Khanna Puja, Chua Pei Jou, Wong Belinda Shu Ee, Yin Changhong, Thike Aye Aye, Wan Wei Keat, Tan Puay Hoon, Baeg Gyeong Hun
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
Oncotarget. 2017 Dec 15;8(70):115370-115383. doi: 10.18632/oncotarget.23265. eCollection 2017 Dec 29.
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 ortholog of human GRAMD1B in our genome-wide RNAi screen to identify novel components of the JAK/STAT signaling pathway in . 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 . 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.
JAK/STAT信号失调与胃癌的分子发病机制有关。然而，促进胃癌发生的STAT信号下游效应器仍有待探索。我们之前在全基因组RNAi筛选中鉴定出人类GRAMD1B的直系同源物，以确定JAK/STAT信号通路的新成分。在此，我们研究了GRAMD1B在JAK/STAT相关胃癌发生中的作用。我们发现GRAMD1B的表达受JAK/STAT信号正向调控，GRAMD1B抑制会降低STAT3水平，提示存在正反馈回路。一致地，GRAMD1B和JAK/STAT信号协同作用，通过上调抗凋亡分子Bcl-xL的表达来促进胃癌细胞存活。有趣的是，我们对GRAMD1B的免疫组化分析显示，随着胃组织恶变，GRAMD1B的细胞质染色逐渐减少，但核内积累增加。还发现GRAMD1B表达水平与胃癌患者的临床病理特征显著相关，尤其是肿瘤分级和淋巴结状态。此外，GRAMD1B和pSTAT3（Tyr705）在胃组织中呈正相关，从而证实这两种信号分子之间存在密切联系。关于JAK/STAT-GRAMD1B调控的这一新知识加深了我们对JAK/STAT信号在胃癌发生中的理解，并为胃癌新型生物标志物的开发提供了基础。
