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Aging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H2O2. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.
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RNA splicing is a dynamic molecular process in response to environmental stimuli and is strictly regulated by the spliceosome. Sm proteins, constituents of the spliceosome, are key components that mediate splicing reactions; however, their potential role in hepatocellular carcinoma (HCC) is poorly understood. In the study, SNRPD2 (PD2) is found to be the most highly upregulated Sm protein in HCC and to act as an oncogene. PD2 modulates DDX39A intron retention together with HNRNPL to sustain the DDX39A short variant (39A_S) expression. Mechanistically, 39A_S can mediate MYC mRNA nuclear export to maintain high MYC protein expression, while MYC in turn potentiates PD2 transcription. Importantly, digitoxin can directly interact with PD2 and has a notable cancer-suppressive effect on HCC. The study reveals a novel mechanism by which DDX39A senses oncogenic MYC signaling and undergoes splicing via PD2 to form a positive feedback loop in HCC, which can be targeted by digitoxin.
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The prevalence of alcohol-related hepatocellular carcinoma (HCC) has been increasing during the last decade. Cancer research requires cell lines suitable for both in vitro and in vivo assays. However, there is a lack of cell lines with a high in vivo metastatic capacity for this HCC subtype. Herein, a new HCC cell line was established, named HCC-ZJ, using cells from a patient diagnosed with alcohol-related HCC. The karyotype of HCC-ZJ was 46, XY, del (p11.2). Whole-exome sequencing identified several genetic variations in HCC-Z that occur frequently in alcohol-associated HCC, such as mutations in TERT, CTNNB1, ARID1A, CDKN2A, SMARCA2, and HGF. Cell counting kit-8 assays, colony formation assays, and Transwell assays were performed to evaluate the proliferation, migration, and sensitivity to sorafenib and lenvatinib of HCC-Z in vitro. HCC-ZJ showed a robust proliferation rate, a weak foci-forming ability, a strong migration capacity, and a moderate invasion tendency in vitro. Finally, the tumorigenicity and metastatic capacity of HCC-Z were evaluated using a subcutaneous xenograft model, an orthotopic xenograft model, and a tail-veil injection model. HCCZJ exhibited strong tumorigenicity in the subcutaneous xenograft and orthotopic tumor models. Moreover, HCC-ZJ spontaneously formed pulmonary metastases in the orthotopic tumor model. In summary, a new HCC cell line derived from a patient with alcohol-related HCC was established, which showed a high metastatic capacity and could be applied for in vitro and in vivo experiments during pre-clinical research.Highlights⢠An alcohol-related HCC cell line, HCC-ZJ, was established⢠HCC-ZJ was applicable for in vitro functional experiment and gene editing⢠HCC-ZJ was applicable for in vivo tumor growth and spontaneous metastasis models.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Contagem de Células , Linhagem Celular , Neoplasias Hepáticas/genética , SorafenibeRESUMO
CD103+ DC is crucial for antitumor immune response. As a promising local therapy on cancers, nanosecond pulsed electric field (nsPEF) has been widely reported to stimulate anti-tumor immune response, but the underlying relationship between intratumoral CD103+ DC and nsPEF treatment remains enigmatic. Here, we focused on the behavior of CD103+ DC in response to nsPEF treatment and explored the underlying mechanism. We found that the nsPEF treatment led to the activation and accumulation of CD103+ DC in tumor. Depletion of CD103+ DC via Batf3-/- mice demonstrated CD103+ DC was necessary for intratumoral CD8+ T cell infiltration and activation in response to nsPEF treatment. Notably, NK cells recruited CD103+ DC into nsPEF-treated tumor through CCL5. Inflammatory array revealed CD103+ DC-derived IL-12 mediated the CCL5 secretion in NK cells. In addition, the boosted activation and infiltration of intratumoral CD103+ DC were abolished by cGAS-STING pathway inhibition, following IL-12 and CCL5 decreasing. Furthermore, nsPEF treatment promoting CD103+ DC-mediated antitumor response enhanced the effects of CD47 blockade strategy. Together, this study uncovers an unprecedented role for CD103+ DC in nsPEF treatment-elicited antitumor immune response and elucidates the underlying mechanisms.
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The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.
