Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

Abstract

Aberrant STAT3 activation occurs in most human gastric cancers (GCs) and contributes to the malignant progression of GC, but mechanism(s) underlying aberrant STAT3 remain largely unknown. Here we demonstrated that the gene associated with retinoid interferon-induced mortality 19 (GRIM-19) was severely depressed or lost in GC and chronic atrophic gastritis (CAG) tissues and its loss contributed to GC tumorigenesis partly by activating STAT3 signaling. In primary human GC tissues, GRIM-19 was frequently depressed or lost and this loss correlated with advanced clinical stage, lymph node metastasis, H. pylori infection and poor overall survival of GC patients. In CAG tissues, GRIM-19 was progressively decreased along with its malignant transformation. Functionally, we indentified an oncogenic role of GRIM-19 loss in promoting GC tumorigenesis. Ectopic GRIM-19 expression suppressed GC tumor formation in vitro and in vivo by inducing cell cycle arrest and apoptosis. Moreover, we revealed that GRIM-19 inhibited STAT3 transcriptional activation and its downstream targets by reducing STAT3 nuclear distribution. Conversely, knockdown of GRIM-19 induced aberrant STAT3 activation and accelerated GC cell growth in vitro and in vivo, and this could be partly attenuated by the blockage of STAT3 activation. In addition, we observed subcellular redistributions of GRIM-19 characterized by peri-nuclear aggregates, non-mitochondria cytoplasmic distribution and nuclear invasion, which should be responsible for reduced STAT3 nuclear distribution. Our studies suggest that mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for GC development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of GC.

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…FSP is considered as a marker of fibroblasts in different organs undergoing tissue remodeling and helps to identify fibroblasts derived from EMT in several organs including the liver 5859, 60. Herein, we have shown that possible downstream targets of NFκB and STAT3 pathways including TGFβ, HGF, IL‐6, IL‐8, TNC, collagens I and III were upregulated in fibroblasts infected by H. pylori (cagA+vacA+).…”

“…FSP is considered as a marker of fibroblasts in different organs undergoing tissue remodeling and helps to identify fibroblasts derived from EMT in several organs including the liver 58. H. pylori can stimulate TLRs leading to activation of innate immunity against bacterial inflammation, thus creating an inflammatory microenvironment, a prerequisite for tumor development through activation of NF-κB and STAT3 pathways in human GC 59,60. Herein, we have shown that possible downstream targets of NFκB and STAT3 pathways including TGFβ, HGF, IL-6, IL-8, TNC, collagens I and III were upregulated in fibroblasts infected by H. pylori (cagA+vacA+).…”

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

“…As STAT3 promotes tumor progression by inducing tumor cell proliferation, inhibiting apoptosis and increasing tumor invasion and metastasis by enhancing EMT, GRIM19‐mediated STAT3 inhibition is also reported to be associated with tumor suppression in many cancers. In brief, GRIM19 expression is decreased and negatively correlates with STAT3 activation in gastric cancer, colon cancer, breast cancer, ovarian cancer, and HCC, leading to poor patient prognosis. As we show that GRIM19 expression is negatively correlated with STAT3 activation, low GRIM19 expression is the significant factor for poor prognosis in patients with HCC.…”

STAT3 Interactors as Potential Therapeutic Targets for Cancer Treatment

“…GRIM-19 is also a component of complex I in the electron transport chain and acts as a chaperone to recruit STAT3 into the inner mitochondrial membrane, thus modulating its mitochondria-specific functions [ 135 ]. Recently, Huang and colleagues suggested mitochondrial GRIM-19 as potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer [ 73 ].…”