MicroRNA-34 (miR-34) is a master regulator of tumor suppression. It is downregulated in numerous cancers and inhibits malignant growth by repressing genes involved in various oncogenic signaling ...pathways. Consequently, miR-34 antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. This broad anti-oncogenic activity holds the prospect of creating a new remedy that is effective against tumor heterogeneity. This review focuses on the molecular mechanisms of miR-34-mediated tumor suppression, pharmacologies in animal models of cancer, and a status update of a miR-34 therapy that may be among the first miRNA mimics to reach the clinic.
The Promise of MicroRNA Replacement Therapy BADER, Andreas G; BROWN, David; WINKLES, Matthew
Cancer research (Chicago, Ill.),
09/2010, Volume:
70, Issue:
18
Journal Article
Peer reviewed
Open access
MicroRNAs (miRNA), a class of natural RNA-interfering agents, have recently been identified as attractive targets for therapeutic intervention. The rationale for developing miRNA therapeutics is ...based on the premise that aberrantly expressed miRNAs play key roles in the development of human disease, and that correcting these miRNA deficiencies by either antagonizing or restoring miRNA function may provide a therapeutic benefit. Although miRNA antagonists are conceptually similar to other inhibitory therapies, restoring the function of a miRNA by miRNA replacement is a less well characterized approach. Here, we discuss the specific properties of miRNA replacement and review recent examples that explored the therapeutic delivery of miRNA mimics in animal models of cancer.
The GeneMANIA Cytoscape plugin brings fast gene function prediction capabilities to the desktop. GeneMANIA identifies the most related genes to a query gene set using a guilt-by-association approach. ...The plugin uses over 800 networks from six organisms and each related gene is traceable to the source network used to make the prediction. Users may add their own interaction networks and expression profile data to complement or override the default data. Availability and Implementation: The GeneMANIA Cytoscape plugin is implemented in Java and is freely available at http://www.genemania.org/plugin/. Contact: gary.bader@utoronto.ca; quaid.morris@utoronto.ca
Despite substantial progress in understanding the cancer-signaling network, effective therapies remain scarce due to insufficient disruption of oncogenic pathways, drug resistance and drug-induced ...toxicity. This complexity of cancer defines an urgent goal for researchers and clinicians to develop novel therapeutic strategies. The discovery of microRNAs (miRNAs) provides new hope for accomplishing this task. Supported by solid evidence for a critical role in cancer and bolstered by a unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a yet large number of oncogenic factors and are, therefore, anticipated to be highly efficacious. After the completion of target validation for several candidates, the development of therapeutic miRNAs is now moving to a new stage that involves pharmacological drug delivery, preclinical toxicology and regulatory guidelines.
Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to ...simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive Kras;p53 non-small cell lung cancer mouse model and demonstrated efficacy with a combination of two tumor-suppressive microRNAs (miRNAs). Systemic nanodelivery of miR-34 and let-7 suppressed tumor growth leading to survival advantage. This combinatorial miRNA therapeutic approach engages numerous components of tumor cell-addictive pathways and highlights the ability to deliver multiple miRNAs in a safe and effective manner to target lung tissue.
The Biomolecular Interaction Network Database (BIND: http://bind.ca) archives biomolecular interaction, complex and pathway information. A web-based system is available to query, view and submit ...records. BIND continues to grow with the addition of individual submissions as well as interaction data from the PDB and a number of large-scale interaction and complex mapping experiments using yeast two hybrid, mass spectrometry, genetic interactions and phage display. We have developed a new graphical analysis tool that provides users with a view of the domain composition of proteins in interaction and complex records to help relate functional domains to protein interactions. An interaction network clustering tool has also been developed to help focus on regions of interest. Continued input from users has helped further mature the BIND data specification, which now includes the ability to store detailed information about genetic interactions. The BIND data specification is available as ASN.1 and XML DTD.
Tumor suppressor microRNAs (miRNA) provide a new opportunity to treat cancer. This approach, "miRNA replacement therapy," is based on the concept that the reintroduction of miRNAs depleted in cancer ...cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non-small-cell lung cancer. This formulation is effective when administered locally or systemically. The antioncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy into the clinic.
Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelial-to-mesenchymal transition (EMT) and therefore presumably suppress the early phases of ...metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.
Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has ...been implicated in tumorigenesis. CSCs in many tumors-including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary-have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44+ cell population, but whether miRNAs regulate CD44+ prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44+ prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44+ prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44− prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44+ prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
MicroRNAs (miRNAs) have recently emerged as an important new class of cellular regulators that control various cellular processes and are implicated in human diseases, including cancer. Here, we show ...that loss of let-7 function enhances lung tumor formation in vivo, strongly supporting the hypothesis that let-7 is a tumor suppressor. Moreover, we report that exogenous delivery of let-7 to established tumors in mouse models of non-small-cell lung cancer (NSCLC) significantly reduces the tumor burden. These results demonstrate the therapeutic potential of let-7 in NSCLC and point to miRNA replacement therapy as a promising approach in cancer treatment.
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