Oncomir

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An oncomir (also oncomiR) is a microRNA (miRNA) that is associated with cancer. MicroRNAs are short RNA molecules about 22 nucleotides in length. Essentially, miRNAs specifically target certain messenger RNAs (mRNAs) to prevent them from coding for a specific protein. The dysregulation of certain microRNAs (oncomirs) has been associated with specific cancer forming (oncogenic) events. Many different oncomirs have been identified in numerous types of human cancers. [1]

Contents

Oncomirs are associated with carcinogenesis, malignant transformation, and metastasis. Some oncomir genes are oncogenes, in that overexpression of the gene leads to cancerous growth. Other oncomir genes are tumor suppressors in a normal cell, so that underexpression of the gene leads to cancerous growth. [1] [2] [3] [4]

General mechanism

Oncomirs cause cancer by down-regulating genes by both translational repression and mRNA destabilization mechanisms. [3] These down-regulated genes may code for proteins that regulate the cell's life cycle.

Oncomirs may be at increased or decreased levels within cancerous tissue. In the case of increased oncomir activity, the oncomir is likely suppressing a tumor suppressor gene. In cases of underexpressed oncomirs, regulation is attenuated, allowing the cell to proliferate freely. [5]

Viruses have also been found to have miRNA that mimic parts of natural regulatory human miRNA's. One example is the Epstein–Barr virus (EBV) which is associated with various types of cancer. [5]

History

The first link between miRNA and the growth of cancer was reported in 2002 when researchers observed a down-regulation of miR-15a and miR-16-1 in B-cell chronic lymphocytic leukemia patients. [6] The term is a portmanteau, derived from "oncogenic" + "miRNA", coined by Scott M. Hammond in a 2006 paper characterizing OncomiR-1. [1]

Oncomir addiction

Certain tumors may be "addicted" to oncomirs, meaning that in order to remain tumors, a constant concentration of oncomirs must be present. This is demonstrated by inactivation of the oncomir miR-21. Mice expressing miR-21 contracted pre-B malignant lymphoid-like phenotype tumors. After inactivation of miR-21, the tumors completely regressed. [2] This addiction is part of a more general phenomenon involving oncogenes, called oncogene addiction. [7]

Potential clinical uses of miRNA

Studies have been performed to evaluate the effectiveness of miRNAs as potential markers for cancers. MicroRNAs have shown promise in this area due to their stability and specificity to cells and tumors. A recent study investigated the use of miRNA as a biomarker in pancreatic ductal adenocarcinoma, a form of pancreatic cancer. The study analyzed RNA from biopsied pancreatic cysts to identify deviations in expression of miRNAs. The study found that 228 miRNAs were expressed differently relative to normal pancreatic cells. Included in the findings was an association between hepatocellular carcinoma and the upregulation of miR-92a, a member of OncomiR-1. [8]

Extracellular microRNAs (exRNAs) may also be useful in clinical cancer detection. For example, in a study of cancer patients with a type of lymphoma called diffuse large B-cell lymphoma (DLBCL), serum levels of three miRNA's, miR-21, miR-155 and miR-210, were higher in cancer patients than in healthy controls. In particular, patients with high expression of miR-21 were more apt to have a relapse-free survival. [9] (A table listing cancer type and the associated exRNA biomarker candidates can be found in Kosaka et al.. [10] )

Identified oncomirs

The OncomiR-1 line

The OncomiR-1 cluster of miRNA's is one of the best characterized set of mammalian miRNA oncogenes. The oncomir-1 gene, also known as mir-17-92, encodes a single mRNA transcript that folds into six stem loops. Several cancer-associated oncomirs are generated from these stem loops, including miR-17, miR-18, miR-19a, miR-20, miR-19b, and miR-92. It has been shown that miRNA's from the OncomiR-1 line inhibit cell death, thus increased expression of oncomir-1 leads to the development of tumors. The oncomir-1 products inhibit expression of the transcription factor E2F1, which may impact apoptosis via the ARF-p53 pathway. It is predicted that there are several hundred target mRNAs for each miRNA, and therefore likely many additional targets for the OncomiR-1 line [1]

