Origins

The miR-26 microRNA is a small

non-coding RNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non- ...

that is involved in regulating

gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...

. The miR-26 family is composed of miR-26a-1, miR-26a-2 and miR-26b located in chromosomes 3, 12 and 2, respectively. Pre-miR-26 with stem-loop structure is processed into mature miR-26 by a series of enzymes of intranuclear and intracytoplasm. The mature miRNA of miR-26a-1 and miR-26a-2 possesses the same sequence, with the exception of 2 different nucleotides in mature miR-26b. miR-26 appears to be a

vertebrate Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...

specific

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. m ...

and has now been predicted or experimentally validated in many vertebrate species
MIPF0000043
.

Expressions

miR-26 expression is induced in response to

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

and upregulated during

smooth muscle cell Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mu ...

(SMC) differentiation and

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs ...

. Moreover, miR-26 is consistently down-regulated in a wide range of malignant tumors, such as

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 th ...

nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess ( fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...

, and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

. On the contrary, miR-26a is overexpressed in high-grade

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

and

cholangiocarcinoma Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stoo ...

. Elevated expression of miR-26b has been reported in

pituitary tumor Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. and

bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become ma ...

. miR-26 is emerging as critical regulators in carcinogenesis and tumor progression by acting either as oncogenes or tumor suppressor genes in various cancers.

miR-26a roles

:Smooth muscle cell (SMC) differentiation :miRNA-26a is found to be significantly upregulated during SMC differentiation and downregulated in

abdominal aortic aneurysm Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta such that the diameter is greater than 3 cm or more than 50% larger than normal. They usually cause no symptoms, except during rupture. Occasionally, abdominal ...

(AAA) formation. Inhibition of miRNA-26a accelerates SMC differentiation, and also promotes apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunts differentiation. MicroRNA-26a targets the expression of SMAD-1 and SMAD-4, members of the

TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

superfamily signaling cascade. Inhibition of miRNA-26a increases gene expression of SMAD-1 and SMAD-4, while overexpression inhibits SMAD-1. :Hepatocellular carcinoma :miR-26a has been found to induce cell cycle arrest at the G₁ phase in human

cells, in part through direct downregulation of

cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the ''CCND2'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein ...

and

cyclin E Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase, G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphoryla ...

2. miR-26a also directly suppresses expression of

estrogen receptor alpha Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex h ...

(Erα). Overexpression of miR-26a brings about negative regulation of both cell proliferation and of the cell cycle. Therapeutic miR-26a delivery using

adeno-associated virus Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus '' Dependoparvovirus'', which in turn belongs to the family '' Parvoviridae''. They are small (approximately 26 nm in ...

(AAV) is able to inhibit cancer cell formation while also inducing tumour-specific apoptosis and providing dramatic protection from disease progression without toxicity. :Nasopharyngeal carcinoma :miR-26a is commonly downregulated in

samples and cell lines. It directly represses expression of the oncogene

EZH2 Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme (EC 2.1.1.43) encoded by gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl group ...

(enhancer of zeste homolog 2), which in turn causes inhibition of cell growth and cell-cycle progression. miR-26a again suppresses

tumorigenesis 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 abn ...

in nasopharyngeal cells ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'', with suppressed expression of

c-myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...

, cyclins D3 and E2, and cyclin-dependent kinases CDK4 and CDK6. p14^ARF and p21^CIPI CDK inhibitor expression are conversely enhanced, mediated chiefly by EZH2 expression. :Breast cancer :There is downregulation of miR-26a in breast cancer specimens and cell lines, and it has been shown to functionally antagonise human breast

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 abnor ...

. miR-26a directly regulates the expression of metadherin (MTDH) and EZH2. It further induces apoptosis, inhibition of colony formation and tumorigenesis of breast cancer cells ''in vivo''. A decrease in MTDH and EZH2 expression has been shown to be accompanied by an increase in apoptosis, whilst re-expression of MTDH partially reverses miR-26a's pro-apoptotic effect. :Lung cancer :miR-26a plays an important role as an anti-oncogene in the molecular mechanism of human lung cancer. miR-26a expression is down-regulated in human lung cancer tissues relative to normal tissues. Meanwhile, the overexpression of miR-26a in the A549 human lung cancer cell line dramatically inhibits cell proliferation, blocks G1/S phase transition, induces apoptosis, and inhibits cell metastasis and invasion in vitro. Enhancer of zeste homolog 2 (EZH2) is a potential target of miR-26a. :Glioma :miR-26a might serve as an oncogene in the carcinogenesis of

. It has been found overexpressed in a subset of high-grade gliomas and directly targets the PTEN transcript. Overexpression of miR-26a in glioma primarily results from amplification at the miR-26a-2 locus, a genomic event strongly associated with monoallelic PTEN loss.miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. :Burkitt lymphoma :miR-26a plays a role as a potential tumor-suppressor in

MYC ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes ref ...

