Héctor Herranz1,5, Xin Hong1,2,5, Nguyen Thanh Hung3, P. Mathijs Voorhoeve3,4, and Stephen M Cohen1,2
1 - Institute of Molecular and Cell Biology, Singapore 138673, Singapore
2 - Department of Biological Sciences, National University of Singapore, Singapore 119613, Singapore
3 - Duke-NUS (National University of Singapore) Graduate Medical School, Singapore 169857, Singapore
4 - Department of Biochemistry, National University of Singapore, Singapore 119613, Singapore.
5 - These authors contributed equally to this work.
Published in Genes & Development on 15 July 2012.
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MicroRNAs (miRNAs) are emerging as cooperating factors that promote the activity of oncogenes in tumor formation and disease progression. This poses the challenge of identifying the miRNA targets responsible for these interactions. In this study, we identify the growth regulatory miRNA bantam and its target, Socs36E, as cooperating factors in EGFR-driven tumorigenesis and metastasis in a Drosophila model of epithelial transformation. bantam promotes growth by limiting expression of Socs36E, which functions as a negative growth regulator. Socs36E has only a modest effect on growth on its own, but behaves as a tumor suppressor in combination with EGFR activation. The human ortholog of SOCS36E, SOCS5, behaves as a candidate tumor suppressor in cellular transformation in cooperation with EGFR/RAS pathway activation.
Depletion of Socs36E leads to malignant transformation of tissue overexpressing EGFR. (A) Optical cross-sections of third instar wing discs labeled with DAPI to show the nuclei (blue), anti-DE-cadherin (red), and Dlg (green). (B) Histogram showing mRNA levels of mmp1 and snail measured by quantitative real time PCR. RNA was prepared from discs of the indicated genotypes. Data were normalized to rp49. The data show mean +- SD from three technical replicates of a representative experiment. Comparable results were obtained in independent experiments. (C) Two images of the same host fly implanted with fragments of an apG4 UASEGFR, UAS-GFP, UAS-Socs36ERNAi wing imaginal disc at 1 d and 15 d after implantation of the GFP-labeled disc fragment (white arrowhead). (D) Summary of the results of disc fragment injection experiments. (E) Examples of GFP-positive metastases found in the eye (left) and invading the gut (right).
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