OncomiR Resources and Databases

There are a few online resources and databases for collecting and annotating the oncogenic and tumor-suppressive miRNAs:

OncoMir Cancer Database Online database to access TCGA miRNA sequencing based expression data from over 10,000 tumor and normal tissues. OncomiRDB: a database for the experimentally verified oncogenic and tumor-suppressive microRNAs.

miRCancer: microRNA Cancer Association Database

HMDD: Human microRNA Disease Database

PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes

Oncomir A collection of microRNA expression databases

Characteristics and mechanisms of some well defined oncomirs

miR-17

MicroRNA-17, or miR-17, is a member of the OncomiR-1 family and one of the first miRNA to be identified as an oncogene. miR-17 has been confirmed to target the cell cycle transcription factor E2F1, a protein that not only promotes cell growth but also death. [11]

miR-19

MicroRNA-19, or miR-19, is a member of the OncomiR-1 family, and consists of three sub classifications in both humans and mice: mir-19a, mir-19b1 and miR-19b2. miR-19 has been shown to downregulate phosphatase and tensin homolog (PTEN) effectively increasing activity of the cellular survival-promoting signal pathway PI3K-Akt. [11]

miR-21

miR-21 Structure. MiR-21 Structure.gif
miR-21 Structure.

MicroRNA-21, or miR-21, a specific oncomir, becomes more abundant in human cancer. MicroRNA-21 elevation has been found in a wide variety of cancers, including glioblastoma, breast, colorectal, lung, pancreas, skin, liver, gastric, cervical, thyroid, and various lymphatic and hematopoietic cancers. [12] It has been found to down-regulate the tumor suppressor PDCD4, thus aiding in the cancer's invasion, intravasation and metastasis. [13]

miR-155

MicroRNA-155, or miR-155, is a commonly over-expressed oncomir in human cancers. In human breast cancer, it has been identified to target the gene which encodes for a protein called suppressor of cytokine signaling 1 (SOCS1). Recent research suggests that miR-155 negatively regulates SOCS1, but may be a feasible target in breast cancer therapy. [14]

miR-569

Over expression of miR-569 in breast epithelial cells leads to downregulation of a tumor suppressor gene. Cell growth increases. Pathway of carcinogenesis by miR-569.pdf
Over expression of miR-569 in breast epithelial cells leads to downregulation of a tumor suppressor gene. Cell growth increases.

A strong association has been identified between miR-569 and 3q26.2, a chromosomal locus that is amplified in some breast cancers. Altered expression of the miR-569 gene has been demonstrated to affect growth and proliferation of breast epithelial cells. Ectopic expression of miR-569 resulted in tumor cell proliferation and metastasis. This occurs through miR-569 inhibition of TP53INP1, a tumor suppressor gene. In comparison to normal tissues and less malignant tumors, TP53INP1 occurs at lower levels in more invasive cancers, presumably in part due to the role played by miR-569. [15]

List of identified oncomirs

Anti-oncomirs

Anti-oncomirs are a class of miRNAs that negatively regulate oncogenes. [16] Let-7 is the first identified anti-oncomir that functions as a "post-transcriptional-gatekeeper" of certain genes that control cell growth. For example, in lung cancer some oncogenes are down-regulated by Let-7, which functions to maintain normal cell progression. Other anti-oncomirs, including miR-143 and miR-145, have been shown to down-regulate a wide range of human cancer cell lines. [17] Tumor formation has been observed when miR-143 and miR-145 are down-regulated, particularly in colon and gastric cancer cells. When expressed in colon cancer cells, miR-143 and miR-145 are able to slow growth at the translational level by interfering with MAPK7, an enzyme responsible for cell growth. As an avenue of therapeutic research, chemical devitalization (i.e., artificial modification) of miR-143 and miR-145 may prove to be more effective version of their natural counterparts. Specifically, modified miRNAs may be imparted with increased resistance to nucleases that would otherwise break down the miRNAs.

See also

Related Research Articles

<span class="mw-page-title-main">Oncogene</span> Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

Zbtb7, whose protein product is also known as Pokemon, is a gene that functions as a regulator of cellular growth and a proto oncogene.

