GNAI subunits differentially regulate colitis-associated tumorigenesis 4797

Abstract Description G protein alpha i (GNAI) subunits include GNAI1, GNAI2 and GNAI3. A previous study demonstrates that GNAI2 is a tumor suppressor because GNAI2 knockout mice develop spontaneous colitis and colitis-associated cancer (CAC). However, in our facilities, we have observed spontaneous colitis but not CAC phenotypes in the same GNAI2 knockout mice. To determine the relationship between GNAI subunits and CAC tumorigenesis, we have used human CAC specimens, experimental CAC mouse model, and flow cytometry, RNAseq and pharmacology approaches. We have found that GNAI3 is significantly downregulated whereas GNAI2 is upregulated in specimens of patients with CAC. Low GNAI3 or high GNAI2 expression is significantly associated with poor survival of colorectal cancer. In mice, although loss of either GNAI1 or GNAI3 results in significantly increased CAC incidences, loss of both GNAI1 and GNAI3 (GNAI1;3) leads to many more CAC tumors in the colon. The increased CAC tumorigenesis in GNAI1;3DKO mice is caused by marked increases in GNAI2 or immune checkpoint expression, activation of IL-6-NF-kB signaling and tumor-infiltrating myeloid derived suppressor cells (MDSCs). MDSC depletion compound, immune checkpoint blockade, GNAI2 loss, or GNAI2 deletion in immune cells of GNAI1;3 double knockout mice strikingly reduces MDSC tumor infiltration and CAC tumorigenesis in GNAI1;3DKO mice. Our study demonstrates that GNAI1;3 protect against whereas GNAI2 promotes CAC tumorigenesis. Funding Sources NIH U01CA188387-01, R01 AI054128 and Yao Family Professorship Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)