MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers

Seike, Masahiro; Goto, Akiteru; Okano, Toshio; Bowman, Elise D.; Schetter, Aaron J.; Horikawa, Izumi; Mathé, Ewy A.; Jen, Jin; Yang, Ping; Sugimura, Haruhiko; Gemma, Akihiko; Kudoh, Shoji; Croce, Carlo M.; Harris, Curtis C.

doi:10.1073/pnas.0905234106

Cited by 474 publications

(373 citation statements)

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“…In our collection, however, we found significantly higher levels of miR-21 in early-stage tumors. This finding, together with the demonstration of miR-21 overexpression in experimental mouse lung cancers, suggests that miR-21 upregulation could be an early event in lung tumorigenesis, as it has also been suggested by a recent study showing that miR-21 is the most aberrantly increased miRNA also in lung tumors of never smokers (Seike et al, 2009). Further studies will be necessary to establish if individual variations in miR-21 expression could be a risk factor for the development of lung cancer in humans.…”

Section: Discussionsupporting

confidence: 73%

“…This is supported by the identification of networks targeted in thyroid reported here, showing that miR-21 in these cells could contribute to genomic instability, typical of advanced cancers. Conversely, miR-21 overexpression in lung could be advantageous preferentially in the early stages of tumor progression, as suggested by data indicating that in this cell type miR-21 is mainly involved in protection from apoptosis (Seike et al, 2009), which, in turn, is mainly critical in early stages of tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…The top-scored upregulated miRNA is miR-21, a miRNA found overexpressed in several solid and hematopoietic malignancies (Krichevsky and Gabriely, 2009). In vitro studies have demonstrated that miR-21 knockdown in tumor cell lines leads to increased apoptotic cell death (Seike et al, 2009). Furthermore, miR-21 depletion reduces the growth of tumor cell lines xenografts in mice (Si et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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“…Seike et al [185] reported that miRNA microarray data showed higher levels of miR-21 in EGFR-mutant cases, and in vitro analyses using NSCLC cell lines showed that activated EGFR signalling upregulated miR-21 expression. A statistically significant positive correlation was observed between miR-21 expression levels and p-EGFR levels in NSCLC cell lines.…”

Section: Preclinical Studiesmentioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as nonsmall cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level.

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“…26 A different profiles of miRNA expression was observed in lung carcinomas from never-smokers vs smokers. 27 Recent studies demonstrated that EGFR may be a functional target of miRNAs. 28,29 MiRNA-128, which is frequently deleted in lung cancers, directly downregulated EGFR, but did not correlate with EGFR mutation and prognosis.…”

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confidence: 99%

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

et al. 2010

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MicroRNA (miRNA) expression is deregulated in lung cancer, and some miRNAs are associated with poor prognosis and survival. In this study, we investigated the miRNA expression in lung adenocarcinomas with different oncogenic mutations, including EGFR-positive, KRAS-positive and EGFR/KRAS-negative tumors. The expression of 319 miRNAs was evaluated by Exiqon/Luminex microarray, and expression of individual miRNAs was validated by individual RT-PCR assays (Applied Biosystems). Overall, miRNA expression was similar among three mutationally different groups with most upregulated miRNAs being miR-20a, miR-328, miR-34c and miR-18b and most downregulated miRNAs being miR-32, miR-137 and miR-342. Four miRNAs (miR-155, miR-25, miR-495 and miR-7g) were expressed differently among these tumors. miR-155 was upregulated only in EGFR/KRAS-negative group, miR-25 was upregulated only in EGFR-positive group and miR-495 was upregulated only in KRAS-positive adenocarcinomas. In opposite, let-7g was downregulated in all three groups, with more significant downregulation in EGFR/KRASnegative adenocarcinomas. Principal component analysis (PCA) revealed significant correlation between miRNA expression patterns and somatic mutations. In this study, we demonstrated that despite the similarity in miRNA expression among lung adenocarcinomas with different somatic mutations, some miRNAs showed unique expression patterns, which were in strong correlation with the mutation type, suggesting different carcinogenic pathway for these tumors. These miRNAs can be further explored for their diagnostic and prognostic use.

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MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers

Cited by 474 publications

References 50 publications

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

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