Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Hong-Yue Ren,Wen-Ming Liu,Fan Liu,Yu Liu,Pan Zhou,Jin-Xing Shen,Gui-Li Huang,Dong-Yan Shen

doi:10.18632/oncotarget.14267

Hong-Yue Ren, Wen-Ming Liu + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.14267

Copy DOI

Abstract

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1β/Akt signaling activation, which suggested a positive feedback loop of IL-1β/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

Highlights

Gastric carcinoma (GC) is ranked as the second most common cancer and is the leading cause of cancer-related deaths in the world [1]
LY294002 could reverse the effect of retinoic acid receptor α (RARα) overexpression on the expression of PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1 (Figure 5C), which indicated that RARα might regulate the cell development and progression via activation of phosphatidylinositide 3-kinase (PI3K)/Akt signaling
Our results suggested that targeting RARα might be a potentially beneficial for treatment of gastric carcinoma (GC)

Summary

INTRODUCTION

Gastric carcinoma (GC) is ranked as the second most common cancer and is the leading cause of cancer-related deaths in the world [1]. The significance of chronic inflammation in carcinogenesis has gained more and more attention [11] Such inflammatory response seems to be regulated by many proinflammatory cytokines, that can have autocrine, paracrine and endocrine effects. Cytokine and other growth factors such as insulin, epidermal growth factor and vascular endothelial growth factor can trigger the activation of signaling pathway including phosphatidylinositide 3-kinase (PI3K)/Akt through binding to their cell surface receptors. PI3K/Akt signaling pathway regulates a variety of cellular activities, in particular, previous reports have indicated it has participated in tumorigenesis and tumor progression by promoting cell proliferation [15, 16]. Knockdown of RARα could suppress PI3K/Akt signaling, leading to inhibition metastatic abilities and increasing drug susceptibility of GC cells. We identify a positive feedback loop of IL-1β/Akt/RARα/Akt signaling, suggesting an oncogenic potential of RARα involved in the development of GC

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS