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MicroRNAs in cancer metastasis

MicroRNAs (miRNAs, miRs) have emerged during the recent years as an exciting novel principle of post-transcriptional control of gene expression. They constitute a large family of non-coding small RNAs which occur as single-stranded RNAs of ~22 nucleotides (nt) in length (range 19-25 nt). Their genes are mostly located witin intergenic regions, or within introns of annotated genes, and occur individually or within clusters. MiRNA-genes are transcribed by RNA polymerase II into local hairpin structures called primary microRNAs (pri-miRNAs) and these are then processed to pre-miRNAs in the nucleus by the RNAse III enzyme, Drosha, and the double stranded RNA-binding protein, Pasha. Pre-miRNAs are then exported to the cytoplasm, where they are cleaved by another RNase III type enzyme, Dicer, to generate a ~22 nt RNA duplex. One strand of the miRNA duplex is usually selected as mature miRNA, and is assembled into a silencing complex (RISC), while the other strand is degraded. Every RISC contains a single-stranded small RNA guide bound to a member of the Argonaute family of proteins. The miRNA and Argonaute protein act together to bind and silence target mRNAs. Perfectly complementary targets are efficiently silenced by the endonucleolytic cleavage activity of some Argonaute proteins, but the vast majority of predicted targets in animals are only partially paired. They bind RISC using the “seed” of the miRNA, nucleotides 2-7, and are translationally repressed and/or degraded by a pathway distinct from the endonucleolytic activity of RISC.

In the meantime, a high number of miRNAs has been linked to several processes associated with cancer. Depending on which mRNAs are targeted, miRNAs can function as both oncogenes (OncomiRs) and tumor suppressors and this comprehension has caused an immense awareness of their potential as targets or tools for cancer therapies (see, e.g., our review).

miRNA-driven molecular networks

Our specific interest for the function of miRNAs in cancer metastasis came with our observation that miR-21 is acting as a key inhibitor of tumor and metastasis suppressor Pdcd4 in colorectal cancer. We found that miR-21 is post-transcriptionally downregulating Pdcd4 expression, thereby stimulating three different steps of the metastastic cascade, invasion, intravasation, and the establishment of metastatic lesions. Consequently, we increased our interest in this area and implicated further miRNAs as novel regulators of metastasis of different carcinoma entities, e.g. miR-200c, miR-34a, or the miR-30-family, amongst others, in part also finding evidence that particular miRNAs could serve as molecular mediators or biomarkers of therapy response. Recently, together with national and international collaborators, we extended out interest to decipher miRNA-driven molecular networks driving progression and metastasis and suggested a metastatically relevant network of miR-21, miR-34a, Pdcd4, Src, and PTEN. In a recent systematic profiling approach, we discovered and validated several novel miRNAs to be significantly deregulated in resected colorectal patient metastasis tissue as compared to the matched primary tumors and corresponding normal background tissues. From these, we functionally concluded a first novel molecular network of particular miRNAs which act, at least in part, via 5 novel, in part common targets, which all culminate in EMT-regulation, orchestrating invasion, in vivo intravasation and metastasis in vivo. Comparative data in this work suggest that the network we identified might be relevant for metastasis of several different cancer entities. Ongoing research interests of our group focus on identifying genomic/epigenetic and molecular causes of miRNA-deregulation during metastasis, and on identifying (miRNA-driven) molecular networks that drive site-specific metastasis.

Selected publications

  • Asangani IA, Rasheed SAK, Nikolova D, Leupold JH, Colburn NH, Post S, Allgayer H: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis. Oncogene, 3;27(15):2128-36, 2008.
    http://www.ncbi.nlm.nih.gov/pubmed/17968323
  • Utikal J, Abba M, Novak D, Moniuszko M, Allgayer H. Function and significance of MicroRNAs in benign and malignant human stem cells. Semin Cancer Biol. 2015 Dec; 35:200-11. Review.
    http://www.ncbi.nlm.nih.gov/pubmed/26192966
  • Ceppi P, Mudduluru G, Regalla K, Rap I, Scagliotti GV, Papotti M, Allgayer H: Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small-cell lung cancer. Mol Cancer Res Sept 8(9): 1207-16, 2010.
    http://www.ncbi.nlm.nih.gov/pubmed/20696752
  • Mudduluru G, Nesson George-William JN, Muppala S, Asangani IA, Regalla K, Nelson LD, Allgayer H: Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Bioscience Reports 31(3): 185-97, 2011.
    http://www.ncbi.nlm.nih.gov/pubmed/20815812
  • Meseguer S, Mudduluru G, Escamilla JM, Allgayer H, Barettino D. Micro-RNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). Journal of Biol Biochemistry Feb 11 286(6):4150-64, 2011.
    http://www.ncbi.nlm.nih.gov/pubmed/21118818
  • Mudduluru G, Ceppi P, Regalla K, Scagliotti GV, Papotti M, Allgayer H: Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene. 2011 Jun 23; 30(25):2888-99.
    http://www.ncbi.nlm.nih.gov/pubmed/21317930
  • Muppala S, Mudduluru G, Leupold JH, Buergy D, Sleeman JP, Allgayer H. CD24 induces expression of the oncomir miR-21 via Src, and CD24 and Src are both post-transcriptionally downregulated by the tumor suppressor miR-34a. PLoS One. 2013;8(3).
    http://www.ncbi.nlm.nih.gov/pubmed/23533633
  • Mudduluru G, Abba M, Batliner J, Patil N, Scharp M, Lunavat TR, Leupold JH, Oleksiuk O, Juraeva D, Thiele W, Rothley M, Benner A, Ben-Neriah Y, Sleeman J, Allgayer H. A Systematic Approach to Defining the microRNA Landscape in Metastasis. Cancer Res. 2015 Aug 1;75(15):3010-9.
    http://www.ncbi.nlm.nih.gov/pubmed/26069251

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