User:Jjaccaz/sandbox

Origins
In molecular biology, miR-194 microRNA precursor is a small non-coding RNA gene that regulated gene expression. Its expression has been verified in mouse (MI0000236, MI0000733) and in human (MI0000488, MI0000732). mir-194 appears to be a vertebrate-specific miRNA and has now been predicted or experimentally confirmed in a range of vertebrate species (MIPF0000055). The mature microRNA is processed from the longer hairpin precursor by the Dicer enzyme. In this case, the mature sequence is excised from the 5' arm of the hairpin. miR-194 can be derived from two separate loci on human genome, miR-194-1 is encoded on chromosome 1 and miR-194-2 is encoded on chromosome 11.They form a cluster with miR-215 and  miR-192, respectively. They initially appear as relatively long transcripts called pri-miRNA, the pri-miR-194-1 corresponds to the cluster miR-194-1/miR-215 and the pri-miR-194-2 to the cluster miR-194-2/miR-192. In other species miR-194 can be derived from two others separate loci : miR-194a and miR-194b.

Expressions
miR-194 is specifically expressed in the human gastro-intestinal tract, it is induced during the differentiation of intestinal epithelial cell.

miR-194 is highly expressed in the liver and was shown to regulate liver functions. miR-194 is generally repressed during cancer.

Species Distribution
miR-194 is a vertebrate-specific miRNA which is found in species like :

lizard (Anolis carolinensis), monkeys ( Geoffroy's spider monkey (Ateles geoffroyi), gorilla (Gorilla gorilla), rhesus macaque (Macaca mulatta), southern pig-tailed macaque (Macaca nemestrina), Bornean orangutan (Pongo pygmaeus), Common chimpanzee (Pan troglodytes)) , cow (Bos taurus) , common carp (Cyprinus carpio) , dog (Canis familiaris) , chinese hamster (Cricetulus griseus) , zebrafish (Danio rerio) , horse (Equus caballus) , chicken (Gallus gallus) , platypus (Ornithorhynchus anatinus) , medaka aor japanese killifish (Oryzias latipes) , sea lamprey (Petromyzon marinus) , rat (Rattus norvegicus) , Wild boar (Sus scrofa) , Zebra Finch (Taeniopygia guttata) , xenopus (Xenopus tropicalis)

Colorectal cancer

 * miR-194 is significantly downregulated in colorectal cancer (CRC) tissues. There is a lower expression of miR-194 in HT-29, HCT-116 and SW-620 CRC cell lines compared to normal colorectal tissues. Lower expression level of miR-194 in patients with CRC tend to be associated with increased tumor size . The tumor suppressor protein p53 induced miR-194, which was identified as a robust p53-responsive miRNa species. miR-194 might have a tumor suppressor function.
 * Conversely, miR-194 might have an angiogenesis effect in CRC cells, down-regulating THBS1, the transcript of thrombospondin-1 (TSP-1), an endogenous inhibitor of angiogenesis..

Colorectal liver metastases

 * miR-194 is significantly downregulated at the liver invasion front. Analysis showned that enhanced expression of miR-194 at the liver invasion front is an adverse prognostic marker of tumor recurrence and overall survival. miR-194, in addition to its oncogenic capacities, is a negative regulator of activated hepatic stellate cells (HSC) which are overexpressed at the liver invasion front. The hypothesis that the overexpression of HSC at the liver invasion front might result from reduced expression of miR-194 was formulated. Inversely the overexpression of miR-194 might results in enhanced HSC expression which could explain why liver invasion front specific enhanced expression of miR-194 is associated with a rather poor prognosis.

Gastric cancer

 * In gastric cancer, patients with lower miR-194 expression tended to have larger tumor size and more advanced pT stage. It was shown that miR-194 expression is significantly lower in Borrmann IV type gastric cancer than in Borrmann I, II and III types. miR-194 interacts with N-cadherin and negatively regulates its expression at the translational level. Aberrant expression of N-cadherin has been proved to be associated with invasiveness of carcinoma cells and poor prognosis for gastric cancer. Therefore, miR-194 may play an antimetastatic role by negatively regulating N-cadherin expression in gastric cancer progression.

Adenocarcinoma of the esophagus

 * An elevated expression of miR-194 was found in adenocarcinoma (ADC). miR-194 is differently expressed between ADC patients with or without Barrett's. miR-194 is overexpressed in Barrett's associated ADC.

Liver cancer

 * miR-194 is highly expressed in hepatic epithelial cells, but not in mesenchymal-like cells (Kupffer cells and stellate cells). The overexpression of miR-194 in mesenchymal-like cells significantly reduce N-cadherin protein levels and the abilities in invasion and migration. The potential targets of miR-194 are genes implied in metastasis or  epithelial-mesenchymal transition like HBEGF, RAC1, PTPN12, ITGA9, SOCS2, and DNMT3A. Therefore, miR-194 may suppress metastasis of liver cancer cells by targeting several genes that function at the different stages of cancer progression and metastasis.
 * Futhermore, a protein, FZD6, has been identified as an endogenous target of miR-194. The role of FZD6 is to activate pathways which are known to promote malignancy in virus-related hepatocellular carcinoma. In tumor tissue, the expression of miR-194 is decreasing and the expression of FZD6 is increasing. The reexpression of miR-194 induce 70% inhibition of FZD6 expression.