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Poly[ADP-ribose] polymerase (PARP) inhibitors, which selectively kills homologous recombination (HR) repair-deficient cancer cells, are widely employed to treat cancer patients harboring BRCA1/2 mutations. However, they display limited efficacy in tumors with wild-type (WT) BRCA1/2. Thus, it is crucial to identify new druggable HR repair regulators and improve the therapeutic efficacy of PARP inhibitors via combination therapies in BRCA1/2-WT tumors. Here, we show that the depletion of ribonucleotide reductase (RNR) subunit p53R2 impairs HR repair and sensitizes BRCA1/2-WT cancer cells to PARP inhibition. We further demonstrate that the loss of p53R2 leads to a decrease of HR repair factor CtIP, as a result of dNTPs shortage-induced ubiquitination of CtIP. Moreover, we identify that casein kinase II (CK2) phosphorylates p53R2 at its ser20, which subsequently activates RNR for dNTPs production. Therefore, pharmacologic inhibition of the CK2-mediated phosphorylation of p53R2 compromises its HR repair capacity in BRCA1/2-WT cancer cells, which renders these cells susceptible to PARP inhibition in vitro and in vivo. Therefore, our study reveals a novel strategy to inhibit HR repair activity and convert BRCA1/2-proficient cancers to be susceptible to PARP inhibitors via synthetic lethal combination.
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BACKGROUND AIMS: Regulatory T cells (Tregs) are an obstacle to PD-1 blockade-mediated antitumor efficacy. However, the behaviors of Tregs response to anti-PD-1 in HCC and the characteristics of Tregs tissue adaptation from peripheral lymphoid tissues to the tumor are still unclear. APPROACH RESULTS: Here, we determine that PD-1 monotherapy potentially augments the accumulation of tumor CD4 + Tregs. Mechanistically, anti-PD-1 mediates Tregs proliferation in lymphoid tissues rather than in the tumor. Increased peripheral Tregs burden replenishes intratumoral Tregs, raising the ratio of intratumoral CD4 + Tregs to CD8 + T cells. Subsequently, single-cell transcriptomics revealed that neuropilin-1 (Nrp-1) supports Tregs migration behavior, and the genes of Crem and Tnfrsf9 regulate the behaviors of the terminal suppressive Tregs. Nrp-1 + 4-1BB - Tregs stepwise develop to the Nrp-1 - 4-1BB + Tregs from lymphoid tissues into the tumor. Moreover, Treg-restricted Nrp1 depletion abolishes anti-PD-1-upregulated intratumoral Tregs burden and synergizes with the 4-1BB agonist to enhance the antitumor response. Finally, a combination of the Nrp-1 inhibitor and the 4-1BB agonist in humanized HCC models showed a favorable and safe outcome and evoked the antitumor effect of the PD-1 blockade. CONCLUSION: Our findings elucidate the potential mechanism of anti-PD-1-mediated intratumoral Tregs accumulation in HCC and uncover the tissue adaptation characteristics of Tregs and identify the therapeutic potential of targeting Nrp-1 and 4-1BB for reprogramming the HCC microenvironment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linfócitos T CD8-Positivos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neuropilina-1/genética , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Bacteria are important symbionts for humans, which sustain substantial influences on our health. Interestingly, some bastrains have been identified to have therapeutic applications, notably for antitumor activity. Thereby, oncologists have developed various therapeutic models and investigated the potential antitumor mechanisms for bacteria-mediated cancer therapy (BCT). Even though BCT has a long history and exhibits remarkable therapeutic efficacy in pre-clinical animal models, its clinical translation still lags and requires further breakthroughs. This review aims to focus on the established strains of therapeutic bacteria and their antitumor mechanisms, including the stimulation of host immune responses, direct cytotoxicity, the interference on cellular signal transduction, extracellular matrix remodeling, neoangiogenesis, and metabolism, as well as vehicles for drug delivery and gene therapy. Moreover, a brief discussion is proposed regarding the important future directions for this fantastic research field of BCT at the end of this review.
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Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Processamento Alternativo/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/metabolismo , Éxons/genética , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Proteínas Repressoras/genética , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Regulação para CimaRESUMO
Tumorigenesis is frequently accompanied by chronic inflammation, and the tumor microenvironment (TME) can be considered an ecosystem that consists of tumor cells, endotheliocytes, fibroblasts, immune cells and acellular components such as extracellular matrix. For tumor cells, their survival advantages are dependent on both genetic and epigenetic alterations, while other cells mainly present epigenetic modifications. Macrophages are the most plastic type of immune cells and undergo diverse epigenetic alterations in the TME. Some of these epigenetic modifications mitigate against cancer progression, and others accelerate this process. Due to the complex roles of macrophages in the TME, it is urgent to understand their epigenetic modifications associated with the TME. Here, we mainly summarize recent findings on TME-associated epigenetic alterations of tumor-associated macrophages (TAMs), including DNA methylation, posttranslational modifications of histone proteins, chromatin remodeling, and noncoding RNA-mediated epigenetic regulation. At the end of this review, we also discuss the translational potential of these epigenetic modifications for developing novel cancer therapies targeting TAMs.
