Nemlich Yael, Besser Michal J, Schachter Jacob, Markel Gal
Ella Lemelbaum Institute for Immuno-Oncology Israel.
Sackler Faculty of Medicine, Department of Clinical Microbiology and Immunology Tel Aviv 69978, Israel.
Am J Cancer Res. 2020 Aug 1;10(8):2677-2686. eCollection 2020.
Melanoma cells utilize multiple mechanisms to exit the primary tumor mass, invade the surroundings and subsequently distant tissues. We have previously reported that the expression of the RNA editing enzyme ADAR1 (adenosine deaminase acting on RNA) is downregulated in metastatic melanoma, which facilitates proliferation and invasion. Here we show that ADAR1 controls melanoma invasiveness by regulating ITGB3 expression via miR-30a and miR-30d. ADAR1 overexpression or knockdown leads to an increase or decrease, respectively, in the expression of both microRNAs. The effect is independent of RNA-editing. Dual luciferase assays show that both microRNAs directly regulate the expression of the ITGB3 integrin. Overexpression of the miR-30a or miR-30d lead to a decrease in ITGB3 and a resultant decreased invasive and metastatic capacities. Neutralization of the endogenous miR-30a or miR-30d leads to the opposite effect. The microRNAs regulate ITGB3 levels probably through a post-transcriptional effect, as both mRNA and protein levels of ITGB3 are affected. These results further expand our knowledge on the ADAR1-ITGB3 network and its central role in acquisition of the invasive phenotype of metastatic melanoma.
黑色素瘤细胞利用多种机制脱离原发性肿瘤块，侵入周围组织并随后转移至远处组织。我们之前报道过，RNA编辑酶ADAR1（作用于RNA的腺苷脱氨酶）的表达在转移性黑色素瘤中下调，这促进了细胞增殖和侵袭。在此我们表明，ADAR1通过经由miR - 30a和miR - 30d调节ITGB3的表达来控制黑色素瘤的侵袭性。ADAR1的过表达或敲低分别导致这两种微小RNA的表达增加或减少。该效应与RNA编辑无关。双荧光素酶测定表明，这两种微小RNA均直接调节整合素ITGB3的表达。miR - 30a或miR - 30d的过表达导致ITGB3减少，进而导致侵袭和转移能力下降。内源性miR - 30a或miR - 30d的中和则产生相反的效果。这些微小RNA可能通过转录后效应调节ITGB3水平，因为ITGB3的mRNA和蛋白质水平均受到影响。这些结果进一步扩展了我们对ADAR1 - ITGB3网络及其在转移性黑色素瘤侵袭表型获得中的核心作用的认识。
