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

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.

Interleukin-1 Beta—A Friend or Foe in Malignancies?

“…Chronic high-level expression of bioactive IL-1β is an important promotor of tumor development [ 209 ]. IL-1β is involved in the positive feedback loop of IL-1β/Akt/retinoic acid receptor α (RARα) signaling, and thereby transmits the oncogenic property of RARα in gastric carcinoma [ 279 ]. In transgenic mice the expression of human IL-1β induced spontaneous gastric cancer, correlating with early recruitment of MDSC to the stomach [ 236 ].…”

<p>Retinoic acid receptor &alpha; facilitates human colorectal cancer progression via Akt and MMP2 signaling</p>

“…Accumulating evidence indicates that aberrant RARα expression is a common phenomenon in multitude cancers, including leukemia, breast cancer, lung cancer, and gastric carcinoma 10,27–29. Despite the reports of the promotional role of RARα in carcinogenesis of CRC or a potential marker of prognosis in CRC,18 the exact role and expression are yet to be ascertained in CRC progression.…”