Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression

Abstract

Background: Most patients with hepatitis B virus (HBV) infection will develop hepatocellular carcinoma (HCC). This study aimed to explore the potential mechanism of miR-142-3p in HCC caused by HBV infection.Methods: HepG2 cells and M1 macrophages were cocultured and then infected with HBV to establish an in vitro model. MicroRNA (miRNA) and messenger RNA (mRNA) expression was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The protein expressions of COX2, ACSL4, PTGS2, GPX4, and NOX1 were analyzed by Western blot. Flow cytometry and TUNEL assays were used to assess cell reactive oxygen species (ROS) and ferroptosis, respectively. Cell invasion and migration were measured by Transwell assay. To evaluate the ferroptosis of M1-type macrophages, glutathione (GSH), malondialdehyde (MDA), and Fe 2+ content was detected by corresponding kits. Dual luciferase reporter gene detection verified the targeting relationship between miR-142-3p and SLC3A2.Results: MiR-142-3p was highly expressed in HBV-infected HCC patients and HBV-infected M1-type macrophages. Inhibition of miR-142-3p or overexpression of SLC3A2 reversed ferroptosis and inhibited the proliferation, migration, and invasion of HCC cells.Conclusions: Our findings indicated that miR-142-3p promoted HBV-infected M1-type macrophage ferroptosis through SLC3A2, affecting the production of GSH, MDA, and Fe 2+ and accelerating the development of HCC. The regulation of miR-142-3p and its target genes will help to clarify the pathogenesis of HCC induced by HBV infection and provide new theoretical foundations and therapeutic targets.

Polygonatum cyrtonema Hua Polysaccharides Protect BV2 Microglia Relief Oxidative Stress and Ferroptosis by Regulating NRF2/HO-1 Pathway

“…In this experiment, not only was GPX4 protein inhibited by RSL3, but ERASTIN inhibited SLC7A11 after treatment using ferroptosis inducers without PCP. Other ferroptosis-related proteins, such as ACLS4, NQO1, COX2, and NOX1, revealed specific expression upon ferroptosis [ 55 ]. It was demonstrated that NOX1 reacts with NADPH and reduces its level after the expression of PTGS2 (COX2) is activated, leading to the accumulation of ROS and thus triggering ferroptosis.…”

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

“…Moreover, miR‐142‐3p downregulated SLC3A2, which promoted the proliferation, migration, and aggression of HCC cells and induced ferroptosis in HBV‐infected M1 macrophages. [ 78 ] Glutamine synthase 2 (GLS2) played a significant role in promoting ferroptosis by increasing the conversion of glutamate to α‐ketoglutarate, consequently increasing lipid reactive oxygen species (ROS) production in HCC. [ 79 ] Additionally, the expression of Apolipoprotein C1 (APOC1) was found to be substantially higher in tumor‐associated macrophages in HCC tissues than in normal tissues.…”

Potential therapeutic applications of extracellular vesicles in the immunopathogenesis of COVID-19

“…Recently, it has been proposed that exosomal-miRNA could be considered as a biomarker to monitor patients with hepatitis B virus (HBV) infection. Hu Z, et al have shown that EVs enriched with miR-142-3p secreted by tumor cells and M1 macrophages in HBV-infected patients with hepatocellular carcinoma [67] . Furthermore, EVs derived from HCV-infected cells are composed of HCV RNA, argonaute-2 (Ago2), HSP90, and miR-122 potentially could enhance the stability of HCV RNA mediating the HCV proliferation [68] , [69] .…”