ADAR1-mediated regulation of melanoma invasion.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Nemlich Y,Baruch EN,Besser MJ,Shoshan E,Bar-Eli M,Anafi L,Barshack I,Schachter J,Ortenberg R,Markel G

doi

10.1038/s41467-018-04600-2

subject

Has Abstract

pub_date

2018-05-31 00:00:00

pages

2154

issue

1

issn

2041-1723

pii

10.1038/s41467-018-04600-2

journal_volume

9

pub_type

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