miRNA for gene regulation and DNA repair

Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease.[141] A manually curated, publicly available database, miR2Disease, documents known relationships between miRNA dysregulation and human disease.[142]

Inherited diseases

A mutation in the seed region of miR-96, causes hereditary progressive hearing loss.[143]

A mutation in the seed region of miR-184, causes hereditary keratoconus with anterior polar cataract.[144]

Deletion of the miR-17~92 cluster, causes skeletal and growth defects.[145]

Cancer

Role of miRNA in a cancer cell

 

The first human disease known to be associated with miRNA deregulation was chronic lymphocytic leukemia.[45] Many other miRNAs also have links with cancer[45] and accordingly are sometimes referred to as “oncomirs“. In malignant B cells miRNAs participate in pathways fundamental to B cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches and the production and class-switching of immunoglobulins. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.[45]

A study of mice altered to produce excess c-Myc — a protein with mutated forms implicated in several cancers — shows that miRNA affects the cancer development. Mice engineered to produce a surplus of types of miRNA found in lymphoma cells developed the disease within 50 days and died two weeks later. In contrast, mice without the surplus miRNA lived over 100 days.[45] Leukemia can be caused by the insertion of a viral genome next to the 17-92 array of microRNAs, leading to increased expression of this microRNA.[45]

Another study found that two types of miRNA inhibit the E2F1 protein, which regulates cell proliferation. miRNA appears to bind to messenger RNA before it can be translated to proteins that switch genes on and off.[45]

By measuring activity among 217 genes encoding miRNAs, patterns of gene activity that can distinguish types of cancers were identified. miRNA profiling can determine whether patients with chronic lymphocytic leukemia had slow growing or aggressive forms of the cancer.[45]

A novel miRNA-profiling-based screening assay for the detection of early-stage colorectal cancer is undergoing a clinical trial. Early results showed that blood plasma samples collected from patients with early, resectable (Stage II) colorectal cancer could be distinguished from those of sex-and age-matched healthy volunteers. Sufficient selectivity and specificity could be achieved using small (less than 1 mL) samples of blood.[146][147]

Another role for miRNA in cancers is to use their expression level for prognoses. For example, one study on NSCLC samples found that low miR-324a levels could serve as an indicator of poor survival.[148] Either high miR-185 or low miR-133b levels may correlate with metastasis and poor survival in colorectal cancer.[149] Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene.[150] Optimal treatment for cancer involves accurately identifying patients for risk-stratified therapy. Those with a rapid response to initial treatment may benefit from truncated treatment regimens, showing the value of accurate disease response measures. Cell-free miRNA are highly stable in blood, are overexpressed in cancer and are quantifiable within the diagnostic laboratory. In classical Hodgkin lymphoma, plasma miR-21, miR-494, and miR-1973 are promising disease response biomarkers.[151] Circulating miRNAs have the potential to assist clinical decision making and aid interpretation of positron emission tomography combined with computerized tomography. They can be performed at each consultation to assess disease response and detect relapse.

A 2009 study explored miR-205 targeted for inhibiting the metastatic nature of breast cancer.[152] Five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) are down-regulated in tumour progression of breast cancer.[153]

A 2015 study used a triple helix of three miRNAs embedded in a dextran aldehyde/dendrimer gel in a mouse model of triple negative breast cancer. mir-205 and mir-212 targeted specific RNAs, while the other miRNA stabilized the others. The treatment reduced tumor sizes by 90% with survival times of 75 days.[154][155]

DNA repair and cancer

DNA damage is considered to be the primary underlying cause of cancer.[156] If DNA repair is deficient, damage can accumulate. Such damage can cause mutational errors during DNA replication due to error-prone translesion synthesis. Accumulated damage can also cause epigenetic alterations due to errors during DNA repair.[157][158] Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms).

Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases.[159] However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor.

Among 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1, most were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene.[160] However, up to 15% of MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.[161]

In 29–66%[162][163] of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient, but the MGMT promoter is not methylated.[162] In glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3’UTR (the three prime untranslated region of MGMT mRNA).[162] Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.

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connie dello buono

Health educator, author and enterpreneur motherhealth@gmail.com or conniedbuono@gmail.com ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at www.clubalthea.com Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at quora.com and posts in this site.

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