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MiRNAs: the Next Generation Drugs in Human Cancer


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MiRNAs: the Next Generation Drugs in Human Cancer

In the past few years, therapeutic microRNA (miRNA) is some of the most important biopharmaceuticals that are in commercial space as future medicines. The discovery of therapeutic miRNA is considered one of the most exhilarating and significant therapeutic breakthroughs in pharmaceutical development. Therapeutic miRNAs will enter the clinic as next generation drugs and has the potential to contribute significantly to the future of medicine.

1. MiRNAs overview

The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system and it is summarized in the fact that “DNA makes RNA, which encodes protein.” Naturally occurring miRNAs are very short transcripts that never produce a protein or amino acid chain, but act by regulating protein expression during cellular processes such as growth, development and differentiation at the transcriptional, post-transcriptional and/or translational level. MiRNAs have been known to bind to messenger RNA (mRNA) at the 3’-untranslated region (UTR) and cause the downregulation of protein-coding genes.

2. MiRNAs as cancer ubiquitous players

MiRNAs that are up- or down-regulated in malignancies are respectively referred to as oncogenic or tumor-suppressor miRNAs. Functional studies performed in cancer cell lines or mouse models of various malignancies through over-expression or knockdown of miRNAs have supported a role for some of these miRNAs in tumorigenesis.

2.1. MiRNAs have been proven to work as oncogenes

Over-expression of the oncogenic mir-17-92 gene cluster led to a lymphoproliferative disorder, and higher-level expression of the cluster in MYC-driven B-cell lymphomas dramatically increased tumorigenicity[1, 2].

2.2. MiRNAs can act also as tumor suppressors

Over-expression of tumor suppressor miRNAs, such as let-7g, reduced tumor burden in a K-RAS murine lung cancer model[3]. The miR-15a/16-1-deletion has been demonstrated to accelerate the proliferation of both human and mouse B cells by modulating the expression of genes controlling cell-cycle progression[4].

Human cancer miRNA

Cancer Type
Bladder Cancer Endometrial Cancer Hepatocellular Carcinoma Lung Cancer Ovarian Cancer
Breast Cancer Gastric Cancer Immunopathology Lymphoma Pancreatic Cancer
Brain Cancer Head and Neck Cancer Inflammatory Melanoma Prostate Cancer
Colorectal Cancer Heart Disease Leukemia Muscle Disease Serum and Plasma

3. MiRNAs as diagnostics

miRNAs have been proposed as being useful in diagnostics as biomarkers for diseases and different types of cancer. miRNA expression patterns have been linked to clinical outcomes, given that miRNAs modulate tumor behavior such as tumor progression and metastasis. Expression of let-7 is downregulated in non-small cell lung cancer patients and is associated with poor prognosis[5]. Advances in miRNA detection, such as ISH or RT-PCR, may allow miRNAs to be used as diagnostic and prognostic markers in the clinic.

4. MiRNAs as therapeutics

RNA-based therapeutics has demonstrated great promise for the treatment of different diseases. Advances in delivery of miRNA inhibitors and mimics hold the promise of quickly translating our knowledge of miRNAs into treating disease. Systemic delivery of a miRNA mimic for miR-26a in a murine model of HCC reduced tumor size[6]. Systemic administration of antisense oligonucleotide therapeutics to miR-122, a liver-enriched miRNA, in mice and primates was shown to alter lipid metabolism and hepatitis C viral load, resulting in reduced liver damage[7]. MiRNA antagomirs targeting experiments have demonstrated the feasibility of manipulating miRNA levels in vivo and represent a therapeutic strategy for silencing miRNAs in disease. “miRNA sponges” have been exploited to reduce miRNA expression in mammalian cells and mouse models by using RNA transcripts expressed from strong promoters containing miRNA-complementary binding sites[8].

5. Creative Biogene is committed to providing outstanding miRNA products and comprehensive services to facilitate and simplify your miRNA investigation.

Services / Products Expressway to Discovery
miRNA expression plasmids Over-express miRNAs for function studies
miRNA mimics Mimic endogenous mature miRNA molecules
miRNA inhibitors Inhibit miRNAs for loss of function studies
microUP™ miRNA agomir Up-regulate the endogenous miRNA activity
microDOWN™ miRNA antagomir Block miRNA’s regulation of a target gene
miRNA sponge Sequester miRNAs for loss-of-function studies
miRNA 3’UTR clones miRNA target identification and functional validation of predicted targets
miRNA qPCR primer set Validated human, mouse and rat primers amplify mature miRNAs to quantitate and study their expression
MiqScript™ miRNA qRT-PCR detection kit Detect mature miRNAs and study their expression profiles

References:

  1. He L, Thomson J M, Hemann M T, et al. A microRNA polycistron as a potential human oncogene[J]. nature, 2005, 435(7043): 828.
  2. Xiao C, Srinivasan L, Calado D P, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes[J]. Nature immunology, 2008, 9(4): 405.
  3. Kumar M S, Erkeland S J, Pester R E, et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family[J]. Proceedings of the National Academy of Sciences, 2008, 105(10): 3903-3908.
  4. Klein U, Lia M, Crespo M, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia[J]. Cancer cell, 2010, 17(1): 28-40.
  5. Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis[J]. Cancer cell, 2006, 9(3): 189-198.
  6. Kota J, Chivukula R R, O'Donnell K A, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model[J]. Cell, 2009, 137(6): 1005-1017.
  7. Krützfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’[J]. Nature, 2005, 438(7068): 685.
  8. Ebert M S, Sharp P A. MicroRNA sponges: progress and possibilities[J]. Rna, 2010, 16(11): 2043-2050.

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