Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy?

Abstract

MicroRNAs (miRNAs) were discovered more than a decade ago as noncoding, single-stranded small RNAs (B22 nucleotides) that control the timed gene expression pattern in Caenorhabditis elegans life cycle. A number of these evolutionarily conserved, endogenous miRNAs have been shown to regulate mammalian cell growth, differentiation and apoptosis. miRNAs are multispecific by nature. The individual miRNA is capable of modulating the expression of a network of mRNAs that it binds by imperfect sequence complementarity. Human cancers commonly exhibit an altered expression profile of miRNAs with oncogenic (miR-21, miR-106a and miR-155) or tumor-suppressive (let-7, miR-15a/16, miR-34a and miR-143/145) activity. As consistent with the natural function of miRNAs in specifying cellular phenotype, miRNA-based cancer gene therapy offers the theoretical appeal of targeting multiple gene networks that are controlled by a single, aberrantly expressed miRNA. Reconstitution of tumor-suppressive miRNA, or sequence-specific knockdown of oncogenic miRNAs by 'antagomirs,' has produced favorable antitumor outcomes in experimental models. We discuss pending issues that need to be resolved prior to the consideration of miRNA-based experimental cancer gene therapy. These include the need for definitive mRNA target validation, our incomplete understanding of rate-limiting cellular components that impact the efficiency of this posttranscriptional gene-silencing phenomenon, the possibility for nonspecific immune activation and the lack of a defined, optimal mode of delivery.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…52 microRNAs (miRNAs) are small, non-coding RNAs and post-transcriptional inhibitory regulators of gene expression. miR-143, a tumor suppressor miRNA, which is downregulated in many tumors, 66 targets HK-II mRNA. [67][68][69][70][71][72] miR-143 is also expressed in the heart where forced expression decreases the expression of HK-II.…”

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…Furthermore, the miR-449a target site is unique to the HDAC-1 3 0 UTR indicating the specificity of miR-449a to HDAC-1. Much work has been done over the past few years studying the potential for small RNAs, including miRNAs, as therapeutics (reviewed in Tong and Nemunaitis (2008)). Because a single miRNA has the potential to target a number of genes, miRNAs with potent tumor-suppressive function could be very useful in malignancies resulting from multiple genetic abnormalities.…”

MicroRNA-451 Inhibits Growth of Human Colorectal Carcinoma Cells via Downregulation of Pi3k/Akt Pathway

“…On the contrary, miRNA could be silenced by antisensing oligonucleotides and antagomirs. Regulation on miRNAs that inhibit tumor progression or on cancerogenic miRNAs may benefit the treatment of CRC and inhibit the progression of precancerous lesions (Tong and Nemunaitis 2008).…”