A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

Nadal, Ernest; Zhong, Jin; Lin, Jules; Reddy, Rishindra M.; Ramnath, Nithya; Chang, Andrew C.; Beer, David G.; Chen, Guoan

doi:10.1158/1078-0432.ccr-13-3348

Cited by 91 publications

(85 citation statements)

References 48 publications

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“…Our findings, together with other results, indicated that miR-409-3p might function as a tumor suppressor in human cancers. Interestingly, Nadal and his groups identified a microRNA cluster at 14q32 drives aggressive lung adenocarcinoma, and further confirmed that eleven of 22 miRNAs associated with poor survival were encoded in a large miRNA cluster at 14q32, including 3 miRNAs encoded at 14q32 (miR-411, miR-370, and miR-376a) [26]. Although it is also originated from the chromosome 14q32 region, it acts as a tumor suppressor in LAD cells.…”

Section: Discussionmentioning

confidence: 94%

MicroRNA-409-3p Functions as a Tumor Suppressor in Human Lung Adenocarcinoma by Targeting c-Met

Wan

Zhu²,

Xu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Dysregulation of microRNAs is correlated with tumor development. The aim of this study is to investigate the clinicopathologic and prognostic significance of microRNA (miR)-409-3p and its tumor suppressor roles in lung adenocarcinoma (LAD). Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect miR-409-3p expression in LAD tissues and corresponding noncancerous tissues. Additionally, the correlations of miR-409-3p expression with clinicopathologic factors and prognosis of patients were statistically analyzed. Next, we investigated whether miR-409-3p could function as a tumor suppressor in LAD cells via regulation of Akt signaling by targeting receptor tyrosine kinase (c-Met). Results: MiR-409-3p was significantly downregulated in LAD tissues compared with corresponding noncancerous tissues. Low miR-409-3p expression was observed to be significantly correlated with poorer tumor differentiation, advanced pTNM stage and higher incidence of lymph node metastasis. Multivariate Cox regression analyses showed that miR-409-3p expression was an independent prognostic factor for LAD patients. Functional analyses indicated that miR-409-3p could inhibit growth, induce apoptosis, reduce migration and invasion in LAD cells via inactivation of Akt signaling by targeting c-Met. Conclusions: MiR-409-3p was an independent prognostic factor and functioned as a tumor suppressor in LAD via regulation of Akt signaling by targeting c-Met.

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Section: Discussionmentioning

confidence: 94%

MicroRNA-409-3p Functions as a Tumor Suppressor in Human Lung Adenocarcinoma by Targeting c-Met

Wan

Zhu²,

Xu³

et al. 2014

Cell Physiol Biochem

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“…Deregulation of small ncRNAs, mainly miRNAs, expressed from this locus has been associated with development and progression of different tumors, including lung, in both humans and mice [5–7]. While individual genes expressed from this locus have been associated with lung cancer patient outcome, a signature of three miRNAs has been shown to better predict overall survival and recurrence-free survival [8]. This combined prediction signature suggests that the analysis of multiple genes encoded at DLK1-DIO3 may be more biologically informative than the analysis of any single gene.…”

Section: Introductionmentioning

confidence: 99%

Deregulation of small non-coding RNAs at the DLK1-DIO3 imprinted locus predicts lung cancer patient outcome

et al. 2016

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Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer. In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers. Deregulated expression of a microRNA (miRNA) cluster mapping to this locus was also associated with patient outcome, suggesting the importance of this locus to lung cancer disease phenotypes. The DLK1-DIO3 locus is complex, and encodes several protein-coding genes, in addition to long and short non-coding RNAs. While the role of miRNAs is established, the biological importance of another relevant class of small RNAs, PIWI-interacting RNAs (piRNAs), has not been investigated. When somatically expressed, piRNAs regulate gene transcription through DNA methylation. Interestingly, their expression patterns have been observed to be altered in cancer and correlated with patient outcome. Here, we characterize the somatic expression of piRNAs encoded at DLK1-DIO3 in two independent cohorts of lung adenocarcinoma and lung squamous cell carcinoma and investigate their associations with patient outcome. We find that the expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting patient outcome, further emphasizing the importance of regulation at this locus in lung cancer.

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“…Likewise, in human lung adenocarcinoma, the DLK1-DIO3 locus is reportedly upregulated compared to healthy lung tissue [20, 25]. Nadal et al reported that high DLK1-DIO3 locus miRNA expression was furthermore correlated with a significantly reduced overall survival in patients.…”

Section: Discussionmentioning

confidence: 99%

“…Nadal et al reported that high DLK1-DIO3 locus miRNA expression was furthermore correlated with a significantly reduced overall survival in patients. Particularly the expression of miR-370, miR-441 and miR-376a predicted a poor clinical outcome [25]. Another class of small noncoding RNAs, piRNAs, is also encoded by the DLK1-DIO3 locus.…”

Section: Discussionmentioning

confidence: 99%

“…This is a novel perspective, as the available reports on DLK1-DIO3 locus deregulation in human NSCLC are based on expression or methylation data derived from bulk tumors [20, 25–27]. In contrast, in murine lung adenocarcinomas, Valdmanis et al demonstrated that the Dlk1-Dio3 locus upregulation was specific to Tomato-labelled sorted Kras G12D mutant cancer cells [20].…”

Section: Discussionmentioning

confidence: 99%

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Snail mediates repression of the Dlk1-Dio3 locus in lung tumor-infiltrating immune cells

et al. 2018

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The epithelial-mesenchymal transition-inducing transcription factor Snail contributes to tumor progression in different malignancies. In the present study, we used a transcriptomics approach to elucidate the mechanism of Snail-mediated tumor growth promotion in a KrasLSL-G12D/+;p53fl/fl mouse model of lung adenocarcinoma. We discovered that Snail mediated the downregulation of the imprinted Dlk1-Dio3 locus, a complex genomic region containing protein-coding genes and non-coding RNAs that has been linked to tumor malignancy in lung cancer patients. The Dlk1-Dio3 locus repression mediated by Snail was found to occur specifically in several populations of tumor-infiltrating immune cells. It could be reproduced in primary splenocytes upon ex vivo culture with conditioned medium from Snail-expressing cancer cell lines, which suggests that a Snail-induced soluble factor secreted by the cancer cells mediates the Dlk1-Dio3 locus repression in immune cells, particularly in lymphocytes. Our findings furthermore point towards the contribution of Snail to an inflammatory tumor microenvironment, which is in line with our previous report of the Snail-mediated recruitment of pro-tumorigenic neutrophils to the lung tumors. This underlines an important role for Snail in influencing the immune compartment of lung tumors and thus contributing to disease progression.

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A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

Cited by 91 publications

References 48 publications

MicroRNA-409-3p Functions as a Tumor Suppressor in Human Lung Adenocarcinoma by Targeting c-Met

MicroRNA-409-3p Functions as a Tumor Suppressor in Human Lung Adenocarcinoma by Targeting c-Met

Deregulation of small non-coding RNAs at the DLK1-DIO3 imprinted locus predicts lung cancer patient outcome

Snail mediates repression of the Dlk1-Dio3 locus in lung tumor-infiltrating immune cells

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