Mir-375
Pancreas-specific microRNA
From Wikipedia, the free encyclopedia
The miR-375 microRNA (miRNA) is a short RNA molecule located on human chromosome 2 in between the CRYBA2 and CCDC108 genes.[1] miRNAs are small (18–25 nucleotides), non-coding RNAs that regulate genes post-transcriptionally by inhibiting translation and/or causing mRNA degradation.[1] miR-375 is specifically expressed in the pancreatic islets, brain and spinal cord.[2][3] Genetic manipulation of miR-375 levels can decrease cancer development and autoimmunity in affected cell types.
| mir-375 | |
|---|---|
Conserved secondary structure of mir-375 | |
| Identifiers | |
| Symbol | mir-375 |
| Rfam | RF00700 |
| miRBase family | MIPF0000114 |
| Other data | |
| RNA type | microRNA |
| Domain | Eukaryota; |
| PDB structures | PDBe |
Roles in development
Diabetes
miR-375 plays a critical role in diabetes by regulating the expression of related genes involved in pancreatic islet formation, pancreatic development, and β-cell secretion.[4] These processes are related to diabetes because pancreatic islets contain β-cells that produce insulin, a hormone that regulates blood sugar.[5] A person with diabetes will have high blood sugar either because their cells are not responding to insulin or because their pancreatic beta cells are not producing enough of it.[5] In patients with type 2 diabetes, β-cell mass is reduced by up to 60% when compared to healthy individuals.[6] Similarly, there is a decrease in β-cell mass per pancreatic area when miR-375 is knocked out in mice.[7] In addition, miR-375 shows elevated expression levels during pancreatic development, which coincide with higher insulin expression and β-cell proliferation.[4][5] Thus, evidence suggests that miR-375 is important for normal pancreatic islet formation and insulin secretion from β-cells.[5] Because of the role miR-375 plays in regulating processes essential for healthy sugar metabolism, it may be a potential target for treating diabetes.[5]
Diabetes is currently managed with exogenous insulin and islet cell transplantation.[5] However, these treatments fall short in their attempts to reestablish the natural regulation of blood sugar and are limited by the scarcity of donor tissue, respectively.[5] To address these concerns, scientists have begun investigating the potential of human embryonic stem cells (hESCs), which are cells that can develop into many adult cell types including pancreatic β-cells.[5] As such, hESCs have the potential to provide a limitless source of insulin-producing β-cells.[5] However, creating mature β-cells from hESCs has proved challenging for researchers because the hESC-derived cells often secreted other hormones in addition to insulin.[5] miR-375 may provide a new way to mature hESCs into β-cells because of its high expressivity in β-cells and its function in insulin release.[5] Therefore, miR-375 is a promising target for the treatment of diabetes.
Roles in cancer
| Affected organ | Proposed mechanisms/applications |
|---|---|
| Liver | In cancerous liver cells, known as hepatocellular carcinomas (HCC), miR-375 acts as a tumour suppressor. This was evidenced by a decrease in the rate of uncontrolled cell division through the inhibition of a well-known oncogene, AEG-1, in response to miR-375 overexpression.[8]
Recent studies show that when miR-375 is introduced into HCC cell lines, there is a reduction in cell proliferation, motility, and migration, as well as an increase in apoptosis in vitro.[9][10][11] In vivo studies in mouse models of HCC also show reduced tumour growth with no apparent side effects.[9][10][11] These results support potential strategies to increase miR-375 levels in HCCs to prevent metastasis. |
| Esophagus | miR-375 overexpression inhibits tumour growth and metastasis of esophageal cancer cells by inhibiting insulin-like growth factor 1 receptor and proteins involved in the PI3K/Akt signalling pathway.[12] The PI3K/Akt signalling pathway promotes aerobic glycolysis, which is a hallmark of rapidly dividing cancer cells.[12] Hence, a potential strategy for inhibiting proliferation in esophageal cancer cells would be to increase intracellular miR-375 levels. |
| Skin | Increased expression of miR-375 in Merkel cell carcinomas (MCC) is used as a marker to differentiate MCC from other common skin cancers.[13] |
Immunity
miR-375 is involved in many autoimmune diseases, such as inflammatory bowel diseases (IBD) and type 1 diabetes mellitus (T1DM).[4] For instance, miR-375 can be used as a factor to distinguish between the different types of IBD (e.g. Crohn's disease vs ulcerative colitis).[14] In patients with T1DM, miR-375 dysregulation was observed in a number of tissues that were directly linked to the development of the disease.[15] Furthermore, miR-375 is involved in the molecular aspects of immunity as miR-375 silencing decreases the production of pro-inflammatory macrophages and subsequent inflammatory response.[16] While pro-inflammatory macrophages are responsible for killing pathogens, a sustained pro-inflammatory response leads to a long list of disorders (e.g. arthritis, asthma, atherosclerosis, blindness, cancer, and diabetes).[17]
Since miR-375 silencing inhibits the production of pro-inflammatory macrophages, it can delay the onset of atherosclerosis (the main underlying cause of heart attacks and strokes) in mice, indicating its therapeutic potential in conditions accompanied by chronic inflammation.[16] Interestingly, miR-375 enhances macrophage migration into cancer cells by targeting PNX and TSN3, which are both proteins involved maintaining cell structure and organization.[18]