Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression

Swathi V. Iyer, Atul Ranjan, Harold K. Elias, Alejandro Parrales, Hiromi Sasaki, Badal C. Roy, Shahid Umar, Ossama W. Tawfik and Tomoo Iwakuma ()
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Swathi V. Iyer: University of Kansas Medical Center
Atul Ranjan: University of Kansas Medical Center
Harold K. Elias: Icahn School of Medicine at Mount Sinai
Alejandro Parrales: University of Kansas Medical Center
Hiromi Sasaki: University of Kansas Medical Center
Badal C. Roy: University of Kansas Medical Center
Shahid Umar: University of Kansas Medical Center
Ossama W. Tawfik: University of Kansas Medical Center
Tomoo Iwakuma: University of Kansas Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract The ability of cancer cells to survive and grow in anchorage- and serum-independent conditions is well correlated with their aggressiveness. Here, using a human whole-genome shRNA library, we identify TMIGD3 isoform1 (i1) as a factor that suppresses this ability in osteosarcoma (OS) cells, mainly by inhibiting NF-κB activity. Knockdown of TMIGD3 increases proliferation, tumour formation and metastasis of OS cells. Overexpression of TMIGD3 isoform1 (i1), but not isoform3 (i3) which shares a common C-terminal region, suppresses these malignant properties. Adenosine A3 receptor (A3AR) having an identical N-terminal region shows similar biological profiles to TMIGD3 i1. Protein expression of TMIGD3 and A3AR is lower in human OS tissues than normal tissues. Mechanistically, TMIGD3 i1 and A3AR commonly inhibit the PKA−Akt−NF-κB axis. However, TMIGD3 i1 only partially rescues phenotypes induced by A3AR knockdown, suggesting the presence of distinct pathways. Our findings reveal an unappreciated role for TMIGD3 i1 as a suppressor of NF-κB activity and OS progression.

Date: 2016
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DOI: 10.1038/ncomms13561

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