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Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor-derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV-vWF levels are found in a larger cohort of HCC-sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late-stage HCC patients markedly augment angiogenesis, tumor-endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti-vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF-overexpressing cells. sEV-vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co-administration of anti-vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient-derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor-derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor-endothelial intercellular communication.

SUBMITTER: Wong SWK

PROVIDER: S-EPMC10502836 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma.

Wong Samuel Wan Ki SWK Tey Sze Keong SK Mao Xiaowen X Fung Hiu Ling HL Xiao Zhi-Jie ZJ Wong Danny Ka Ho DKH Mak Lung-Yi LY Yuen Man-Fung MF Ng Irene Oi-Lin IO Yun Jing Ping JP Gao Yi Y Yam Judy Wai Ping JWP

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230630 26

Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor-derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV-vWF levels are found in a larger cohort of HCC-sEV samples and metastatic HCC cell lines compared to their respective normal cou ...[more]

PMID: 37387563

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Project description:BackgroundIt is well-established that most Hepatocellular carcinoma (HCC) patients die of metastasis, yet the potential mechanisms orchestrating metastasis remain poorly understood. Current evidence suggests that the dysregulation of METTL3-mediated m6A methylation modification is closely associated with cancer progression. STAT3 is an oncogenic transcription factor that reportedly plays a central role in the occurrence and development of HCC. However, the relationship between METTL3 and STAT3 in HCC metastasis remains unclear.MethodsThe relationship between METTL3 expression and the survival of HCC patients was assessed by online tools GEPIA and Kaplan-Meier Plotter. Western blotting, Tissue microarray (TMA), and immunohistochemistry (IHC) staining were used to evaluate the expression levels of METTL3 and STAT3 in HCC cell lines and metastatic and non-metastatic tissues. Methylated RNA immunoprecipitation (MeRIP), MeRIP sequencing (MeRIP-seq), qRT-PCR, RNA immunoprecipitation (RIP), Western blotting and luciferase reporter gene assay were utilized to clarify the mechanism of METTL3 regulating STAT3 expression. Immunofluorescence staining, Western blotting, qRT-PCR, Co-immunoprecipitation (Co-IP), IHC staining, TMA and Chromatin immunoprecipitation (ChIP) assay were performed to explore the mechanism of STAT3 modulating METTL3 localization. Cell viability, wound healing and transwell assay, and orthotopic xenograft model were used to evaluate the role of METTL3-STAT3 feedback loop in the promotion of HCC metastasis in vitro and in vivo.ResultsMETTL3 and STAT3 are both abundantly expressed in high-metastatic HCC cells and tissues. Moreover, a positive correlation was found between the expression of STAT3 and METTL3 in HCC tissues. Mechanistically, METTL3 could induce the m6A modification of STAT3 mRNA, and then promote the translation of m6A-contained STAT3 mRNA by interacting with the translation initiation machinery. In contrast, STAT3 promoted nuclear localization of METTL3 via transcriptionally upregulating WTAP, a vital member of the methyltransferase complex, and facilitated the methyltransferase function of METTL3. METTL3 and STAT3 form a positive feedback loop to accelerate HCC metastasis in vitro and in vivo.ConclusionsOur findings reveal a novel mechanism of HCC metastasis and uncover the METTL3-STAT3 feedback signaling as a potential target for the anti-metastatic treatment of HCC. Video Abstract.

Project description:BackgroundEmerging evidence indicates that circular RNAs (circRNAs) and m6A RNA methylation participate in the pathogenesis and metastasis of multiple malignancies including hepatocellular carcinoma (HCC). However, it remains undocumented how circRNAs form a feedback loop with the m6A modification contributing to HCC.MethodsA novel hsa_circ_0017114 (circGPR137B) was identified from three pairs of primary HCC and adjacent normal tissues by circRNA expression profiling. The association of circGPR137B and miR-4739 with clinicopathological parameters and prognosis in patients with HCC was analyzed by RT-qPCR, fluorescence in situ hybridization and TCGA cohorts. The role of circGPR137B in HCC was estimated in vitro and in vivo. RT-qPCR, western blot, m6A dot blot, RIP, MeRIP and dual-luciferase reporter assays were used to validate the reciprocal regulation of the feedback loop among circGPR137B, miR-4739 and m6A demethylase FTO. Meanwhile, the expression, function and prognosis of FTO in HCC were investigated by RT-qPCR, western blot, TCGA and rescue experiments.ResultsWe identified a new dramatically downregulated circGPR137B in HCC tissues, and found that downregulation of circGPR137B or upregulation of miR-4739 was associated with poor prognosis in patients with HCC. Ectopic expression of circGPR137B strikingly repressed the proliferation, colony formation and invasion, whereas knockdown of circGPR137B harbored the opposite effects. Moreover, restored expression of circGPR137B inhibited tumor growth and lung metastasis in vivo. Further investigations showed that circGPR137B, co-localized with miR-4739 in the cytoplasm, acted as a sponge for miR-4739 to upregulate its target FTO, which mediated m6A demethylation of circGPR137B and promoted its expression. Thus, a feedback loop comprising circGPR137B/miR-4739/FTO axis was formed. FTO suppressed cell growth and indicated favorable survival in patients with HCC.ConclusionOur results demonstrate that circGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loop. This positive feedback mechanism executed by functional coupling between a circRNA sponge and an m6A modification event suggests a model for epigenetics.

Dataset Information

Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma.

Publications

Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma.

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