Home
This Title All WIREs
WIREs RSS Feed
How to cite this WIREs title:
WIREs RNA
Impact Factor: 4.928

miR‐146a‐5p: Expression, regulation, and functions in cancer

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Cancer as we know it is actually an umbrella term for over 100 very unique malignancies in various tissues throughout the human body. Each type, and even subtype of cancer, has different genetic, epigenetic, and other cellular events responsible for malignant development and metastasis. Recent work has indicated that microRNAs (miRNAs) play a major role in these processes, sometimes by promoting cancer growth and other times by suppressing tumorigenesis. miRNAs are small, noncoding RNAs that negatively regulate expression of specific target genes. This review goes into an in‐depth look at the most recent finding regarding the significance of one particular miRNA, miR‐146a‐5p, and its involvement in cancer. Target gene validation and pathway analysis have provided mechanistic insight into this miRNA's purpose in assorted tissues. Additionally, this review outlines novel findings that suggest miR‐146a‐5p may be useful as a noninvasive biomarker and as a targeted therapeutic in several cancers. This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Model of miR‐146a‐5p in prostate cancer. (a) In normal prostate cells, sufficient expression levels of miR‐146a allow for suppression of target genes. This is in part due to transcriptional activation of the miRNA by FOXP3. In these cells, miR‐146a can downregulate EGFR, RAC1, and ROCK1. It can also control IRAK1 and TRAF6 expression, leaving NF‐κB in the inactive state in the cytoplasm. Regulation of these genes allows miR‐146a to block cell proliferation, invasion, metastasis, survival, and motility. (b) In prostate cancer cells, miR‐146a expression is significantly reduced due to several factors. CpG sites in the miR‐146a promoter region are highly methylated, which is supported by lncRNA PVT1. EZH2 associates with corepressor protein YY1 at the miR‐146a promoter, leading to decreased expression of the miRNA. These events cause miR‐146a targets to be overexpressed in these cells. EGFR signaling activates the MAPK and PI3K pathways, resulting in increased cell proliferation, invasion, and survival. The GTPase RAC1 can also activate MAPK signaling. IRAK1 and TRAF6 transduce signals that lead to NF‐κB activation, translocation to the nucleus, and transcription of cancer‐supportive genes. ROCK1, a serine/threonine protein kinase, promotes actin polymerization, which supports cell motility. Finally, exosomes released by prostate cancer cells exposed to hypoxic conditions contain less miR‐146a than exosomes from prostate cancer cells grown under normal conditions
[ Normal View | Magnified View ]
Mechanisms controlling miR‐146a‐5p expression in cancer. Cancer cells have been used as models to uncover novel mechanisms regulating miR‐146a expression. (a) miR‐146a expression has been shown to be downregulated in multiple cancers due to hypermethylation of miR‐146a promoter DNA at CpG sites. In prostate cancer cells, the long noncoding RNA (lncRNA) PVT1 can promote this process. (b) miR‐146a expression can be repressed via histone methylation catalyzed by EZH2 and via histone deacetylation by HDAC1. (c) LncRNAs can also act as competing endogenous RNAs (ceRNAs), where they sequester miRNAs and prevent them from regulating their target genes. In endometrial cancer, tumor‐associated macrophages (TAMs) have reduced expression of NIFK‐AS1, a ceRNA for miR‐146a. This leads to higher levels of free miR‐146a, which can then downregulate Notch1. (d) However, in NSCLC tumor cells, a ceRNA called SNHG16 is overexpressed, causing sequestration of miR‐146a. Low levels of the miRNA results in increased rates of cell proliferation, migration, and invasion
[ Normal View | Magnified View ]
Schematic of the miR‐146a‐5p promoter region. miR‐146a is found in Exon 2 of the transcriptional unit on human chromosome 5. A 1000 base pair (bp) region immediately upstream of the transcriptional start site (TSS) is highlighted, not drawn to scale. Putative regulatory protein binding sites are shown as different colored boxes. (*) indicates the functional relevance of the binding site has been experimentally validated using ChIP or mutagenesis assays
[ Normal View | Magnified View ]
Model of miR‐146a‐5p in lung cancer. (a) In normal lung cells, sufficient expression levels of miR‐146a allow for suppression of target genes, including EGFR. The ceRNA SNHG16 is present at normal levels, allowing high concentrations of free miR‐146a. Regulation of IRAK1 leaves NF‐κB in the inactive state in the cytoplasm. Dual inhibition of arachidonic acid metabolizing proteins COX‐2 and FLAP keeps production of eicosanoids PGE2 and LTB4 at baseline levels. miR‐146a can also downregulate cyclins D1, D2, and J, preventing cell cycle progression. Regulation of these genes allows miR‐146a to block cell proliferation, invasion, metastasis, and survival. (b) In NSCLC cells, miR‐146a expression is significantly reduced due in part to methylation of CpG sites at the miR‐146a promoter region and overexpression of ceRNA SNHG16. EGFR signaling activates the MAPK and PI3K pathways, resulting in increased cell proliferation, invasion, and survival. IRAK1 transduces signals that lead to NF‐κB activation, translocation to the nucleus, and transcription of pro‐cancer genes. Increased expression of COX‐2 and FLAP results in higher production and release of PGE2 and LTB4, contributing to a tumor‐supportive microenvironment. Cyclins D1, D2, and J allow for progression of the cell cycle and proliferation. Finally, exosomes released by cisplatin‐resistant NSCLC cells contain reduced amounts of miR‐146a
[ Normal View | Magnified View ]
Models of opposing views of miR‐146a‐5p in breast cancer. (a) Evidence has been presented for miR‐146a as a tumor suppressor in breast cells. miR‐146a expression is significantly reduced in breast cancer cells due to loss of induction by FOXP3 and BRMS1. Loss of miR‐146a‐mediated regulation causes EGFR signaling to activate the MAPK and PI3K pathways, resulting in increased cell proliferation, invasion, and survival. RhoA promotes actin polymerization, which supports cell motility. IRAK1 and TRAF6 transduce signals that lead to NF‐κB activation, translocation to the nucleus, and transcription of cancer‐supportive genes, including IL‐6, IL‐8, and MMP‐9. EMT and metastasis‐related genes are also induced by increased levels of the transcription factor SOX5. (b) Other work suggests miR‐146a is oncogenic in breast epithelial cells. Several reports show increased miR‐146a expression in breast cancer cells, though no direct mechanism explaining this has been proposed. Proteolytic cleavage of Notch receptors leads to the release of the Notch intracellular domain (NICD). The NICD can translocate into the nucleus and promote the transcription of Notch‐dependent genes, many of which support cell proliferation and survival. NUMB is an inhibitor of Notch signaling. Excess miR‐146a causes downregulation of NUMB, resulting in amplified Notch signaling. BRCA1 is also targeted by miR‐146a, preventing this protein from carrying out its function as a DNA damage repair factor
[ Normal View | Magnified View ]

Browse by Topic

Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts