An oncomir (also oncomiR) is a

microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

(miRNA) that is associated with

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. MicroRNAs are short

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

molecules about 22

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules w ...

in length. Essentially, miRNAs specifically target certain

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...

s (mRNAs) to prevent them from coding for a specific protein. The dysregulation of certain microRNAs (oncomirs) has been associated with specific cancer forming (

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

) events. Many different oncomirs have been identified in numerous types of human cancers. Oncomirs are associated with

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing benign tumor. Causes There are ...

, and

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

. Some oncomir genes are

oncogenes 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.

, 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.

General mechanism

Oncomirs cause cancer by down-regulating

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s by both translational repression and

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

destabilization mechanisms. 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. 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.

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. The term is a

portmanteau A portmanteau word, or portmanteau (, ) is a blend of words

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 Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

lymphoid-like phenotype tumors. After inactivation of miR-21, the tumors completely regressed. This addiction is part of a more general phenomenon involving oncogenes, called oncogene addiction.

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 biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

in pancreatic ductal adenocarcinoma, a form of

pancreatic The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

cancer. The study analyzed

from

biopsied A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a disea ...

pancreatic

cyst A cyst is a closed sac, having a distinct envelope and cell division, division compared with the nearby Biological tissue, tissue. Hence, it is a cluster of Cell (biology), cells that have grouped together to form a sac (like the manner in which ...

s to identify deviations in

expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

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 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

and the upregulation of miR-92a, a member of OncomiR-1. 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. (A table listing cancer type and the associated exRNA biomarker candidates can be found in ''Kosaka et al.''.)

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 loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence whe ...

s. 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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

E2F1, which may impact

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

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

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

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.

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.

miR-21

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 Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...

, breast, colorectal, lung, pancreas, skin, liver, gastric, cervical, thyroid, and various lymphatic and hematopoietic cancers. It has been found to down-regulate the tumor suppressor

PDCD4 Programmed cell death protein 4 is a protein that in humans is encoded by the ''PDCD4'' gene. It is one of the targets of an oncomiR, MIRN21. Function This gene encodes a protein localized to the nucleus in proliferating cells. Expression of t ...

, thus aiding in the cancer's invasion,

intravasation Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms ...

and metastasis.

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 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...

(SOCS1). Recent research suggests that miR-155 negatively regulates SOCS1, but may be a feasible target in breast cancer therapy.

miR-569

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 Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

cells.

Ectopic expression Ectopic is a word used with a prefix, ecto, meaning “out of place.” Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is ...

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.

List of identified oncomirs

* miR-15 * miR-16 * miR-17 * miR-18 * miR-19a * miR-19b * miR-20 * miR-21 * miR-92 * miR-125b *

miR-155 MiR-155 is a microRNA that in humans is encoded by the ''MIR155'' host gene or ''MIR155HG''. MiR-155 plays a role in various physiological and pathological processes. Exogenous molecular control ''in vivo'' of miR-155 expression may inhibit mali ...

* miR-569 * miR-196b

Anti-oncomirs

Anti-oncomirs are a class of miRNAs that negatively regulate oncogenes. 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. 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 Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene. Function MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...

, 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

nuclease A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ta ...

s that would otherwise break down the miRNAs.

References

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/ref> {{Cite journal , last1 = Babu , first1 = SG. , last2 = Ponia , first2 = S. , last3 = Kumar , first3 = D. , title = Cellular oncomiR orthologue in EBV oncogenesis , journal = Computers in Biology and Medicine , volume = 41 , issue = 10 , pages = 891–898 , date=Oct 2011 , pmid = 21880309 , doi=10.1016/j.compbiomed.2011.07.007

External links

Oncomir
A collection of databases provided by the University of Minnesota
Services Microrna Oncomir Collection
A table of the most common miRNAs found in cancer Carcinogenesis RNA