Malignancy in FLC-4 cells

 * FLC-4 cells are human hepatoma cells. In the liver miR-194 was shown to suppress SLC7A5 gene expression, which is implicated in malignant phenotype. miR-194 is upregulated by spherical cell shape in FLC-4 cells. Therefore the enhancement of miR-194 level by spherical cell shape would suppress malignancy in FLC-4 cells

Hepatitis B virus

 * miR-194 is significantly up-regulated in hepatitis B e antigen-positive patients. But the older patients with chronic hepatitis B or acute-on-chronic liver failure, have a lower levels of miR-194.

Breast Cancer

 * miR-194 expression is increased by trastuzumab treatment in HER2 overexpressing breast cancer cells. In these cells miR-194 can significantly inhibit cell migration/invasion in vitro, and tumor growth in vivo. miR-194 directly targets the talin2 gene and downregulates talin2 protein, which is a cytoskeletal protein. Depletion of talin2 inhibits cell migration and invasion in breast cancer cells that overexpress HER2. So the upregulation of mir-194 may contribute to the anti-tumor activity of trastuzumab by downregulating talin2 protein expression and inhibiting cell migration/invasion in HER2 overexpressing breast cancer cells.

Endometrial cancer

 * The factor BMI1 induce epithelial-mesenchymal transition in endometrial cancer cells, giving them invasive capability, increasing E-cadherin and decreasing Vimentin. The role of miR-194 could be a suppressor of expression of BMI1 by direct binding to the 3' UTR. The experience demonstrates that the reexpression of miR-194 could reverse epithelial-mesenchymal transition phenotype by reducing expression of BMI1. The restoration of miR-194 expression could be an aims for the endometrial cancer therapeutic.

Multiple myeloma

 * Mdm2 is an important negative regulator of the p53 tumor suppressor and also a p53 responsive gene, this is the p53/Mdm2 autoregulatory loop. The tumor suppressor protein p53 is a key transcriptional activator of pri-miR-194-2 through directly binding to the core promoter element. When Mdm2 is inhibited, miR-194 can be transcriptionally activated by p53 and then modulate Mdm2 expression. The reintroduction of miR-194 in the multiple myeloma (MM) cells, inhibits cell growth and enhances apoptosis. The promoter region of the miR-194-2-192 cluster is hypermethylated in MM cell lines.

Chondrogenic differentiation and Osteoarthrisis

 * In humans, miR-194 level gradually decrease during Adipose-derived stem cells (ASCs) chondrogenic differentiation. SRY-related high mobility group-Box gene 5 ( Sox5) is expressed in the differentiating cartilage elements and controle the production of the cartilage extracellular matrix. Sox5 3'-UTR contains one putative miR-194 binding site, it is a target of miR-194. Sox5 expression is repressed by miR-194 at protein level. Therefore the downregulation of miR-194 leads to an upregulation of Sox5 and results in enhanced chondrogenic differentiation of ASCs.
 * In osteoarthrisis, it was found that miR-194 was upregulated and Sox5 downregulated which supresses the chondrogenic differentiation of ASCs.

Intestinal epithelial cell differentiation

 * Several miRNAs are induced during differentiation of intestinal epithelial cell, but miR-194 is one of the highly induced miRNAs. This regulation is targeted on pri-miRNAs of miR-194, but the induction of pri-miR-194-2 is higher compared with pri-miR-194-1. This process is due to up-regulation by the HNF1A. This transcription factor bind the core element of pri-miR-194-2 promoter and contribute to regulate the expression of miR-194-2.

Renal ischemia reperfusion injury

 * Renal ischemia reperfusion injury (IRI) is associated with significant morbidity and mortality. miR-194 is downregulated in IRI.

Hepatic injury

 * The expression of miR-194 is stable and detectable during hepatic injury in patients after liver transplantation.

Malaria

 * miR-194 expression in spleens and livers is significantly downregulated by Plasmodium chabaudi malaria. This downregulation is larger in livers than spleens and will be required to permit the upregulation of target genes in response to infection.

Zebrafish immunology

 * Experiences showed that overall pattern of miR-194 expression decreased in zebrafish infected by Streptococcus agalatiae and increased in zebrafish infected by Vibrio harveyi. During S.agalatiae and  V.harveyi infection, dynamic changes in miR-194 expression patterns were also observed. Experiences also revealed that miR-194 is involved in immune-related gene expression. miR-194 play important roles in zebrafish immunology.

Circadian clock

 * The core of the molecular pathway regulating circadian clock is the CLOCK/BMAL1 complex and one of his function is to induce the expression of genes which are negative regulators of the family of Period genes (PER1, PER2 and PER3) and others genes. The cluster miR-192/miR-194 targets the 3'UTR of PER genes and the overexpression of this cluster suppresses the synthesis of PER proteins, thereby causing a shortening of the length of the circadian period.