MiR-296 regulation of a cell polarity-cell plasticity module controls tumor progression

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Oncogene (Impact Factor: 8.46). 06/2011; 31(1):27-38. DOI: 10.1038/onc.2011.209
Source: PubMed


The expression of small, non-coding RNA, or microRNAs (miR), is frequently deregulated in human cancer, but how these pathways affect disease progression is still largely elusive. Here, we report on a microRNA, miR-296, which is progressively lost during tumor progression, and correlates with metastatic disease in colorectal, breast, lung, gastric, parathyroid, liver and bile ducts cancers. Functionally, miR-296 controls a global cell motility gene signature in epithelial cells by transcriptionally repressing the cell polarity-cell plasticity module, Scrib. In turn, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration, and tumor cell invasiveness. Re-expression of miR-296 in MDA-MB231 cells inhibits tumor growth, in vivo. Finally, miR-296 or Scrib levels predict tumor relapse in hepatocellular carcinoma patients.
These data identify miR-296 as a global repressor of tumorigenicity, and uncover a previously unexplored exploitation of Scrib in tumor progression in humans.

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Available from: Valentina Vaira
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    • "Of the 375 miRNAs assayed by TaqMan miRNA Array, 125 showed enrichment in the renal stroma and its derivatives based on C T cutoff value of <30 (Fig. 7A) (Table S3). These miRNAs included several miRNAs involved in vascular development (miRs-34a, 126, 145, 296-5p 302a, and 320) (Jeyaseelan et al. 2008; Cordes et al. 2009; Larsson et al. 2009; Liu et al. 2009; Pang et al. 2010; Vaira et al. 2012), members of the miR-17~92 cluster (miRs-17, 19a, 19b, 20a, 20b, 92a), and apoptosis-related miRNAs (miRs-10a, 17 and 106) (Ho et al. 2011) (Fig. 7B). To validate the miRNA profiling data, we performed locked nucleic acid section in situ hybridization (LNA-SISH) and corroborated the expression for miRs-320a, 34a, 126, and 145 (Fig. 7C). "
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    • "Each step was performed at room temperature. Neoplastic lesions were isolated and separated from the normal lung tissue using the LMD 6000 system (Leica Microsystems), as previously described [23]. Microdissected samples were collected into the cap of 0.2-ml microcentrifuge tubes and stored at 4°C. "
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    • "Mir-485 can inhibit breast cancer migration, in addition to inhibition of colony formation in vitro [76]. Mir-296 inhibits Scrib, a regulator of cell motility, thus inhibiting growth in vivo, and repression of this micro-RNA increases tumor invasiveness in vitro [77]. Invasion and adhesion to extracellular matrix is an essential mechanism for metastasis development, and inhibition of this step may result in the low total metastatic burden observed in oligometastases by preventing colonization of distant organs by circulating tumor cells (Fig. 5). "
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