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Neoplasias/genética , Neoplasias/metabolismo , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/metabolismo , Animais , Carcinogênese , Metilação de DNA , Epigênese Genética , Humanos , Processamento de Proteína Pós-TraducionalRESUMO
PD-L1(CD274) is a well-known immunosuppressive molecule, which confers immunoescape features to cancer cells and has become one of the major targets in cancer immunotherapies. Understanding the regulatory mechanisms that control PD-L1 protein expression is important for guiding immune checkpoint blockade therapy. Here, we showed that ubiquitin specific peptidase 5 (USP5) was a novel PD-L1 deubiquitinase in non-small cell lung cancer (NSCLC) cells. USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability. Meanwhile, USP5 protein levels were highly elevated and positively correlated to PD-L1 levels in NSCLC tissues, and were closely correlated with poor prognosis of these patients. In addition, knockdown of USP5 retarded tumor growth in the Lewis lung carcinoma mouse model. Thus, we identified that USP5 was a new regulator of PD-L1 and targeting USP5 is a promising strategy for cancer therapy.
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Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Endopeptidases/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sequência de Aminoácidos , Animais , Antígeno B7-H1/química , Proliferação de Células , Regulação para Baixo , Endopeptidases/química , Feminino , Dosagem de Genes , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Prognóstico , Ligação Proteica , Estabilidade Proteica , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models, but the detailed mechanism remains unsolved. In this report, the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts. Since flagella are key inducers of the host immune response during bacterial infection, flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy. The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects, even when more bacteria were administered to offset the difference in invasion efficiency. Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5 (TLR5) signalling pathway. Indeed, we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma. Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy, thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.
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BACKGROUND: Tumor-infiltrating immune cells are important components of tumor microenvironment (TME), and their composition reflects the confrontation between host immune system and tumor cells. However, the relationship between the composition of infiltrating immune cells, prognosis, and the applicability of anti-PD-1/PD-L1 therapy in hepatocellular carcinoma (HCC) needs systematic examination. METHODS: Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was applied to evaluate the infiltration of immune cells based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) cohort. Diagnostic and prognostic models were constructed based on immune cells, and the models were validated by two external cohorts. The relationship between immune cells and PD-L1 was evaluated by Spearman correlation, and the finding was validated in our in-house HCC sample. RESULT: Patients in TCGA LIHC cohort were classified into six subtypes with different prognosis based on the proportion of tumor-infiltrating immune cells simulated via CIBERSORT. Among 22 types of immune cells, intratumoral PD-L1 mRNA level exhibited linear relationship with the fraction of five types of immune cells (M1 macrophages, plasma cells, CD8+ T cells, resting mast cells, and regulatory T cells), and M1 macrophages showed the strongest relevance (R = 0.26, p < 0.001). Immunohistochemistry of our in-house HCC specimens verified this conclusion. Moreover, intratumoral mRNA levels of M1 macrophage-associated cytokines were positively correlated with PD-L1 level. CONCLUSIONS: Our study demonstrated that the prognosis of HCC patients was associated with the pattern of infiltrating immune cells in TME, and macrophage-associated cytokines might be a potential non-invasive marker for predicting the PD-L1 level for HCC patients.
