GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis
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Puja Khanna1, Pei Jou Chua1, Belinda Shu Ee Wong1, Changhong Yin2, Aye Aye Thike3, Wei Keat Wan3,4, Puay Hoon Tan3 and Gyeong Hun Baeg1
1Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
2Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA
3Division of Pathology, Singapore General Hospital, Singapore 169856, Singapore
4Academic Clinical Program for Pathology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
Gyeong Hun Baeg, email: [email protected]
Keywords: JAK/STAT signaling; GRAMD1B; gastric cancer; apoptosis; immunohistochemistry
Received: July 20, 2017 Accepted: December 03, 2017 Published: December 15, 2017
Dysregulated JAK/STAT signaling has been implicated in the molecular pathogenesis of gastric cancer. However, downstream effectors of STAT signaling that facilitate gastric carcinogenesis remain to be explored. We previously identified the Drosophila ortholog of human GRAMD1B in our genome-wide RNAi screen to identify novel components of the JAK/STAT signaling pathway in Drosophila. Here, we examined the involvement of GRAMD1B in JAK/STAT-associated gastric carcinogenesis. We found that GRAMD1B expression is positively regulated by JAK/STAT signaling and GRAMD1B inhibition decreases STAT3 levels, suggesting the existence of a positive feedback loop. Consistently, GRAMD1B and JAK/STAT 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 pSTAT3 (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 JAK/STAT-GRAMD1B regulation deepens our understanding of JAK/STAT signaling in gastric carcinogenesis and provides a foundation for the development of novel biomarkers in gastric cancer.
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