Mir-26 Micro RNA Precursor Family - MiR-26a Roles

MiR-26a Roles

Smooth muscle cell (SMC) differentiation

miRNA-26a is found to be significantly upregulated during SMC differentiation and downregulated in abdominal aortic aneurysm (AAA) formation. Inhibition of miRNA-26a accelerates SMC differentiation, and also promotes apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunts differentiation. MicroRNA-26a targets the expression of SMAD-1 and SMAD-4, members of the TGF-βsuperfamily signaling cascade. Inhibition of miRNA-26a increases gene expression of SMAD-1 and SMAD-4, while overexpression inhibites SMAD-1.

Hepatocellular carcinoma

miR-26a has been found to induce cell cycle arrest at the G₁ phase in human hepatocellular carcinoma cells, in part through direct downregulation of cyclin D2 and cyclin E2. miR-26a also directly suppresses expression of estrogen receptor alpha (Erα). Overexpression of miR-26a brings about negative regulation of both cell proliferation and of the cell cycle. Therapeutic miR-26a delivery using adeno-associated virus (AAV) is able to inhibit cancer cell formation while also inducing tumour-specific apoptosis and providing dramatic protection from disease progression without toxicity.

Nasopharyngeal carcinoma

miR-26a is commonly downregulated in nasopharyngeal carcinoma samples and cell lines. It directly represses expression of the oncogene EZH2 (enhancer of zeste homolog 2), which in turn causes inhibition of cell growth and cell-cycle progression. miR-26a again suppresses tumorigenesis in nasopharyngeal cells in vivo, with suppressed expression of c-myc, cyclins D3 and E2, and cyclin-dependent kinases CDK4 and CDK6. p14ARF and p21CIPI CDK inhibitor expression are conversely enhanced, mediated chiefly by EZH2 expression.

Breast cancer

There is downregulation of miR-26a in breast cancer specimens and cell lines, and it has been shown to functionally antagonise human breast carcinogenesis. miR-26a directly regulates the expression of metadherin (MTDH) and EZH2. It further induces apoptosis, inhibition of colony formation and tumorigenesis of breast cancer cells in vivo. A decrease in MTDH and EZH2 expression has been shown to be accompanied by an increase in apoptosis, whilst re-expression of MTDH partially reverses miR-26a's pro-apoptotic effect.

Lung cancer

miR-26a plays an important role as an anti-oncogene in the molecular mechanism of human lung cancer. miR-26a expression is down-regulated in human lung cancer tissues relative to normal tissues. Meanwhile, the overexpression of miR-26a in the A549 human lung cancer cell line dramatically inhibits cell proliferation, blocks G1/S phase transition, induces apoptosis, and inhibits cell metastasis and invasion in vitro.Enhancer of zeste homolog 2 (EZH2) is a potential target of miR-26a.

Glioma

miR-26a might serve as an oncogene in the carcinogenesis of glioma. It has been found overexpressed in a subset of high-grade gliomas and directly targets the PTEN transcript. Overexpression of miR-26a in glioma primarily results from amplification at the miR-26a-2 locus, a genomic event strongly associated with monoallelic PTEN loss.miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus.

Burkitt lymphoma

miR-26a plays a role as a potential tumor-suppressor in MYC-induced lymphoma. miR-26a is found to be downregulated in primary human Burkitt lymphoma and MYC-driven lymphoma cell lines. Ectopic expression of miR-26a influences cell cycle progression by targeting the bona fide oncogene EZH2 which is a polycomb protein and global regulator of gene expression. MYC modulates genes important to oncogenesis via deregulation of miRNAs, miR-26a, contributes to the MYC-driven lymphomagenesis.

Human cholangiocarcinoma

miR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. Human cholangiocarcinoma tissues and cell lines have increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increases proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduces these parameters.Overexpression of miR-26a by cholangiocarcinoma cells increases tumor growth in severe combined immune-deficient mice. GSK-3β mRNA is a direct target of miR-26a,miR-26a-mediated reduction of GSK-3β results in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevents miR-26a-induced tumor cell proliferation and colony formation.

Melanoma

miR-26a replacement is proposed as a potential therapeutic strategy for metastatic melanoma. mir-26a is strongly downregulated in melanoma cells compared with primary melanocytes. Treatment of melanoma cell lines with a miR-26a mimic promoted significant and rapid death by apoptosis. mir-26a is proposed to promote this apoptosis by repressing expression of the BAG4/Silencer of Death Domains protein (SODD) through binding the 3'UTR of SODD.[1