GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis.

Dysregulated signaling has been implicated in the molecular pathogenesis of gastric cancer. However, downstream effectors of signaling that facilitate gastric carcinogenesis remain to be explored. We previously identified the Drosophila ortholog of human GRAMD1B in our genome-wide screen to identify novel components of the JAK/duanyu1813 signaling pathway in Drosophila. Here, we examined the involvement of GRAMD1B in gastric carcinogenesis. We found that GRAMD1B expression is positively regulated by JAK/duanyu1813 signaling and GRAMD1B inhibition decreases levels, suggesting the existence of a positive feedback loop. Consistently, GRAMD1B and JAK/duanyu1813 signaling acted synergistically to promote gastric cancer cell survival by upregulating the expression of the anti-apoptotic molecule Bcl-xL. Interestingly, our immunohistochemical analysis for GRAMD1B revealed a gradual loss of cytoplasmic staining but an increase in the nuclear accumulation of GRAMD1B, as gastric tissue becomes malignant. GRAMD1B expression levels were also found to be significantly associated with clinicopathological features of the gastric cancer patients, particularly the tumor grades and lymph node status. Moreover, GRAMD1B and (Tyr705) showed a positive correlation in gastric tissues, thereby confirming the existence of a close link between these two signaling molecules in vivo. This new knowledge about regulation deepens our understanding of JAK/duanyu1813 signaling in gastric carcinogenesis and provides a foundation for the development of novel biomarkers in gastric cancer.

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