRNA pairs (red). P-values determined by two-tailed Wilcoxon rank-sum test. b Number of TCGA normal (N) and tumor (T) samples by cancer type used for analysis. c Scatterplot with regression line, Spearman correlation test score (ρ) and P-value (two-tailed) indicates degree of global concordance observed in expression fold-changes of 5p/3p pairs across 14 cancer types compared with the corresponding normal samples. Each dot represents fold-change of one 5p/3p pair in one cancer type. Significant differential expressions of both, one, and no strands denoted by orange, blue, and gray dots, respectively. d Integrative approach to predict whether individual miRNA target set is enriched with cell survival/growth-associated genes. e Density plots showing distribution of survival/growth-associated miRNA and gene expression changes in the tumor tissues compared with the respective normal tissues. Schematic diagram indicates potential association between miRNA downregulation and induced cell survival/growth. f Pan-cancer (≥5 cancer types) dysregulated miRNA (n = 70) were plotted. Blue and red dots indicate a trend of consistent down and upregulation, respectively, across the cancer types. Gray dots indicate random up- or downregulation. The proportion of down- or upregulations was indicated on the x- and y-axis, respectively. Size of individual dots correlates with number of miRNA. g List of miRNA (blue and orange circles) that were predicted to be associated with cancer cell viability/growth from RNAi or CRISPR screening data. y-axis indicates percentage of the cell lines with which these miRNA had association. Orange dots represent the 5p and 3p strands of a miRNA that both modulate cancer cell survival/growth. h Empirical cumulative distribution of cell lines (y-axis) whose survival/growth might be coordinately regulated by the indicated miRNA 5p/3p pairs, as determined by the GSEA with 10% FDR (x-axis). i Distribution of cancer cells of indicated cancer type whose survival/growth may be regulated by both miR-30a-5p and 3p (left) or both miR-145-5p and 3p (right) as determined from RNAi (top) and CRISPR (bottom) screening data. Dots represent cancer cell lines.CC BY · PubMed Central
Fig. 2 Identifying pan-cancer dysregulated miRNA 5p/3p pairs and their recurrent associations with oncogenic pathways across cancer types. a Heat map represents pan-cancer dysregulated 5p/3p pairs. Cancer types with red or blue color represent significant up- or downregulation, respectively, of the indicated mature miRNA. b Overview of approach used to identify miRNA 5p/3p regulated KEGG pathways in cancer. c, d Determining high-confidence 5p/3p pair–pathway associations based on whether c they had strong (green dots) inverse associations (x-axis) or not (black dots) comparing with the random pairs (y-axis); each dot represents one miRNA-pathway pair, and d the pathway genes were coordinately regulated by the 5p/3p pair. e Determining which 5p/3p pairs coordinately regulate pathways with a trend of co-targeting the same genes (x-axis, toward 1) or different genes (x-axis, toward 0) in the same pathway. Each density curve represents one 5p/3p pair and its potentially regulated pathways across cancer types. f Determination of pathways that were recurrently regulated by miRNA 5p/3p pairs across the cancer types. x-axis denotes frequency (number of cancer types with 5p/3p–pathway association divided by the number of cancer types the regulating 5p/3p pair had concordant dysregulation). g Three-dimensional scatter plot summarizes inversely associated (x-axis), coordinately regulated (y-axis) 5p/3p–pathway pairs that recurrently (z-axis) associated with cancer types where the corresponding regulating 5p/3p pairs had concordant dysregulation. Top five associations are indicated (red dots); red and blue words denotes up- and downregulation in cancer, respectively, compared to normal samples.