-induced lymphoma. miR-26a is found to be downregulated in primary human

Burkitt lymphoma Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. ...

and MYC-driven lymphoma cell lines. Ectopic expression of miR-26a influences cell cycle progression by targeting the bona fide oncogene

which is a polycomb protein and global regulator of gene expression.

modulates genes important to oncogenesis via deregulation of miRNAs, miR-26a, contributes to the MYC-driven lymphomagenesis. :Human cholangiocarcinoma : miR-26a promotes

growth by inhibition of

GSK-3β Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susce ...

and subsequent activation of

β-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...

. Human cholangiocarcinoma tissues and cell lines have increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increases proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduces these parameters. Overexpression of miR-26a by cholangiocarcinoma cells increases tumor growth in severe combined immune-deficient mice. GSK-3β mRNA is a direct target of miR-26a, miR-26a-mediated reduction of GSK-3β results in activation of β-catenin and induction of several downstream genes including

c-Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...

, cyclinD1, and

peroxisome proliferator-activated receptor In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regu ...

δ. Depletion of β-catenin partially prevents miR-26a-induced tumor cell proliferation and colony formation. :Melanoma : miR-26a replacement is proposed as a potential therapeutic strategy for metastatic melanoma. mir-26a is strongly downregulated in melanoma cells compared with primary

melanocyte Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and hear ...

s. Treatment of melanoma cell lines with a miR-26a mimic promoted significant and rapid death by apoptosis. mir-26a is proposed to promote this apoptosis by repressing expression of the BAG4/Silencer of Death Domains protein (SODD) through binding the 3'UTR of SODD. [1

miR-26b roles

:Hypoxia :miR-26 is involved in responses to low oxygen levels and has been shown to suppress cell apoptosis in a hypoxia environment. A proposed mechanism for this is the direct targeting of proapoptotic protein BAK1 by miR-26. :Neuronal differentiation :The expression of genes which, upon activation, induce neural stem cell differentiation into neurons are suppressed by a group of phosphatases known as polymerase II carboxy-terminal domain small phosphatases (CTDSPs). Alongside other phosphatases, CTDSPs make up important components of a REST (repressor element 1 silencing transcription factor)/NRSF (neuron-restrictive silencer factor) protein complex. This REST/NRSF complex controls activation of the genes in turn responsible for control of neural stem cell differentiation. miR-26b, encoded in an intron of the CTDSP2

primary transcript A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs ...

, has been found to target and repress expression of CTDSP2. Mature miR-26b generation is activated during neurogenesis and there is an inactive negative feedback loop in place between miR-26b and CTDSP2 in neuronal stem cells, with inhibition of miR-26b at the precursor level. :Hepatocellular carcinoma :miR-26a/b function synergistically with their host genes,

CTDSPL CTD small phosphatase-like protein is an enzyme that in humans is encoded by the ''CTDSPL'' gene. Interactions CTDSPL has been shown to interact with SNAI1 Zinc finger protein SNAI1 (sometimes referred to as Snail) is a protein that in humans ...

CTDSP2 Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2 is an enzyme that in humans is encoded by the ''CTDSP2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendel ...

and

CTDSP1 Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 is an enzyme that in humans is encoded by the ''CTDSP1'' gene. Interactions CTDSP1 has been shown to interact Advocates for Informed Choice, dba interACT or inter ...

, to block G1/S transition by activating the

pRb The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessi ...

protein in MHCC-97L,

HepG2 Hep G2 (or HepG2) is a human liver cancer cell line. Hep G2 is an immortal cell line which was derived in 1975 from the liver tissue of a 15-year-old Caucasian male from Argentina with a well-differentiated hepatocellular carcinoma. T ...

and

HuH7 Huh7 is an immortalised cell line and may be grown in the laboratory for research purposes. According to the web site huh7.com, it is "a well differentiated hepatocyte-derived carcinoma cell line, originally taken from a liver tumor in a 57-year ...

liver cancer cells. Patients whose tumors have low miR-26 expression have shorter overall survival but a better response to

interferon α The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyt ...

therapy than do patients whose tumors have high expression of the microRNA. :Nasopharyngeal epithelial (CNE) cells :miR-26b is more than 38 fold downregulated in carcinoma of nasopharyngeal epithelia (CNE) cells under

desferrioxamine Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...

