Journal
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
Volume -, Issue -, Pages -Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/08923973.2023.2247552
Keywords
Withaferin A; IGF2BP3; FOXO1; ROS; JAK2/STAT3 signaling; hepatocellular carcinoma
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This study investigated the molecular mechanisms of Withaferin A (WA) in hepatocellular carcinoma (HCC). Both gene and protein expression were analyzed, and the effects on HCC cell proliferation and migration were evaluated. The findings revealed that WA inhibited HCC cell growth and migration by suppressing IGF2BP3, which resulted in ROS accumulation and activation of JAK2/STAT3 signaling via FOXO1.
Objective: This study aimed to investigate the underlying molecular mechanisms of Withaferin A (WA) in hepatocellular carcinoma (HCC).Materials and Methods: The gene and protein expression were analyzed using RT-qPCR and western blot, respectively. The proliferation of HCC cells was evaluated by CCK-8 assays. The migrative ability of HCC cells was measured by transwell assays.Results: We revealed that WA suppressed the proliferation and migration of HCC cells and inhibited IGF2BP3 (insulin like growth factor 2 mRNA binding protein 3) expression. IGF2BP3 abundance reversed the reactive oxygen species (ROS) accumulation and suppression of HCC cell proliferation and migration induced by WA. Besides, IGF2BP3 suppressed ROS production to promote the growth and migration of HCC cells. Furthermore, we found that IGF2BP3 exerted its tumor-promotive and ROS-suppressive effect on HCC cells by regulating the expression of FOXO1 (forkhead box O1). In addition, IGF2BP3-stimulated activation of JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) phosphorylation effectively decreased the transcription of FOXO1. FOXO1 abundance decreased the phosphorylation of JAK2 and STAT3 by increasing ROS level, forming a feedback loop for the inhibition of JAK2/STAT3 signaling activated by IGF2BP3.Conclusions: WA-induced ROS inhibited HCC cell growth and migration through the inhibition of IGF2BP3 to deactivate JAK2/STAT3 signaling, resulting in increased FOXO1 expression to further stimulate ROS production and inhibit JAK2/STAT3 signaling.
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