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans, and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs. miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002). miRNAs are initially transcribed in long transcripts called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

mir-19 microRNA precursor family

There are 89 known sequences today in the microRNA 19 (miR-19) family but it will change quickly. They are found in a large number of vertebrate species. The miR-19 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. Within the human and mouse genome there are three copies of this microRNA that are processed from multiple predicted precursor hairpins:

<span class="mw-page-title-main">MTA1</span> Protein-coding gene in the species Homo sapiens

Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

<span class="mw-page-title-main">MTDH</span> Protein-coding gene in the species Homo sapiens

Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene.

mIRN21 Non-coding RNA in the species Homo sapiens

microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.

miR-137

In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.

mir-145 Non-coding RNA in the species Homo sapiens

In molecular biology, mir-145 microRNA is a short RNA molecule that in humans is encoded by the MIR145 gene. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

mir-200

In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429. There is growing evidence to suggest that miR-200 microRNAs are involved in cancer metastasis.

mir-205 Micro RNA involved in the regulation of multiple genes

In molecular biology miR-205 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. They are involved in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes.

mir-22

In molecular biology mir-22 microRNA is a short RNA molecule. MicroRNAs are an abundant class of molecules, approximately 22 nucleotides in length, which can post-transcriptionally regulate gene expression by binding to the 3' UTR of mRNAs expressed in a cell.

mir-31

miR-31 has been characterised as a tumour suppressor miRNA, with its levels varying in breast cancer cells according to the metastatic state of the tumour. From its typical abundance in healthy tissue is a moderate decrease in non-metastatic breast cancer cell lines, and levels are almost completely absent in mouse and human metastatic breast cancer cell lines. Mir-31-5p has also been observed upregulated in Zinc Deficient rats compared to normal in ESCC and in other types of cancers when using this animal model. There has also been observed a strong encapsulation of tumour cells expressing miR-31, as well as a reduced cell survival rate. miR-31's antimetastatic effects therefore make it a potential therapeutic target for breast cancer. However, these two papers were formally retracted by the authors in 2015.

In molecular biology mir-301 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

In molecular biology mir-885 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

mIR489 Non-coding RNA in the species Homo sapiens

MicroRNA 489 is a miRNA that in humans is encoded by the MIR489 gene.

MicroRNA-125 (miR-125) is a highly conserved microRNA family consisting of miR-125a and miR-125b. MiR-125 can be found throughout diverse species from nematode to humans. MiR-125 family members are involved in cell differentiation, proliferation and apoptosis as a result of targeting messenger RNAs related to these cellular processes. By affecting these cellular processes, miR-125 can cause promotion or suppression of pathological processes including carcinogenesis, muscle abnormalities, neurological disorders and pathologies of the immune system. Moreover, miR-125 also plays an important role in normal immune functions and was described to affect development and function of immune cells as well as playing role in immunological host defense in response to bacterial and viral infections.

