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Identification of tumor suppressor microRNAs by integrative miRNA and mRNA sequencing of matched tumor normal pairs in lung adenocarcinoma

ABSTRACT: Roles of microRNAs (miRNAs) have not yet been explored systematically at the genome scale in lung cancer biology despite their important regulatory functions. Here, we report an integrative analysis of microRNA and mRNA sequencing data for the matched tumor and normal samples from 109 Korean female patients with non-small-cell lung adenocarcinoma. We produced miRNA-Seq and RNA-Seq data for 48 patients and RNA-Seq data only for additional 61 patients. Differential expression analysis with stringent criteria yielded 44 miRNAs and 2,322 genes. Integrative gene set analysis of differentially expressed miRNAs and genes using miRNA-target information yielded several processes related to cell cycle regulation that were targeted by tumor suppressor miRNAs. We performed the colony formation assay in A549 and NCI-H460 cell lines to test the tumor suppressive activity of down-regulated miRNAs in cancer and identified 7 novel tumor suppressor miRNAs. Two miRNAs showed differential survival characteristics in the TCGA LUAD patient cohort, suggesting their prognostic value. Our study not only provides a massive dataset of miRNA and mRNA sequencing from the matched tumor-normal samples but also reports several novel tumor suppressor miRNAs that could be further developed into prognostic biomarkers or RNA therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110907 | GEO | 2019/02/20

REPOSITORIES: GEO

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Project description:Originally linked with development and differentiation, the role of microRNAs (miRNAs) in many important biological processes has emerged and dysregulation of miRNA expression has been connected with cancer pathogenesis. The association between abnormal expression levels of miRNAs and colon cancer has been mainly demonstrated in primary tumors; more recently, non-overlapping sets of oncomirs, tumour suppressor miRNAs and metastamirs have been associated with distinct stages of colo-rectal cancer (CRC) progression. In an attempt to identify changes in both miRNA and gene expression levels along the colon mucosa - primary tumor - liver metastasis- sequence and to classify miRNAs into distinct functional networks according to the expression of their anti-correlated and differentially expressed target genes, we analyzed a large set of sample-matched miRNA and mRNA expression profiles, including the complete non tumor tissue, primary carcinoma and liver metastasis sequence from 8 patients. Our study shows that the largest changes in miRNA and gene expression levels occur in normal mucosa to tumor transition and are almost stably maintained in the subsequent tumor to metastasis transition. Only a few miRNAs were differentially expressed between liver metastasis and primary carcinoma; however, miRNA expression profiles classified better primary tumors and metastases compared to mRNA profiles. By integration of miRNAs and target genes expression data, we were able to infer regulatory networks modulated by miRNAs during colorectal tumorigenesis and metastatic process, and associate them to the affected biological pathways. In particular, we identified a combination of interconnected miRNAs, up- or down-regulated during tumorigenesis, which are organized into distinct sub-networks, each of which includes several regulatory relationships with differentially expressed genes. Among them, the relationship between miR-182, up-regulated in colon cancer, and the anti-correlated ENTPD5 gene was identified for the first time and confirmed in an independent set of samples. We determined miRNA expression profile for 78 samples comprising 23 normal adjacent mucosa (N), 31 primitive colorectal cancer (T) and 24 liver metastases (M), obtained from 45 patients who underwent surgery at University of Padova (Surgery Branch, Department of Oncological and Surgical Sciences) between March 1994 and September 2008. This dataset included 24 samples belonging to 8 patients with matched samples (N, T and M) from the same patients. We also examined the expression profiles for 80 samples, comprising 23 N, 30 T, 27 M, and including 27 per-patient matched samples from 9 patients. Considering both miRNAs and genes expression experiments, we obtained a set of 77 samples (23N, 30T, 24M) with matched miRNAs and genes expression data from the same biological sample, to reconstruct post-transcriptional regulatory networks.

Project description:Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer (OPC). Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment. This prospective study enrolled OPC patients treated between 2016 and 2018 in three centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the EORTC H&N-35 questionnaires. Initially, a group of 10 patients with severe xerostomia was randomly selected and matched with a comparative group of 10 patients without severe xerostomia. Samples were collected before RT, after receiving 20 Gy and within 24 hours after treatment completion. qPCR arrays (QIAGEN, Hilden, Germany) were used to quantify expression levels of 752 miRNAs in the serum at all timepoints. The resulting logistic-regression based model was validated in additional 60 patients: 30 with grade >3 xerostomia and 30 without. Of 152 eligible patients, we successfully recruited 111 patients. Severe xerostomia 3 months after treatment was reported by 63 patients (56.8%). Mean dose delivered to parotid glands was higher in both exploratory and validation cohort. The model based on miR-185-5p and miR-425-5p expression levels measured before the start of radiotherapy had AUC 0.96 (95% CI: 0.88-1.00). The model based on the same miRNAs remained robust when parameters were measured after 20 Gy (AUC 0.90 (95% CI: 0.75-1.00)). These results were confirmed in the validation group. In the validation group pre-radiotherapy model application yielded 73.3% sensitivity and 80.0% specificity. In the samples taken after 20 Gy, the same two miRNAs yielded 67.7% sensitivity and 72.4% specificity. The model including pretreatment miR-185-5p and miR-425-5p levels together with mean parotid dose, yielded 90.0% sensitivity and 80.0% specificity. In the validation cohort, this model yielded 80.6 % sensitivity and 55.2 % specificity. The model based on miRNA levels measured after 20 Gy and mean parotid dose had 80.0 % sensitivity and 100% specificity in the exploratory group. In the validation cohort its performance fell to 71.0 % sensitivity and 58.6 % specificity. Serum expression levels of miR-425-5p and miR-185-5p measured before the start of radiotherapy or during therapy (after 20 Gy) had a significant prognostic value for the occurrence of severe xerostomia 3 months after treatment completion. The variability explained by miRNAs appears to be, at least partially, independent from the one related to the dosimetric data.

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Identification of tumor suppressor microRNAs by integrative miRNA and mRNA sequencing of matched tumor normal pairs in lung adenocarcinoma

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