Fig. 2 Identifying pan-cancer dysregulated miRNA 5p/3p pairs and their recurrent associations with oncogenic pathways across cancer types. a Heat map represents pan-cancer dysregulated 5p/3p pairs. Cancer types with red or blue color represent significant up- or downregulation, respectively, of the indicated mature miRNA. b Overview of approach used to identify miRNA 5p/3p regulated KEGG pathways in cancer. c, d Determining high-confidence 5p/3p pair–pathway associations based on whether c they had strong (green dots) inverse associations (x-axis) or not (black dots) comparing with the random pairs (y-axis); each dot represents one miRNA-pathway pair, and d the pathway genes were coordinately regulated by the 5p/3p pair. e Determining which 5p/3p pairs coordinately regulate pathways with a trend of co-targeting the same genes (x-axis, toward 1) or different genes (x-axis, toward 0) in the same pathway. Each density curve represents one 5p/3p pair and its potentially regulated pathways across cancer types. f Determination of pathways that were recurrently regulated by miRNA 5p/3p pairs across the cancer types. x-axis denotes frequency (number of cancer types with 5p/3p–pathway association divided by the number of cancer types the regulating 5p/3p pair had concordant dysregulation). g Three-dimensional scatter plot summarizes inversely associated (x-axis), coordinately regulated (y-axis) 5p/3p–pathway pairs that recurrently (z-axis) associated with cancer types where the corresponding regulating 5p/3p pairs had concordant dysregulation. Top five associations are indicated (red dots); red and blue words denotes up- and downregulation in cancer, respectively, compared to normal samples.CC BY · PubMed Central
Fig. 3 Individual strands of miR-145 and miR-30a independently modulate cell cycle-associated pathways. a, c Microarray to measure expression differences of miR-145-5p (*P = 2.52 × 10−16; a top), miR-145-3p (**P = 2.64 × 10−21; a bottom), miR-30a-5p (*P = 1.0 × 10−19; c top), and miR-30a-3p (**P = 7.08 × 10−25; c bottom) in an independent cohort of lung adenocarcinoma patient samples (n = 154) compared to normal (n = 20) lung tissue; two-tailed t-tests. b, f GSEA demonstrated downregulated pathways in miR-145-5p or miR-145-3p transfected A549 cells (b top) or TE8 cells (b bottom), and miR-30a-5p or miR-30a-3p transfected A549 cells (f), compared to the control cell line. Pathways were ranked (x-axis) on the basis of negative normalized enrichment scores (y-axis). Cell cycle-associated pathways that are within the top ten pathway list, are indicated and were significantly enriched (FDR < 0.05). d qRT-PCR (in triplicate) for miR-30a-5p (top) and miR-30a-3p (bottom) expression in patient samples of lung adenocarcinoma and normal lung tissue. Individual samples (left) and mean expression (right) shown; *P = 1.98 × 10−6, **P = 2.60 × 10−8, two-tailed t-tests. e qRT-PCR (in triplicate) for miR-30a-5p (top) and miR-30a-3p (bottom) levels in lung adenocarcinoma lines and a normal bronchial epithelial line; #P = 6.62 × 10−4, *P < 6.05 × 10−6, two-tailed t-tests. For qRT-PCR (d and e), miRNA expression was normalized to endogenous small RNA RNU6B and presented as 2−∆Ct. Data are presented as mean values ± SEM in a and c–e. Source data are provided as a Source Data file.
Fig. 3 Individual strands of miR-145 and miR-30a independently modulate cell cycle-associated pathways. a, c Microarray to measure expression differences of miR-145-5p (*P = 2.52 × 10−16; a top), miR-145-3p (**P = 2.64 × 10−21; a bottom), miR-30a-5p (*P = 1.0 × 10−19; c top), and miR-30a-3p (**P = 7.08 × 10−25; c bottom) in an independent cohort of lung adenocarcinoma patient samples (n = 154) compared to normal (n = 20) lung tissue; two-tailed t-tests. b, f GSEA demonstrated downregulated pathways in miR-145-5p or miR-145-3p transfected A549 cells (b top) or TE8 cells (b bottom), and miR-30a-5p or miR-30a-3p transfected A549 cells (f), compared to the control cell line. Pathways were ranked (x-axis) on the basis of negative normalized enrichment scores (y-axis). Cell cycle-associated pathways that are within the top ten pathway list, are indicated and were significantly enriched (FDR < 0.05). d qRT-PCR (in triplicate) for miR-30a-5p (top) and miR-30a-3p (bottom) expression in patient samples of lung adenocarcinoma and normal lung tissue. Individual samples (left) and mean expression (right) shown; *P = 1.98 × 10−6, **P = 2.60 × 10−8, two-tailed t-tests. e qRT-PCR (in triplicate) for miR-30a-5p (top) and miR-30a-3p (bottom) levels in lung adenocarcinoma lines and a normal bronchial epithelial line; #P = 6.62 × 10−4, *P < 6.05 × 10−6, two-tailed t-tests. For qRT-PCR (d and e), miRNA expression was normalized to endogenous small RNA RNU6B and presented as 2−∆Ct. Data are presented as mean values ± SEM in a and c–e. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 Increased levels of miR-30a-5p and miR-30a-3p decreased lung cancer cell growth and migration. a Gene Ontology enrichment analysis based on genes that were significantly downregulated by either miR-30a-5p or miR-30a-3p determined from our RNA-seq data (GSE142695). Biological processes that were significantly enriched with downregulated genes are indicated. b Lung adenocarcinoma lines were transfected with 100 nM miR-30a-5p mimic, miR-30a-3p mimic, or a negative control RNA. MTT assays were performed at the indicated intervals in quadruplicate. Each assay was performed at least four independent times for both cell lines; a representative experiment is shown. For A549, *P < 2.43 × 10−3; for H1993, *P < 2.91 × 10−6; two-tailed t-tests (comparing 5p or 3p mimic to control RNA); error bars are within the symbols. c A549 cells transfected with miR-30a-5p mimic, miR-30a-3p mimic, or control RNA and transwell migration assays performed. Results from one representative experiment from two independent experiments performed is shown; *P = 1.11 × 10−5, **P = 3.15 × 10−6, two-tailed t-tests (comparing 5p or 3p mimic to control RNA, respectively). Data are presented as mean values ± SEM in b and c. Source data are provided as a Source Data file.
Fig. 4 Increased levels of miR-30a-5p and miR-30a-3p decreased lung cancer cell growth and migration. a Gene Ontology enrichment analysis based on genes that were significantly downregulated by either miR-30a-5p or miR-30a-3p determined from our RNA-seq data (GSE142695). Biological processes that were significantly enriched with downregulated genes are indicated. b Lung adenocarcinoma lines were transfected with 100 nM miR-30a-5p mimic, miR-30a-3p mimic, or a negative control RNA. MTT assays were performed at the indicated intervals in quadruplicate. Each assay was performed at least four independent times for both cell lines; a representative experiment is shown. For A549, *P < 2.43 × 10−3; for H1993, *P < 2.91 × 10−6; two-tailed t-tests (comparing 5p or 3p mimic to control RNA); error bars are within the symbols. c A549 cells transfected with miR-30a-5p mimic, miR-30a-3p mimic, or control RNA and transwell migration assays performed. Results from one representative experiment from two independent experiments performed is shown; *P = 1.11 × 10−5, **P = 3.15 × 10−6, two-tailed t-tests (comparing 5p or 3p mimic to control RNA, respectively). Data are presented as mean values ± SEM in b and c. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 Cooperative effects of miRNA 5p/3p-mediated gene regulation in cancer cell proliferation and movement. a Identifying miR-30a and miR-145 5p/3p-mediated gene expression changes across 14 cancer types. A linear regression function was modeled to predict miRNA–mRNA association after controlling for the impact of DNA methylation and gene copy number changes. The rank product statistic was employed to aggregate the miRNA–mRNA regression coefficients across the 14 cancer types and predict significant miRNA–mRNA-negative association recurrence (BH adjusted P < 0.05). b Expression changes of miRNA-target essential genes after transfection of the miR-30-5p or 3p mimics in A549 lung adenocarcinoma cells (the miRNA perturbation profile from our RNA-seq data, GSE142695). The miRNA-essential gene pairs were obtained from regression analysis in TCGA LUAD. Indicated P-values were determined from two-tailed Kolmogorov–Smironov test. n denotes number of predicted target essential genes of the corresponding miRNA. We extracted a common essential gene list from the Hart laboratory (http://hart-lab.org/). c Pathway enrichment analysis to determine pathways that are enriched with recurrently associated genes of the corresponding regulating miRNA indicated on the x- and y-axis. d Recurrent association strength of four cell cycle pathway-associated genes with predicted binding sites for both miR-30a-5p and miR-30a-3p. Adj. P denotes BH adjusted P-value derived from rank product test statistic. e Fold-change (log2) of the expression of the four genes in the indicated sample categories across the 14 cancer types. High or low: Samples with higher or lower expression of both miR-30a-5p and 3p. Mixed: Remaining samples. Data are presented as median with interquartile range. Source data are provided as a Source Data file.
