ADAR1-mediated regulation of melanoma invasion

Yael Nemlich, Erez Nissim Baruch, Michal Judith Besser, Einav Shoshan, Menashe Bar-Eli, Liat Anafi, Iris Barshack, Jacob Schachter, Rona Ortenberg and Gal Markel ()
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Yael Nemlich: Ella Lemelbaum Institute for Immuno-Oncology
Erez Nissim Baruch: Ella Lemelbaum Institute for Immuno-Oncology
Michal Judith Besser: Ella Lemelbaum Institute for Immuno-Oncology
Einav Shoshan: MD Anderson Cancer Center
Menashe Bar-Eli: MD Anderson Cancer Center
Liat Anafi: Sheba Medical Center
Iris Barshack: Sheba Medical Center
Jacob Schachter: Ella Lemelbaum Institute for Immuno-Oncology
Rona Ortenberg: Ella Lemelbaum Institute for Immuno-Oncology
Gal Markel: Ella Lemelbaum Institute for Immuno-Oncology

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.

Date: 2018
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DOI: 10.1038/s41467-018-04600-2

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