Dataset Information

Exosomal circTGFBR2 promotes hepatocellular carcinoma progression via enhancing ATG5 mediated protective autophagy.

ABSTRACT: Exosomes contribute substantially to the communication between tumor cells and normal cells. Benefiting from the stable structure, circular RNAs (circRNAs) are believed to serve an important function in exosome-mediated intercellular communication. Here, we focused on circRNAs enriched in starvation-stressed hepatocytic exosomes and further investigated their function and mechanism in hepatocellular carcinoma (HCC) progression. Differentially expressed circRNAs in exosomes were identified by RNA sequencing, and circTGFBR2 was identified and chosen for further study. The molecular mechanism of circTGFBR2 in HCC was demonstrated by RNA pulldown, RIP, dual-luciferase reporter assays, rescue experiments and tumor xenograft assay both in vitro and vivo. We confirmed exosomes with enriched circTGFBR2 led to an upregulated resistance of HCC cells to starvation stress. Mechanistically, circTGFBR2 delivered into HCC cells via exosomes serves as a competing endogenous RNA by binding miR-205-5p to facilitate ATG5 expression and enhance autophagy in HCC cells, resulting in resistance to starvation. Thus, we revealed that circTGFBR2 is a novel tumor promoter circRNA in hepatocytic exosomes and promotes HCC progression by enhancing ATG5-mediated protective autophagy via the circTGFBR2/miR-205-5p/ATG5 axis, which may be a potential therapeutic target for HCC.

SUBMITTER: Wang X

PROVIDER: S-EPMC10359294 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exosomal circTGFBR2 promotes hepatocellular carcinoma progression via enhancing ATG5 mediated protective autophagy.

Wang Xin X Dong Feng-Lin FL Wang Ying-Qiao YQ Wei Hong-Long HL Li Tao T Li Jie J

Cell death & disease 20230720 7

Exosomes contribute substantially to the communication between tumor cells and normal cells. Benefiting from the stable structure, circular RNAs (circRNAs) are believed to serve an important function in exosome-mediated intercellular communication. Here, we focused on circRNAs enriched in starvation-stressed hepatocytic exosomes and further investigated their function and mechanism in hepatocellular carcinoma (HCC) progression. Differentially expressed circRNAs in exosomes were identified by RNA ...[more]

PMID: 37474520

Similar Datasets

Project description:BackgroundHepatocellular carcinoma (HCC) is the second lethal malignancy among all cancers. Many molecular alterations have been found in HCC. However, the interactions and modulatory mechanisms among these molecules in HCC are still unclear.MethodsCTB-193M12.5 expression in tissues and cells were detected by quantitative polymerase chain reaction (qPCR). In vitro experiments were conducted to evaluate the function of CTB-193M12.5 in cell proliferation, apoptosis, migration and invasion. The interaction between CTB-193M12.5 and nuclear receptor binding SET domain-containing protein 1 (NSD1) was assessed by RNA-protein pull-down and RNA immunoprecipitation assays. The roles of CTB-193M12.5 on WNT10B and Wnt/β-catenin signaling was detected by chromatin immunoprecipitation assay, qPCR, Western blot, and dual luciferase reporter assay.ResultsWe identified a novel prognosis-related long noncoding RNA (lncRNA) CTB-193M12.5 in HCC. CTB-193M12.5 was upregulated in HCC and its high expression was correlated with alpha fetoprotein, large tumor size, aggressive clinical characteristics, and poor survival. Functional experiments showed that CTB-193M12.5 enhanced HCC cellular proliferation, suppressed HCC cellular apoptosis, and promoted HCC cellular migration and invasion. CTB-193M12.5 knockdown exerted opposite effects in HCC. Mechanistic investigation demonstrated that CTB-193M12.5 was mainly distributed in nucleus. Histone methyltransferase NSD1 was identified as a CTB-193M12.5 interactor. CTB-193M12.5 bound and recruited NSD1 to the promoter of WNT10B, leading to an increase in di-methylation of histone H3 at lysine 36 (H3K36me2) and the reduction of tri-methylation of histone H3 at lysine 27 (H3K27me3) at WNT10B promoter. Therefore, CTB-193M12.5 epigenetically activated WNT10B transcription. Through upregulating WNT10B, CTB-193M12.5 further activated Wnt/β-catenin signaling. Functional rescue experiments demonstrated that overexpression of WNT10B reversed the tumor suppressive roles of CTB-193M12.5 knockdown, while Wnt/β-catenin signaling inhibitor ICG-001 abolished the oncogenic roles of CTB-193M12.5 overexpression.ConclusionCTB-193M12.5 was a highly expressed and poor prognosis-related lncRNA in HCC. CTB-193M12.5 functioned as an oncogenic lncRNA through promoting NSD1-mediated WNT10B/Wnt/β-catenin signaling activation.

Project description:BackgroundHepatitis B virus (HBV) infection can exacerbate liver disease progression through multiple mechanisms, eventually leading to hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key regulatory protein of HBV infection, serves as a positive regulator of hepatocarcinogenesis. The indispensability of the M2 subunit of ribonucleotide-diphosphate reductase (RRM2) lies in its role in facilitating DNA replication and repair processes. In our previous investigation, it was postulated that the gene RRM2 exhibits elevated expression levels in several categories of malignant tumors, particularly in HBV-related HCC. Additionally, it was observed that RRM2 is present within protein complexes that are centered on HBx. In the present investigation, the objective of this work was to investigate the potential relationship between the elevated expression of RRM2 in HBV-related HCC and the influence of HBx on this expression. The study attempted to determine the specific mechanism by which RRM2 is implicated in the promotion of hepatocarcinogenesis by HBx. There have been multiple scholarly proposals suggesting that the induction of autophagy by HBx is a significant intermediary factor in the development of HCC. However, the precise carcinogenic function of HBx-induced autophagy remains a subject of debate.ResultsThis work initially investigated the impact of suppressing cellular autophagy on the malignant biological behaviors of HBx-promoted cells using an in vitro cellular model. The findings revealed that the suppression of cellular autophagy partially disrupted the oncogenic effects of HBx. In light of this, we proceeded to conduct more investigations into the regulatory association between RRM2 and HBx-induced autophagy in the upstream-downstream context. Our data indicate that HBx proteins increase the expression of RRM2. Suppression of RRM2 expression not only hinders HBx-induced autophagy, but also worsens the cellular G1/S blockage and reduces the HBx-induced malignant growth of hepatocellular carcinoma tumors, while stimulating apoptosis.ConclusionsTherefore, we hypothesised that RRM2 is a potential downstream target of HBx-induced hepatocarcinogenesis, and mining the oncogenic mechanism of RRM2 is significant in exploring the preventive treatment of HBV-related HCC.

Dataset Information

Exosomal circTGFBR2 promotes hepatocellular carcinoma progression via enhancing ATG5 mediated protective autophagy.

Publications

Exosomal circTGFBR2 promotes hepatocellular carcinoma progression via enhancing ATG5 mediated protective autophagy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets