GRAM DOMAIN-CONTAINING PROTEIN 1B (GRAMD1B) AS A NOVEL REGULATOR OF JAK/STAT SIGNALING MEDIATED TUMORIGENESIS

Abstract

Dysregulated JAK/STAT signaling has been implicated in tumorigenesis, but the mechanisms underlying it are poorly understood. We previously identified the Drosophila ortholog of GRAMD1B as a novel component of the JAK/STAT pathway. Here, we explored its role in JAK/STAT-mediated tumorigenesis. In gastric cancer cells, GRAMD1B expression was found to be positively regulated by JAK/STAT signaling, and GRAMD1B inhibition decreased STAT3 levels, suggesting a positive-feedback loop. Consistently, GRAMD1B acted synergistically with JAK/STAT signaling to promote gastric cancer cell survival by upregulating Bcl-xL expression. Moreover, immunohistochemical analyses confirmed positive correlation between GRAMD1B and phospho-STAT3 expression in gastric tissues. GRAMD1B levels were also found to be regulated by JAK/STAT signaling in breast cancer cells. Its inhibition caused morphological changes and enhanced breast cancer cell migration via JAK2/STAT3 and Akt activation. Taken together, we have identified GRAMD1B as a novel regulator of JAK/STAT-mediated tumorigenesis, thereby providing a foundation for its development as a biomarker.