References

  1. 1 2 3 4 Hammond, SM. (Nov 2006). "RNAi, microRNAs, and human disease". Cancer Chemother Pharmacol. 58 (Suppl 1): s63–8. doi:10.1007/s00280-006-0318-2. PMID   17093929. S2CID   682108.
  2. 1 2 Medina, PP.; Nolde, M.; Slack, FJ. (Sep 2010). "OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma". Nature. 467 (7311): 86–90. Bibcode:2010Natur.467...86M. doi:10.1038/nature09284. PMID   20693987. S2CID   4300593.
  3. 1 2 Cheng, CJ.; Slack, FJ. (2012). "The duality of oncomiR addiction in the maintenance and treatment of cancer". Cancer J. 18 (3): 232–7. doi:10.1097/PPO.0b013e318258b75b. PMC   3369429 . PMID   22647359.
  4. ↑ "Detect microRNAs most commonly found in Cancer". SBI. Retrieved 14 February 2013.
  5. 1 2 Babu, SG.; Ponia, S.; Kumar, D. (Oct 2011). "Cellular oncomiR orthologue in EBV oncogenesis". Computers in Biology and Medicine. 41 (10): 891–898. doi:10.1016/j.compbiomed.2011.07.007. PMID   21880309.
  6. ↑ Calin, GA.; Dumitru, CD.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; et al. (Nov 2002). "Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia". Proc Natl Acad Sci U S A. 99 (24): 15524–9. Bibcode:2002PNAS...9915524C. doi: 10.1073/pnas.242606799 . PMC   137750 . PMID   12434020.
  7. ↑ Weinstein, IB. (Jul 2002). "Cancer. Addiction to oncogenes--the Achilles heal of cancer". Science. 297 (5578): 63–4. doi:10.1126/science.1073096. PMID   12098689. S2CID   23416496.
  8. ↑ Frampton, AE.; Gall, TM.; Castellano, L.; Stebbing, J.; Jiao, LR.; Krell, J. (Jan 2013). "Towards a clinical use of miRNAs in pancreatic cancer biopsies". Expert Rev Mol Diagn. 13 (1): 31–4. doi:10.1586/erm.12.136. PMID   23256701. S2CID   19443977. Full PDF
  9. ↑ Lawrie, C. H.; Gal, S.; Dunlop, H. M.; Pushkaran, B.; Liggins, A. P.; Pulford, K.; Banham, A. H.; Pezzella, F.; Boultwood, J.; Wainscoat, J. S.; Hatton, C. S. R.; Harris, A. L. (2008). "Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma". British Journal of Haematology. 141 (5): 672–675. doi: 10.1111/j.1365-2141.2008.07077.x . PMID   18318758.
  10. ↑ Kosaka, N.; Iguchi, H.; Ochiya, T. (2010). "Circulating microRNA in body fluid: A new potential biomarker for cancer diagnosis and prognosis". Cancer Science. 101 (10): 2087–2092. doi: 10.1111/j.1349-7006.2010.01650.x . PMID   20624164.
  11. 1 2 Hammond, SM. (Feb 2006). "MicroRNAs as oncogenes". Current Opinion in Genetics & Development. 16 (1): 4–9. doi:10.1016/j.gde.2005.12.005. PMID   16361094. Full PDF
  12. ↑ Krichevsky, AM.; Gabriely, G. (Jan 2009). "miR-21: a small multi-faceted RNA". J Cell Mol Med. 13 (1): 39–53. doi:10.1111/j.1582-4934.2008.00556.x. PMC   3823035 . PMID   19175699.
  13. ↑ Asangani, IA.; Rasheed, SA.; Nikolova, DA.; Leupold, JH.; Colburn, NH.; Post, S.; Allgayer, H. (Apr 2008). "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer". Oncogene. 27 (15): 2128–36. doi: 10.1038/sj.onc.1210856 . PMID   17968323.
  14. ↑ Jiang, S.; Zhang, HW.; Lu, MH.; He, XH.; Li, Y.; Gu, H.; Liu, MF.; Wang, ED. (Apr 2010). "MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene". Cancer Res. 70 (8): 3119–27. doi: 10.1158/0008-5472.CAN-09-4250 . PMID   20354188.
  15. ↑ Chaluvally-Raghavan, P.; Zhang, F.; Pradeep, S.; Hee-Dong, H.; Lu, Y.; Borresen-Dale, A. L.; Flores, E. R.; Sood, A. K.; Mills, G. B. (Dec 2012). "OncomiR-569 deregulate p53 pathway and initiate breast oncogenesis". Cancer Res. 72 (24, Supplement 3): P5–10–03. doi:10.1158/0008-5472.SABCS12-P5-10-03.
  16. ↑ Kawk, PB.; Iwasaki, S.; Tomari, Y. (Aug 2010). "The microRNA pathway and cancer". Cancer Science. 101 (11): 2309–2315. doi: 10.1111/j.1349-7006.2010.01683.x . PMID   20726859. Full PDF
  17. ↑ Kitade, Y.; Akao, Y. (Oct 2010). "MicroRNAs and Their Therapeutic Potential for Human Diseases: MicroRNAs, miR-143 and -145, Function as Anti-oncomirs and the Application of Chemically Modified miR-143 as an Anti-cancer Drug". J Pharmacol Sci. 114 (3): 276–280. doi: 10.1254/jphs.10R12FM . PMID   20953119. Full PDF
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