Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos‐ and histology‐related changes in lung cancer

Nymark, Penny; Guled, Mohamed; Borze, Ioana; Faisal, Ali; Lahti, Leo; Salmenkivi, Kaisa; Kettunen, Eeva; Anttila, Sisko; Knuutila, Sakari

doi:10.1002/gcc.20880

Cited by 119 publications

(94 citation statements)

References 53 publications

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“…An integrative lung cancer study was carried out by Nymark et al (2011) using both miRNA and matched gene expression profiling data. The study considered lung cancer patients that were "highly exposed" and "nonexposed" to asbestos.…”

Section: Validation_data2mentioning

confidence: 99%

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Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

Mitra

Edmonds

Sun

et al. 2014

RNA

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While previous studies reported aberrant expression of microRNAs (miRNAs) in non-small cell lung cancer (NSCLC), little is known about which miRNAs play central roles in NSCLC's pathogenesis and its regulatory mechanisms. To address this issue, we presented a robust computational framework that integrated matched miRNA and mRNA expression profiles in NSCLC using feed-forward loops. The network consists of miRNAs, transcription factors (TFs), and their common predicted target genes. To discern the biological meaning of their associations, we introduced the direction of regulation. A network edge validation strategy using three independent NSCLC expression profiling data sets pinpointed reproducible biological regulations. Reproducible regulation, which may reflect the true molecular interaction, has not been applied to miRNA-TF coregulatory network analyses in cancer or other diseases yet. We revealed eight hub miRNAs that connected to a higher proportion of targets validated by independent data sets. Network analyses showed that these miRNAs might have strong oncogenic characteristics. Furthermore, we identified a novel miRNA-TF co-regulatory module that potentially suppresses the tumor suppressor activity of the TGF-β pathway by targeting a core pathway molecule (TGFBR2). Follow-up experiments showed two miRNAs (miR-9-5p and miR-130b-3p) in this module had increased expression while their target gene TGFBR2 had decreased expression in a cohort of human NSCLC. Moreover, we demonstrated these two miRNAs directly bind to the 3 ′ untranslated region of TGFBR2. This study enhanced our understanding of miRNA-TF co-regulatory mechanisms in NSCLC. The combined bioinformatics and validation approach we described can be applied to study other types of diseases.

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Section: Validation_data2mentioning

confidence: 99%

“…comm.). Both the data sets were processed and normalized accordingly as described by Nymark et al (2011). We considered seven asbestos-nonexposed NSCLC samples and corresponding matched normal samples that had both miRNA and gene expression profiling information (see Supplemental Tables S1, S4 for more details).…”

Section: Validation_data2mentioning

confidence: 99%

Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

Mitra

Edmonds

Sun

et al. 2014

RNA

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“…Microarray studies have identified a number of miRNAs that are up-or downregulated in pancreatic cancer. Recently, miR148b has been shown to be deregulated in some other types of cancers, such as overexpressed in ovarian cancer (12) and lung cancer (13), whereas downregulated in pancreatic cancer (14,15), gastric cancer (16), and colorectal cancer (17). However, the exact role of miR-148b in carcinogenesis of pancreatic cancer has not been revealed yet.…”

Section: Introductionmentioning

confidence: 99%

miR-148b Functions as a Tumor Suppressor in Pancreatic Cancer by Targeting AMPKα1

Zhao

Zhang

Liu

et al. 2013

Molecular Cancer Therapeutics

109

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miRNAs are small noncoding RNAs that participate in a variety of biologic processes, and dysregulation of miRNA is always associated with cancer development and progression. Aberrant expression of miR-148b has been found in some types of cancer, but its expression and potential biologic role in pancreatic cancer are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 48 pairs of human pancreatic cancer tissues and five cell lines. Furthermore, the deregulated miR-148b was correlated with increased tumor size, late tumor-node-metastasis stage, lymphatic invasion, distant metastasis, and worse prognosis in pancreatic cancer. Functional studies indicated overexpression of miR-148b dramatically suppressed the growth of cancer cells, attributable to induction of apoptosis and cell-cycle arrest at S-phase. Meanwhile, miR-148b remarkably inhibited invasion and enhanced chemosensitivity of pancreatic cancer cells. Moreover, ectopic expression of miR-148b was able to inhibit tumorigenicity in nude mice. Further studies revealed that AMPKa1 might be the direct target gene of miR-148b, and overexpressed AMPKa1 inversely correlated with miR-148b in pancreatic cancer. Silencing of AMPKa1 with RNA interference inhibited the growth of pancreatic cancer cells in vitro and in vivo and also induced apoptosis, cell-cycle arrest, and inhibited invasion of cancer cells, which is consistent with the effects of miR-148b overexpression. In conclusion, miR-148b can inhibit cell proliferation, invasion, and enhance chemosensitivity of pancreatic cancer by targeting AMPKa1. Our present results implicate the potential effects of miR-148b on prognosis and treatment of pancreatic cancer.

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“…6 Our pioneering genomic investigations have revealed changes in miRNA profile and an accumulation of genomic alterations in asbestos-related lung cancer. [7][8][9] Not only miRNAs but also other epigenetic mechanisms, such as DNA methylation are fundamental in the regulation of gene expression and carcinogenesis. Cancer has been characterized by global DNA hypomethylation-targeting often the non-coding regions-as well as site-specific hypermethylation of CpG islands (CGI) in tumor suppressor gene promoters.…”

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confidence: 99%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 3 10 219 , mean change in beta [D] 20.09), GPR135 (FDR 1.87 3 10 28 , mean D 20.09) and TPO (FDR 8.58 3 10 25 , mean D 20.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.Lung cancer is the leading cause of cancer-related deaths, accounting for around every fifth global cancer death. 1 While tobacco smoking remains the principal risk factor for lung carcinogenesis, exposure to asbestos, a group of naturally occurring fibrous silicate minerals with multiple commercial applications, is the most important occupational risk factor for lung cancer. 2 Asbestos exposure causes 6 to 23% of all male lung cancers (estimates depending on the exposure and population), and >107,000 deaths annually from asbestosrelated diseases. 3,4 All forms of asbestos are carcinogenic to

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Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos‐ and histology‐related changes in lung cancer

Cited by 119 publications

References 53 publications

Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

miR-148b Functions as a Tumor Suppressor in Pancreatic Cancer by Targeting AMPKα1

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

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