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BACKGROUND: Cancer vaccines are a promising strategy for cancer immunotherapy. Cancer vaccines elicits a specific cytotoxic immune response to tumor antigens. However, the efficacy of traditional peptide-based cancer vaccines is limited due to the inefficient delivery of antigens and adjuvants to dendritic cells (DCs). Therefore, it is necessary to develop a novel rationally designed cancer vaccine to maximize its desired effects. METHODS: A Self-assembling Vehicle-free Multi-component Antitumor nanoVaccine (SVMAV) was constructed by using an unsaturated fatty acid docosahexaenoic acid (DHA)-conjugated antigen and R848 (a Toll-like receptor 7/8 agonist) to encapsulate stattic (a signal transducer and activator of transcription 3 inhibitor). The characteristics of SVMAV were investigated. The ability of SVMAV to promote DC functions was examined by in vitro analysis. The antitumor effects of SVMAV and its combination with antiprogrammed cell death protein 1 antibody (aPD-1) were also investigated in vivo. The potential application of SVMAV for neoantigen-targeted, personalized cancer vaccines was examined in an orthotopic hepatocellular carcinoma model. RESULTS: The obtained SVMAV efficiently migrated into lymph nodes and primed CD8+ T cells for exert neoantigen-specific killing by promoting the antigen uptake by DCs, stimulating DC maturation, and enhancing antigen cross-presentation, due to the simultaneous delivery of the antigen, R848 and stattic. SVMAV could not only yield a robust antitumor effect for primary melanoma allografts, but also exert a protective effect for lung metastases. Moreover, combination treatment of SVMAV and aPD-1 exerted synergistic antitumor activity and extended the survival duration of melanoma-bearing mice. Notably, a cell line-specific neoantigen-based SVMAV was designed according to predicted neoantigens for Hepa1-6 cells to examine the potential application of SVMAV for personalized cancer vaccine. Encouragingly, neoantigen-specific SVMAV achieved stronger antitumor activity than aPD-1 in an orthotopic hepatocellular cancer model established with Hepa1-6 cells. CONCLUSIONS: In summary, this study offers an efficient codelivery platform for neoantigens and immunoregulatory compounds to enhance immune responses during cancer immune therapy.
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Vacinas Anticâncer/farmacologia , Imunoterapia/métodos , Nanopartículas/administração & dosagem , Fator de Transcrição STAT3/antagonistas & inibidores , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Células HEK293 , Humanos , Imunidade , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Glicoproteínas de Membrana/agonistas , Camundongos , Camundongos Endogâmicos C57BL , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismoRESUMO
New strategies to fabricate nanomedicines with high translational capacity are urgently desired. Herein, a new class of self-assembled drug cocktails that addresses the multiple challenges of manufacturing clinically useful cancer nanomedicines was reported. Methods: With the aid of a molecular targeted agent, dasatinib (DAS), cytotoxic cabazitaxel (CTX) forms nanoassemblies (CD NAs) through one-pot process, with nearly quantitative entrapment efficiency and ultrahigh drug loading of up to 100%. Results: Surprisingly, self-assembled CD NAs show aggregation-induced emission, enabling particle trafficking and drug release in living cells. In preclinical models of human cancer, including a patient-derived melanoma xenograft, CD NAs demonstrated striking therapeutic synergy to produce a durable recession in tumor growth. Impressively, CD NAs alleviated the toxicity of the parent CTX agent and showed negligible immunotoxicity in animals. Conclusions: Overall, this approach does not require any carrier matrices, offering a scalable and cost-effective methodology to create a new generation of nanomedicines for the safe and efficient delivery of drug combinations.
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Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Camundongos , Nanomedicina/métodos , Taxoides/farmacologiaRESUMO
Cytokinesis, the final step of mitosis, is critical for maintaining the ploidy level of cells. Cytokinesis is a complex, highly regulated process and its failure can lead to genetic instability and apoptosis, contributing to the development of cancer. Human hepatocellular carcinoma is often accompanied by a high frequency of aneuploidy and the DNA ploidy pattern observed in human hepatocellular carcinoma results mostly from impairments in cytokinesis. Many key regulators of cytokinesis are abnormally expressed in human hepatocellular carcinoma, and their expression levels are often correlated with patient prognosis. Moreover, preclinical studies have demonstrated that the inhibition of key cytokinesis regulators can suppress the growth of human hepatocellular carcinoma. Here, we provide an overview of the current understanding of the signaling networks regulating cytokinesis, the key cytokinesis regulators involved in the initiation and development of human hepatocellular carcinoma, and their applications as potential diagnostic and therapeutic biomarkers.
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Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Citocinese/fisiologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Animais , Humanos , Transdução de Sinais/fisiologiaRESUMO
The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.