Fig. 5 Cooperative effects of miRNA 5p/3p-mediated gene regulation in cancer cell proliferation and movement. a Identifying miR-30a and miR-145 5p/3p-mediated gene expression changes across 14 cancer types. A linear regression function was modeled to predict miRNA–mRNA association after controlling for the impact of DNA methylation and gene copy number changes. The rank product statistic was employed to aggregate the miRNA–mRNA regression coefficients across the 14 cancer types and predict significant miRNA–mRNA-negative association recurrence (BH adjusted P < 0.05). b Expression changes of miRNA-target essential genes after transfection of the miR-30-5p or 3p mimics in A549 lung adenocarcinoma cells (the miRNA perturbation profile from our RNA-seq data, GSE142695). The miRNA-essential gene pairs were obtained from regression analysis in TCGA LUAD. Indicated P-values were determined from two-tailed Kolmogorov–Smironov test. n denotes number of predicted target essential genes of the corresponding miRNA. We extracted a common essential gene list from the Hart laboratory (http://hart-lab.org/). c Pathway enrichment analysis to determine pathways that are enriched with recurrently associated genes of the corresponding regulating miRNA indicated on the x- and y-axis. d Recurrent association strength of four cell cycle pathway-associated genes with predicted binding sites for both miR-30a-5p and miR-30a-3p. Adj. P denotes BH adjusted P-value derived from rank product test statistic. e Fold-change (log2) of the expression of the four genes in the indicated sample categories across the 14 cancer types. High or low: Samples with higher or lower expression of both miR-30a-5p and 3p. Mixed: Remaining samples. Data are presented as median with interquartile range. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 Cooperation of all four strands of miR-30a and miR-145 in cancer cell growth and movement. Lung adenocarcinoma lines transfected with miR-30a-5p, miR-30a-3p, miR-145-5p, and/or miR-145-3p miRNA mimic, or control RNA at the indicated concentrations. Control RNA was also added to equalize the total amount of RNA transfected. a, b, d MTT assays performed at intervals, in quadruplicate. Each assay was performed 2–4 independent times for both cell lines and one representative experiment is shown. For a, A549 *P < 6.18 × 10−5, H1993 *P < 2.36 × 10−2 (comparing 5p + 3p to 5p or 3p alone); for b, A549 *P < 9.21 × 10−6, H1993 *P < 1.91 × 10−2 (comparing 5p + 3p to 5p or 3p alone at both concentrations); for d, A549 *P < 1.69 × 10−4 and **P < 7.02 × 10−5, H1993 *P < 4.27 × 10−4 and **P < 2.82 × 10−3 (*, comparing 30a-5p/3p+145-5p/3p to 30a-5p/3p or 145-5p/3p at both concentrations and **, comparing 25 nM 30a-5p/3p+145-5p/3p to 50 nM 30a-5p/3p or 145-5p/3p); two-tailed t-tests. c, f Transwell migration assays were performed 2 (c) or 4 (f) independent times and results from one representative experiment are shown for each. For c, *P = 2.3 × 10−3 and **P = 2.0 × 10−4; for f, P-values indicated; two-tailed t-tests. Representative images shown in f (x10 magnification; scale bars, 200 μm). e Colony formation assays were performed two independent times, in triplicate, and a representative experiment and images (no magnification) are shown. P-values indicated; two-tailed t-tests. Data are presented as mean values ± SEM; error bars are within the symbols in a, b, and d. Source data are provided as a Source Data file.
