Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop

Zhang, J; Sun, Qing‐Yuan; Zhang, Z; Ge, Shengfang; Han, Ze‐Guang; Chen, WT

doi:10.1038/onc.2012.28

Cited by 208 publications

(163 citation statements)

References 35 publications

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“…(12,28) Also, many reports have indicated that these miRNAs function as tumor suppressors. (11,12) In this study, we confirmed that the miR-143 ⁄ 145 cluster was significantly reduced in RCC and functioned as a tumor suppressor, similar to its role in other cancers. MiRNAs are unique in their ability to regulate multiple protein-coding genes.…”

Section: Discussionsupporting

confidence: 77%

“…(7,9,10) According to miRNA signatures, miR-143 and miR-145 are the most frequently downregulated miRNAs in various types of human cancers. (11,12) Both miR-143 and miR-145 are known to be located close together on human chromosome 5q32, where they form a cluster. (13) Several reports have suggested that these clustered miRNAs function as tumor suppressors, targeting several oncogenic genes.…”

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confidence: 99%

“…(13) Several reports have suggested that these clustered miRNAs function as tumor suppressors, targeting several oncogenic genes. (11,12) However, functional analysis of this cluster has not yet been carried out in RCC.…”

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Tumor‐suppressive microRNA‐143/145 cluster targets hexokinase‐2 in renal cell carcinoma

et al. 2013

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Our recent studies of microRNA (miRNA) expression signatures have indicated that the miR-143/145 cluster is significantly downregulated in several types of cancer and represents a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in cancer cells and to identify novel molecular targets of the miR-143/145 cluster in renal cell carcinoma (RCC). The expression levels of miR-143 and miR-145 were significantly downregulated in RCC tissues compared with adjacent non-cancerous tissues. A significant positive correlation was recognized between miR-143 and miR-145 expression. Restoration of mature miR-143 or miR-145 in 786-O and A498 RCC cells revealed that both mature miRNAs significantly inhibited cancer cell proliferation and invasion, suggesting that the miR-143/145 cluster functioned as a tumor suppressor in RCC. Gene expression data and in silico database analysis showed that the hexokinase-2 (HK2) gene, which encodes a glycolytic enzyme crucial for the Warburg effect in cancer cells, was a candidate target of the miR-143/145 cluster. Luciferase reporter assays showed that both miR-143 and miR-145 directly regulated HK2. In RCC clinical specimens, the expression of HK2 was significantly higher in cancer tissues than in non-cancerous tissues. Silencing HK2 suppressed RCC cell proliferation and invasion, suggesting that HK2 has oncogenic functions in RCC. Thus, our data showed that loss of the tumor-suppressive miR-143/145 cluster enhanced RCC cell proliferation and invasion through targeting HK2. (Cancer Sci 2013; 104: 1567-1574 R enal cell carcinoma (RCC) is a disease in which cancer cells form in the tubules of the kidney. Globally, the incidence and mortality rates of RCC are increasing 2-3% per decade.(1) The 5-year survival rate of advanced-stage RCC is very poor (5-10%) due to recurrence or distant metastasis.(2)The latest treatment for RCC includes molecular targeted therapies, which have been developed and are being widely used for patients with metastatic or recurrent RCC. However, these types of therapies are not expected to have curative effects. Therefore, to improve outcomes in patients with RCC, it is necessary to fully elucidate the molecular mechanisms of RCC.The discovery of non-coding RNAs (ncRNAs) in the human genome was an important conceptual breakthrough in the postgenome sequencing era, (4) and it is now evident that improved understanding of ncRNAs is necessary for continued progress in cancer research. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (19-22 bases in length) that regulate protein-coding gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs are unique in their ability to regulate multiple protein-coding genes and are predicted to regulate more than 60% of the protein-coding genes in the human genome. (6) A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers and that they play signif...

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Section: Discussionsupporting

confidence: 77%

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confidence: 99%

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Tumor‐suppressive microRNA‐143/145 cluster targets hexokinase‐2 in renal cell carcinoma

et al. 2013

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“…In addition, p53 can directly bind the microprocessor complex to stimulate the post-transcriptional processing of another subset of pri-miRNAs exemplified by the bicistronic pri-miR-143/145 without affecting its transcription rate (11,145). miR-34A, miR-143, and miR-145 regulate many target RNAs that likely contribute to p53-related phenotypes (22,24,26,64,68,72,73,129,167). Expression of physiologically relevant levels of miR-34A, miR-143, and miR-145 inhibits cell growth and increases apoptosis, consistent with a role for these miRNAs in the p53 DDR (22,167).…”

Section: Figmentioning

confidence: 99%

“…miR-34A, miR-143, and miR-145 regulate many target RNAs that likely contribute to p53-related phenotypes (22,24,26,64,68,72,73,129,167). Expression of physiologically relevant levels of miR-34A, miR-143, and miR-145 inhibits cell growth and increases apoptosis, consistent with a role for these miRNAs in the p53 DDR (22,167). The full complement of targets of p53-regulated miRNAs has not been determined but together, p53 can presumably regulate the expression of thousands of transcripts and proteins through this mechanism (85).…”

Section: Figmentioning

confidence: 99%

Post-Transcriptional Regulation of DNA Damage-Responsive Gene Expression

McKay

2014

Antioxidants & Redox Signaling

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Significance: Production of proteins requires the synthesis, maturation, and export of mRNAs before their translation in the cytoplasm. Endogenous and exogenous sources of DNA damage pose a challenge to the coordinated regulation of gene expression, because the integrity of the DNA template can be compromised by DNA lesions. Cells recognize and respond to this DNA damage through a variety of DNA damage responses (DDRs). Failure to deal with DNA damage appropriately can lead to genomic instability and cancer. Recent Advances: The p53 tumor suppressor plays a dominant role in DDR-dependent changes in gene expression, but this transcription factor is not solely responsible for all changes. Recent evidence indicates that RNA metabolism is integral to DDRs as well. In particular, post-transcriptional processes are emerging as important contributors to these complex responses. Critical Issues: Transcriptional, post-transcriptional, and translational regulation of gene expression is subject to changes in response to DNA damage. How these processes are intertwined in the unfolding of DDR is not fully understood. Future Directions: Many complex regulatory responses combine to determine cell fate after DNA damage. Understanding how transcriptional, post-transcriptional, and translational processes interdigitate to create a web of regulatory interactions will be one of the key challenges to fully understand DDRs. Antioxid. Redox Signal. 20, 640-654.

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