Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

Tanaka, Norimitsu; Toyooka, Shinichi; Soh, Junichi; Kubo, Takafumi; Yamamoto, Hiromasa; Maki, Yuho; Muraoka, Takayuki; Shien, Kazuhiko; Furukawa, Masashi; Ueno, Toshihide; Asano, Hiroaki; Tsukuda, Kazunori; Aoe, Keisuke; Miyoshi, Shinichiro

doi:10.1016/j.lungcan.2011.10.002

Cited by 99 publications

(64 citation statements)

References 25 publications

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“…Furthermore, methylation of miR-34b/c was found to be associated with metastasis in several types of cancer including colorectal and lung cancer, carcinoma of the breast, head and neck cancer, and malignant melanoma (10). Downregulation of miR-34 genes has been associated with elevated risk of metastasis and advanced stages of ovarian, breast and small cell lung cancer (11)(12)(13). Furthermore, tumor relapse correlated with low miR-34a expression in non-small cell lung cancer (14).…”

Section: Introductionmentioning

confidence: 99%

Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

Siemens¹,

Neumann²,

Jackstadt³

et al. 2013

Clinical Cancer Research

132

105

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Purpose: Here, we determined whether epigenetic inactivation of miR-34a and miR-34b/c genes may serve as a prognostic marker for distant metastases in colon cancer.Experimental Design: Using a case-control study design of 94 primary colon cancer samples with and without liver metastases, we determined CpG methylation frequencies of miR-34a and miR-34b/c promoters, expression of miR-34a, and its targets c-Met, Snail, and b-catenin and their prognostic value.Results: miR-34a methylation was detected in 45.1% (n ¼ 42 of 93) of the samples and strongly associated with metastases to the liver (P ¼ 0.003) and lymph nodes (P ¼ 0.006). miR-34b/c methylation was detected in 91.9% of the samples (n ¼ 79/86). A significant inverse correlation between miR-34a methylation and expression of mature miR-34a (P ¼ 0.018) was detected. Decreased miR-34a expression was associated with upregulation of c-Met, Snail, and b-catenin protein levels (P ¼ 0.031, 0.132, and 0.004), which were associated with distant metastases (P ¼ 0.001, 0.017, and 0.005). In a confounder-adjusted multivariate regression model miR-34a methylation, high c-Met and b-catenin levels provided the most significant prognostic information about metastases to the liver (P ¼ 0.014, 0.031, and 0.058) and matched pairs showed a higher prevalence of these risk factors in the samples with distant spread (P ¼ 0.029). Finally, we obtained statistical evidence indicating that the simultaneous detection of these three markers has the highest prognostic value.Conclusions: Silencing of miR-34a and upregulation of c-Met, Snail, and b-catenin expression is associated with liver metastases of colon cancer. Detection of miR-34a silencing in resected primary colon cancer may be of prognostic value, especially in combination with detection of c-Met and b-catenin expression.

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Section: Introductionmentioning

confidence: 99%

Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

Siemens¹,

Neumann²,

Jackstadt³

et al. 2013

Clinical Cancer Research

132

105

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“…More importantly, acute miR-34 expression also leads to tumor repression in vivo in both a genetically engineered lung adenocarcinoma model and multiple xenograft models (Wiggins et al 2010;Kasinski and Slack 2012). Consistently, a low-level miR-34 expression has been detected in a variety of human cancer types due to aberrant transcriptional regulation, genomic deletions, and promoter hypermethylation (Kaghad et al 1997;Lodygin et al 2008;Hermeking 2009;Wang et al 2011b;Tanaka et al 2012). These observations imply the functional significance of miR-34 deficiency in tumorigenesis and suggest that miR-34 miRNAs could act as important components of the tumor suppressor network.…”

mentioning

confidence: 79%

“…miR-34 loci were frequently hypermethylated and down-regulated in human non-small-cell lung cancers (NSCLCs) (Lodygin et al 2008;Wang et al 2011b;Tanaka et al 2012). Similarly, the expression of miR-34 was readily detected in both neonatal and adult mouse lungs but was significantly decreased in the terminal lung adenocarcinomas induced by activating Kras mutation (Kras G12D ) and p53 deletion (Fig.…”

Section: Mir-34a Deficiency Promotes Krasmentioning

confidence: 95%

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

et al. 2014

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As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 39 untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

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“…Lost or reduced expression of miR-34 or hypermethylation of its promoter have been observed in multiple cancers, including both small cell and non-small cell lung cancers (95)(96)(97). Overexpression of miR-34 in lung cancer cells or animal models leads to inhibition of the initiation or progression of cancer or sensitization to radiotherapy (98,99).…”

Section: Mir-34/449 Function As a Tumor Suppressormentioning

confidence: 99%

The Roles of MicroRNAs and Protein Components of the MicroRNA Pathway in Lung Development and Diseases

Cushing

Jiang

Kuang

et al. 2015

Am J Respir Cell Mol Biol

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Decades of studies have shown evolutionarily conserved molecular networks consisting of transcriptional factors, diffusing growth factors, and signaling pathways that regulate proper lung development. Recently, microRNAs (miRNAs), small, noncoding regulatory RNAs, have been integrated into these networks. Significant advances have been made in characterizing the developmental stage-or cell type-specific miRNAs during lung development by using approaches such as genome-wide profiling and in situ hybridization. Results from gain-or loss-of-function studies revealed pivotal roles of protein components of the miRNA pathway and individual miRNAs in regulating proliferation, apoptosis, differentiation, and morphogenesis during lung development. Aberrant expression or functions of these components have been associated with pulmonary disorders, suggesting their involvement in pathogenesis of these diseases. Moreover, genetically modified mice generated in these studies have become useful models of human lung diseases. Challenges in this field include characterization of collective function and responsible targets of miRNAs specifically expressed during lung development, and translation of these basic findings into clinically relevant information for better understanding of human diseases. The goal of this review is to discuss the recent progress on the understanding of how the miRNA pathway regulates lung development, how dysregulation of miRNA activities contributes to pathogenesis of related pulmonary diseases, and to identify relevant questions and future directions.

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Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

Cited by 99 publications

References 25 publications

Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

The Roles of MicroRNAs and Protein Components of the MicroRNA Pathway in Lung Development and Diseases

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