Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Март 18, 2023

Abstract Background Circular RNAs (circRNAs) can be encapsulated into exosomes to participate in intercellular communication, affecting the malignant progression of a variety tumors. Dysfunction CD8 + T cells is main factor immune escape from hepatocellular carcinoma (HCC). Nevertheless, effect exosome-derived circRNAs on T-cell dysfunction needs further exploration. Methods The circCCAR1 tumorigenesis and metastasis HCC was assessed by vitro vivo functional experiments. function measured enzyme-linked immunosorbent assay (ELISA), western blotting flow cytometry. Chromatin immunoprecipitation, biotinylated RNA pull-down, MS2 pull-down assays were used exploration mechanism. A mouse model with reconstituted human system components (huNSG mice) constructed explore role exosomal resistance anti-PD1 therapy HCC. Results Increased levels existed tumor tissues plasma patients, culture supernatant cells. CircCCAR1 accelerated growth vivo. E1A binding protein p300 (EP300) eukaryotic translation initiation 4A3 (EIF4A3) promoted biogenesis circCCAR1, Wilms 1-associated (WTAP)-mediated m6A modification enhanced stability insulin-like 2 mRNA-binding 3 (IGF2BP3). acted as sponge for miR-127-5p upregulate its target WTAP feedback loop comprising circCCAR1/miR-127-5p/WTAP axis formed. secreted heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-dependent manner. Exosomal taken caused stabilizing PD-1 protein. immunotherapy. Furthermore, increased cell division cycle apoptosis regulator 1 (CCAR1) induced EP300 CCAR1 β-catenin protein, which transcription PD-L1. Conclusions enhances released contributes immunosuppression facilitating induces immunotherapy, providing potential therapeutic strategy patients.

Язык: Английский

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Immune checkpoint inhibitor resistance in hepatocellular carcinoma

Cancer Letters, Год журнала: 2022, Номер 555, С. 216038 - 216038

Опубликована: Дек. 16, 2022

Язык: Английский

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Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Фев. 15, 2023

Abstract As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy recent years. They extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious tumor patients, become pioneer drugs since they were incorporated into practice. In addition, that infiltrated tissues found to be state exhaustion or anergy, there is upregulation many immune checkpoints (ICs) on their surface, suggesting similar ability respond ICIs as traditional effector T cells. Studies shown targeting ICs can reverse dysfunctional microenvironment (TME) exert effects by improving γδT-cell proliferation activation enhancing cytotoxicity. Clarification functional TME mechanisms underlying interaction with will solidify combined good treatment option.

Язык: Английский

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Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16484 - 16484

Опубликована: Ноя. 18, 2023

Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged new paradigm shift in oncology. ICIs, programmed cell death protein 1 (PD-1) inhibitors, provided source of hope for patients advanced HCC. Yet, the eligibility criteria HCC ICIs are still missing piece puzzle. Circular RNAs (circRNAs) recently class non-coding that play fundamental role cancer pathogenesis. Structurally, circRNAs resistant to exonucleolytic degradation longer half-life than their linear counterparts. Functionally, possess capability influence various facets tumor microenvironment, especially at tumor–immune synapse. Notably, been observed control expression molecules within cells, potentially impeding effectiveness ICIs. Therefore, this renders them potential cancer-immune biomarkers diagnosis, prognosis, regimen determinants. In review, authors shed light on structure functional roles and, most importantly, highlight promising immunomodulation

Язык: Английский

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Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Фев. 17, 2023

Circular RNAs (circRNAs) have important regulatory functions in cancer, but the role of circRNAs tumor microenvironment (TME) remains unclear. Moreover, we also explore effects si-circRNAs loaded nanoparticles as therapeutic agent for anti-tumor vivo.We conducted bioinformatics analysis, qRT-PCR, EdU assays, Transwell co-culture system and multiple orthotopic xenograft models to investigate expression function circRNAs. Additionally, PLGA-based with were used evaluate potential nanotherapeutic strategy response.We identified oncogene SERPINE2 derived circRNA, named cSERPINE2, which was notably elevated breast cancer closely related poor clinical outcome. Functionally, exosomal cSERPINE2 shuttled associated macrophages (TAMs) enhanced secretion Interleukin-6 (IL-6), leading increased proliferation invasion cells. Furthermore, IL-6 turn EIF4A3 CCL2 levels within cells a positive feedback mechanism, further enhancing biogenesis promoting recruitment TAMs. More importantly, developed nanoparticle si-cSERPINE2, effectively attenuated progression vivo.Our study illustrates novel mechanism that mediates loop between TAMs promote progression, may serve promising treatment cancer.