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Carcinogênese/genética , Matriz Extracelular/genética , Neoplasias/genética , Microambiente Tumoral/genética , Humanos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
As the most prevalent type of mRNA modification in mammals, N6-methyladenosine (m6A) is involved in various biological processes. Accumulating studies have indicated that the deregulation of m6A RNA modification is linked to cancer and other diseases. However, its implications in hepatocellular carcinoma (HCC) remain poorly characterized. Herein, we sought to investigate the expression pattern of 13 key regulators for m6A RNA modification and to evaluate their prognostic value in HCC. First, we systematically analyzed data from The Cancer Genome Atlas (TCGA) database pertaining to patient clinical information and mRNA gene expression data. We found that 11 out of 13 key regulators for m6A RNA modification showed significantly higher expression levels in HCC. Subsequently, we identified two subgroups (clusters 1 and 2) via consensus clustering based on the expression of 13 m6A RNA methylation regulators. Cluster 2 had a worse prognosis and was also significantly correlated with higher histological grade and pathological stage when compared with cluster 1. Moreover, cluster 2 was remarkedly enriched for cancer-related pathways. We further constructed a robust risk signature of five regulators for m6A RNA modification. Further analysis indicated that this risk signature could be an independent prognostic factor for HCC, and the prognostic relevance of this five-gene risk signature was successfully validated using the Gene Expression Omnibus (GEO) dataset. Finally, we established a novel prognostic nomogram on the basis of age, gender, histological grade, pathological stage, and risk score to precisely predict the prognosis of patients with HCC. In summary, we herein uncovered the vital role of regulators for m6A RNA modification in HCC and developed a risk signature as a promising prognostic marker in HCC patients.
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Natural compounds have been confirmed as one of the most feasible solutions for hard-to-treat cancers such as hepatocellular carcinoma (HCC). Erianin, a natural bibenzyl compound from Dendrobium chrysotoxum, has been recently discovered with anticancer property in cancer cells. However, the roles and the molecular mechanisms of erianin in HCC remain unknown. The present study evaluates the effect of erianin on human HCC cells by inhibiting cell proliferation, inducing apoptotic-related cell death and hampering tumorigenicity. Furthermore, it was found that erianin could cause irreparable DNA damage, induce G2/M arrest and deregulate mitotic regulators. It was also observed that many cells with damaged DNA induced by erianin could overcome G2/M arrest and enter mitosis, leading to abnormal mitosis, and subsequently mitotic catastrophe and apoptotic-related cell death. The present study confirmed that erianin could be a potential antitumor agent for HCC clinical treatment.
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Bibenzilas/uso terapêutico , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Dano ao DNA/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Mitose/efeitos dos fármacos , Fenol/uso terapêutico , Animais , Bibenzilas/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Dano ao DNA/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Nus , Mitose/fisiologia , Fenol/farmacologiaRESUMO
Although some formats of nanomedicines are now available for clinical use, the translation of new nanoparticles to the clinic remains a considerable challenge. Here, we describe a simple yet cost-effective strategy that converts a toxic drug, cabazitaxel, into a safe and effective nanomedicine. The strategy involves the ligation of drug molecules via a self-immolating spacer, followed by dimerization-induced self-assembly to assemble stable nanoparticles. Self-assembled cabazitaxel dimers could be further refined by PEGylation with amphiphilic polymers suitable for preclinical studies. This protocol enables the formation of systemically injectable nanoparticles (termed SNPs) with nearly quantitative entrapment efficiencies and exceptionally high drug loading (> 86%). In healthy mice, PEGylated SNPs show a favorable safety profile, with reduced systemic toxicity and negligible immunotoxicity. In two separate mouse xenograft models of cancer, administration of SNPs produces efficient antitumor activity with durable tumor suppression during therapeutic studies. Overall, this methodology opens up a practical and expedient route for the fabrication of clinically useful nanomedicines, transforming a hydrophobic and highly toxic drug into a systemic self-deliverable nanotherapy. STATEMENT OF SIGNIFICANCE: Despite the great progress in cancer nanomedicines, clinical translation of nanomedicines still remains a considerable challenge. In this study, we designed a self-assembling nanoplatform based on cabazitaxel dimer reversibly ligated via a bioactivatable linker. This approach enabled the generation of systemically injectable nanomedicines with quantitative entrapment efficiencies and exceptionally high drug loading (> 86%), which greatly obviates concerns about excipient-associated side effects. Self-assembled dimeric cabazitaxel exhibited a higher safety profile than free cabazitaxel and negligible immunotoxicity in animals. This is a practical and expedient example how the chemical ligation of a hydrophobic and highly toxic anticancer drug can be leveraged to create a self-assembling delivery nanotherapy which preserves inherent pharmacologic efficacy while reduces in vivo systemic and immune toxicity.