Fig. 6 Cooperation of all four strands of miR-30a and miR-145 in cancer cell growth and movement. Lung adenocarcinoma lines transfected with miR-30a-5p, miR-30a-3p, miR-145-5p, and/or miR-145-3p miRNA mimic, or control RNA at the indicated concentrations. Control RNA was also added to equalize the total amount of RNA transfected. a, b, d MTT assays performed at intervals, in quadruplicate. Each assay was performed 2–4 independent times for both cell lines and one representative experiment is shown. For a, A549 *P < 6.18 × 10−5, H1993 *P < 2.36 × 10−2 (comparing 5p + 3p to 5p or 3p alone); for b, A549 *P < 9.21 × 10−6, H1993 *P < 1.91 × 10−2 (comparing 5p + 3p to 5p or 3p alone at both concentrations); for d, A549 *P < 1.69 × 10−4 and **P < 7.02 × 10−5, H1993 *P < 4.27 × 10−4 and **P < 2.82 × 10−3 (*, comparing 30a-5p/3p+145-5p/3p to 30a-5p/3p or 145-5p/3p at both concentrations and **, comparing 25 nM 30a-5p/3p+145-5p/3p to 50 nM 30a-5p/3p or 145-5p/3p); two-tailed t-tests. c, f Transwell migration assays were performed 2 (c) or 4 (f) independent times and results from one representative experiment are shown for each. For c, *P = 2.3 × 10−3 and **P = 2.0 × 10−4; for f, P-values indicated; two-tailed t-tests. Representative images shown in f (x10 magnification; scale bars, 200 μm). e Colony formation assays were performed two independent times, in triplicate, and a representative experiment and images (no magnification) are shown. P-values indicated; two-tailed t-tests. Data are presented as mean values ± SEM; error bars are within the symbols in a, b, and d. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 7 A four-miRNA expression signature correlates with patient overall survival across diverse cancer types. Kaplan–Meier plots of overall survival according to a survival predictor based on the average expression of miR-145-5p, miR-145-3p, miR-30a-5p, and miR-30a-3p. For each cancer type, patient samples were ranked according to the average expression of the four miRNA and divided into four quartiles. Lowest (blue lines) and highest (orange lines) quartile groups were used for Kaplan–Meier survival analyses; statistical significance was measured using log-rank test. False-discovery rate (FDR) values were determined.
Fig. 7 A four-miRNA expression signature correlates with patient overall survival across diverse cancer types. Kaplan–Meier plots of overall survival according to a survival predictor based on the average expression of miR-145-5p, miR-145-3p, miR-30a-5p, and miR-30a-3p. For each cancer type, patient samples were ranked according to the average expression of the four miRNA and divided into four quartiles. Lowest (blue lines) and highest (orange lines) quartile groups were used for Kaplan–Meier survival analyses; statistical significance was measured using log-rank test. False-discovery rate (FDR) values were determined.CC BY · PubMed Central

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Metadata

Authors
Mitra, R., Adams, C. M., Jiang, W., Greenawalt, E., & Eischen, C. M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-02-20
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-14713-2
PMC
PMC7033124
Cited by
81
References
5
Language
en
Licence
Funders
U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA177786, P30CA056036)

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