Язык: Английский

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Extracellular vesicles remodel tumor environment for cancer immunotherapy

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Дек. 13, 2023

Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles including exosomes have emerged therapeutic agents actively involved in a diverse range of pathological conditions. Mounting evidence suggests that alterations the quantity composition extracellular (EVs) contribute to remodeling immune-suppressive tumor microenvironment (TME), thereby influencing efficacy immunotherapy. This revelation sparked clinical interest utilizing EVs for sensitization. In this perspective article, we present comprehensive overview origins, generation, interplay among various components within TME. Furthermore, discuss pivotal role reshaping TME during tumorigenesis their specific cargo, such PD-1 non-coding RNA, which influence phenotypes critical cells Additionally, summarize applications different anti-tumor therapies, latest advancements engineering cancer immunotherapy, challenges encountered translation. light these findings, advocate broader understanding impact on TME, will unveil overlooked vulnerabilities potentially enhance existing immunotherapies.

Язык: Английский

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Liquid biopsy for human cancer: cancer screening, monitoring, and treatment

MedComm, Год журнала: 2024, Номер 5(6)

Опубликована: Май 28, 2024

Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining growth information require accurate easy-to-operate detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real-time tool detecting directly or indirectly released by tumors in human body fluids, which suitable the of new modalities. Liquid has not been widely used clinical practice, there are fewer reviews related applications. This review summarizes applications components (e.g., circulating cells, DNA, extracellular vesicles, etc.) tumorigenesis progression. includes development process techniques biopsies, early screening tumors, detection, guiding therapeutic strategies (liquid biopsy-based personalized medicine prediction response). Finally, current challenges future directions proposed. In sum, this will inspire researchers to use technology promote realization individualized therapy, improve efficacy provide better options patients.

Язык: Английский

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Cancer-derived exosomes as novel biomarkers in metastatic gastrointestinal cancer

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 1, 2024

Abstract Gastrointestinal cancer (GIC) is the most prevalent and highly metastatic malignant tumor has a significant impact on mortality rates. Nevertheless, swift advancement of contemporary technology not seamlessly aligned with evolution detection methodologies, resulting in deficit innovative efficient clinical assays for GIC. Given that exosomes are preferentially released by myriad cellular entities, predominantly originating from neoplastic cells, this confers composition enriched cancer-specific constituents. Furthermore, exhibit ubiquitous presence across diverse biological fluids, endowing them inherent advantages non-invasiveness, real-time monitoring, specificity. The unparalleled render as an ideal liquid biopsy biomarker early diagnosis, prognosticating potential development GIC metastasis. In review, we summarized latest research progress possible targets cancer-derived (CDEs) emphasis mechanisms exosome promoting metastasis, highlighting roles CDEs treatment

Язык: Английский

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Extracellular vesicles in tumor immunity: mechanisms and novel insights

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Фев. 14, 2025

Extracellular vesicles (EVs), nanoscale secreted by cells, have attracted considerable attention in recent years due to their role tumor immunomodulation. These facilitate intercellular communication transporting proteins, nucleic acids, and other biologically active substances, they exhibit a dual development immune evasion mechanisms. Specifically, EVs can assist cells evading surveillance attack impairing cell function or modulating immunosuppressive pathways, thereby promoting progression metastasis. Conversely, also transport release immunomodulatory factors that stimulate the activation regulation of system, enhancing body's capacity combat malignant diseases. This functionality presents promising avenues targets for immunotherapy. By examining biological characteristics influence on immunity, novel therapeutic strategies be developed improve efficacy relevance cancer treatment. review delineates complex immunomodulation explores potential implications approaches, aiming establish theoretical foundation provide practical insights advancement future EVs-based immunotherapy strategies.

Язык: Английский

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CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3ζ

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Сен. 22, 2022

Abstract Background Circular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development many diseases, including tumors. This study aimed to investigate potential roles circPAK1 in hepatocellular carcinoma (HCC). Methods High-throughput sequencing was performed on 3 pairs HCC matched normal tissues determine upregulated circRNAs. The expression level detected by qRT-PCR paired liver tissue samples. effects proliferation, invasion, metastasis apoptosis cells were evaluated vitro vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material evaluate its therapeutic effect HCC. sequencing, RNA-sequencing, probe pull-down, immunoprecipitation Co-Immunoprecipitation assays explore relationship between circPAK1, 14–3-3ζ, p-LATS1 YAP. Exosomes isolated from lenvatinib-resistant cell lines used exosomal lenvatinib resistance. Results CircPAK1, novel circRNA, is highly expressed tumor as well correlated poor outcomes patients. Functionally, knockdown inhibited migration, invasion angiogenesis while overexpression promoted progression. tumor-promoting phenotypes confirmed animal Importantly, application CS/si-circPAK1 showed better growth metastasis. Mechanistically, enhanced progression inactivating Hippo signaling pathway, this kind inactivation based competitively binding 14–3-3 ζ YAP, which weakens recruitment cytoplasmic fixation thus promoting YAP nucleus localization. Additionally, could be transported exosomes sensitive induce resistance receipt cells. Conclusion CircPAK1 exerts oncogenic function localization, leading pathway. Exosomal may drive lenvatinib, providing target for

Язык: Английский

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