(DFOM) induced hypoxia condition. The expression levels of miR-26b and

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

protein are inversely correlated in DFOM-treated CNE cells. Overexpression of miR-26b in DFOM-treated CNE cells inhibits cell proliferation through targeting COX-2. :Breast cancer :miR-26b plays a protective role in the molecular etiology of human breast cancer by promoting apoptosis. Expression of miR-26b is decreased in human breast cancer and seven human breast cancer cell lines,

MCF7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-wor ...

, HCC1937,

MDA-MB-231 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture are used for developing new diagnostic tests and new treatments for dis ...

MDA-MB-468 MDA-MB-468 is a cell line that was isolated from a 51-year-old female human in 1977, and is commonly used in breast cancer research. MDA-MB-468 cells were extracted from a pleural effusion of mammary gland and breast tissues, and have proven useful ...

MDA-MB-453 MDA-MB-453 is a human breast cancer Cell culture#Isolation of cells, cell line. MDA-MB-453 Characteristics History The MDA-MB-453 cell cancer line was derived in 1976 from the pericardial effusion of a 48-year-old female who was suffering fr ...

, BT-549 and BT-474. Overexpression of miR-26b impairs viability and triggers apoptosis of human breast cancer MCF7 cells.

SLC7A11 Cystine/glutamate transporter is an antiporter that in humans is encoded by the ''SLC7A11'' gene. The SLC7A11 gene codes for a sodium-independent cystine-glutamate antiporter that is chloride dependent, known as system Xc- or xCT. It regulates ...

is identified as a direct target of miR-26b and its expression is remarkably increased in both breast cancer cell lines and clinical samples. :Colorectal cancer :The expression of miR-26b is significantly decreased in the

embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they cons ...

line HUES-17s and colorectal cancer (CRC) cell line

LoVo An earth oven, ground oven or cooking pit is one of the simplest and most ancient cooking structures. At its most basic, an earth oven is a pit in the ground used to trap heat and bake, smoke, or steam food. Earth ovens have been used in many pl ...

cells, compared with other three colorectal cell lines SW480,

HT29 HT-29 is a human colon cancer cell line used extensively in biological and cancer research. Characteristics Initially derived in 1964 by Jorgen Fogh from a 44-year-old Caucasian female, HT-29 cells form a tight monolayer while exhibiting similarit ...

and

Caco-2 Caco-2 (from ''Cancer coli'', "colon cancer") is an immortalized cell line of human colorectal adenocarcinoma cells. It is primarily used as a model of the intestinal epithelial barrier. In culture, Caco-2 cells spontaneously differentiate into a ...

. Overexpression of miR-26b expression by miR-26 mimics transfection leads to the significant suppression of the cell growth and the induction of apoptosis in LoVo cells in vitro, and the inhibition of tumour growth in vivo. Four genes (TAF12, PTP4A1, CHFR and ALS2CR2) with intersection are the targets of miR-26b. The regulatory pathways of miR-26b are significantly associated with the invasiveness and metastasis of CRC cells. :Glioma :miR-26b may act as a tumor suppressor in

. Low level expression of miR-26b has been found in glioma cells. The level of miR-26b is inversely correlated with the grade of glioma. EphA2 is a direct target of miR-26b. Over-expression of miR-26b in glioma cells represses the endogenous level of EphA2 protein. Ectopic expression of miR-26b inhibits the proliferation, migration, invasion and

vasculogenic mimicry __NOTOC__ Vasculogenic mimicry is the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumour cells. This process differs from angiogenesis in that it occurs ''de novo'' without the presence of endothelial ...

of human glioma cells. :Growth-hormone (GH)-producing pituitary tumors :miR-26b has been found to directly target and regulate the expression of the PTEN tumour suppressor gene, mutations of which lead to activation of a PI3K/AKT signalling pathway, increased cell survival and an onset of

oncogenesis 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 abnor ...

. The regulation of PTEN by miR-26b sees direct effects of miR-26b on pituitary cell tumour behaviour, with miR-26b inhibition suppressing pituitary tumour growth in

xenografts Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenogra ...

. Another microRNA, miR-128 microRNA precursor, miR-128, regulates expression of a BMI1 gene which suppresses PTEN expression levels by binding to its promoter region. Inhibition of miR-26b expression alongside upregulation of miR-128 suppresses the colony-forming ability and invasiveness of pituitary tumour cells.

References

External links