Mir-16 microRNA precursor family
Encyclopedia
The miR-16 microRNA precursor family is a group of related small non-coding RNA
genes that regulates gene expression
. miR-16, miR-15, mir-195 and miR-457 are related microRNA precursor sequences from the mir-15 gene family
(http://www.mirbase.org/cgi-bin/mirna_summary.pl?fam=MIPF0000006). This microRNA family appears to be vertebrate
specific and its members have been predicted or experimentally validated in a wide range of vertebrate species (MIPF0000006).
miR-16 precursor was discovered through detailed expression profile and Karyotype
analyses of patient
s by Calin and colleagues. Karyotyping of chromosome
structures from individuals with B-cell chronic lymphocytic leukaemias (B-CLL) found that more than half have alterations in th 13q14 region. Deletions of this well characterised 1 megabase region of the genome was also observed in approximately 50% of mantle cell lymphoma
, up to 40% of multiple myeloma
, and 60% of prostate cancer
s. Comprehensive screenings of the region at the time did not provide consistent evidence of involvement from any of the known gene
s at the time. Using CD5+
B-lymphocytes, which is known to accumulate with B-CLL progression, the minimal region lost from 13q14 region was scrutinised for regulatory elements. Publicly available sequence database
s were used to identify a gene cluster which encodes the homologue
to the human
miR15 and miR16 from the Caenorhabditis elegans
.
B-lymphocytes in CLL suggests the miR16 may be involved in cellular differentiation
. In animal model
s single-stranded microRNA species act by binding
to imperfect mRNA complements
, typically to the 3' UTR, although targets have also been observed in the coding sequence
of the mRNA. Downregulation of miR16 (as well as miR15) was observed in diffuse large B-cell lymphoma
. miR16 has been shown to bind to a nine base pair
to a complementary sequence in the 3' UTR region of BCL2, which is an anti-apoptotic
gene involved in an evolutionarily conserved pathway in programmed cell death
.
,
including malignancies of the breast
, colon
,brain
, lung
,lymphatic system
,ovaries
,pancreas
, prostate
, and stomach. This difference in expression levels can be used distinguish between cancer
ous and healthy tissues
and to determine clinical prognosis
. The fact that pathology
is associated with a different expression profile has led to the proposal that disease
specific biomarkers can provide potential targets for directed clinical intervention. More recently, there is evidence that in colorectal cancer
that the efficacy
of treatment with the monoclonal antibody cetuximab
can be assessed by the expression pattern of colorectal carcinoma
after therapy
.
miR-16 and miR-15a are clustered within a 0.5 kbp
region in Chromosome 13
(13q14) in humans, a chromosomal region shown to be deleted or down-regulated in approximately more than half of B-CLL, the most prevalent form of leukemia in adults.Carcinogenesis
is a gradual process, involving multiple genetic mutations, thus every patient with malignancy presents with a heterogeneous population of cells
. The fact that mir-16 microRNA loss is observed in a large proportion of cells indicates the change occurred early in cancer
development and a target for therapeutic intervention.
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
genes that regulates gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. miR-16, miR-15, mir-195 and miR-457 are related microRNA precursor sequences from the mir-15 gene family
Gene family
A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions...
(http://www.mirbase.org/cgi-bin/mirna_summary.pl?fam=MIPF0000006). This microRNA family appears to be vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
specific and its members have been predicted or experimentally validated in a wide range of vertebrate species (MIPF0000006).
Background
The humanHuman
Humans are the only living species in the Homo genus...
miR-16 precursor was discovered through detailed expression profile and Karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
analyses of patient
Patient
A patient is any recipient of healthcare services. The patient is most often ill or injured and in need of treatment by a physician, advanced practice registered nurse, veterinarian, or other health care provider....
s by Calin and colleagues. Karyotyping of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
structures from individuals with B-cell chronic lymphocytic leukaemias (B-CLL) found that more than half have alterations in th 13q14 region. Deletions of this well characterised 1 megabase region of the genome was also observed in approximately 50% of mantle cell lymphoma
Mantle cell lymphoma
Mantle cell lymphoma is one of the rarest of the non-Hodgkin's lymphomas , comprising about 6% of NHL cases. There are only about 15,000 patients presently in the U.S. While it is difficult to treat and seldom considered cured, investigations into better treatments are actively pursued worldwide...
, up to 40% of multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
, and 60% of prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
s. Comprehensive screenings of the region at the time did not provide consistent evidence of involvement from any of the known gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s at the time. Using CD5+
CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
B-lymphocytes, which is known to accumulate with B-CLL progression, the minimal region lost from 13q14 region was scrutinised for regulatory elements. Publicly available sequence database
Sequence database
In the field of bioinformatics, a sequence database is a large collection of computerized nucleic acid sequences, protein sequences, or other sequences stored on a computer...
s were used to identify a gene cluster which encodes the homologue
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
to the human
Human
Humans are the only living species in the Homo genus...
miR15 and miR16 from the Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
.
Gene targets
In the original publication which identified the action of miR15 and miR16 in the development of B-CLL, Calin and colleagues proposed that miR16 could be the targets with imperfect base pairing for 14 genes. Increased CD5+CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
B-lymphocytes in CLL suggests the miR16 may be involved in cellular differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. In animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s single-stranded microRNA species act by binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
to imperfect mRNA complements
Complementarity (molecular biology)
In molecular biology, complementarity is a property of double-stranded nucleic acids such as DNA, as well as DNA:RNA duplexes. Each strand is complementary to the other in that the base pairs between them are non-covalently connected via two or three hydrogen bonds...
, typically to the 3' UTR, although targets have also been observed in the coding sequence
Coding strand
When referring to DNA transcription, the coding strand is the DNA strand which has the same base sequence as the RNA transcript produced...
of the mRNA. Downregulation of miR16 (as well as miR15) was observed in diffuse large B-cell lymphoma
Diffuse large B cell lymphoma
Diffuse large B-cell lymphoma is a type of aggressive non-Hodgkin lymphoma. It accounts for approximately 40% of lymphomas among adults. The median age at diagnosis is 70 years, but it also occurs in children and young adults...
. miR16 has been shown to bind to a nine base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
to a complementary sequence in the 3' UTR region of BCL2, which is an anti-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
gene involved in an evolutionarily conserved pathway in programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
.
Clinical relevance
Altered expression of microRNA has been observed in cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
,
including malignancies of the breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, colon
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
,brain
Glioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
, lung
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
,lymphatic system
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
,ovaries
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
,pancreas
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, prostate
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, and stomach. This difference in expression levels can be used distinguish between cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
ous and healthy tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
and to determine clinical prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
. The fact that pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
is associated with a different expression profile has led to the proposal that disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
specific biomarkers can provide potential targets for directed clinical intervention. More recently, there is evidence that in colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
that the efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
of treatment with the monoclonal antibody cetuximab
Cetuximab
Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
can be assessed by the expression pattern of colorectal carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
after therapy
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
.
miR-16 and miR-15a are clustered within a 0.5 kbp
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
region in Chromosome 13
Chromosome 13 (human)
Chromosome 13 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 13 spans about 114 million base pairs and represents between 3.5 and 4 % of the total DNA in cells....
(13q14) in humans, a chromosomal region shown to be deleted or down-regulated in approximately more than half of B-CLL, the most prevalent form of leukemia in adults.Carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
is a gradual process, involving multiple genetic mutations, thus every patient with malignancy presents with a heterogeneous population of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. The fact that mir-16 microRNA loss is observed in a large proportion of cells indicates the change occurred early in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
development and a target for therapeutic intervention.