Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.
Cancer is a major cause of incidence rate and mortality worldwide. In recent years, cancer immunotherapy has made great progress in the preclinical and clinical treatment of advanced malignant tumors. However, cancer patients will have transient cancer suppression reaction and serious immune related adverse reactions when receiving immunotherapy. In recent years, nanoparticle-based immunotherapy, which can accurately deliver immunogens, activate antigen presenting cells (APCs) and effector cells, provides a new insight to solve the above problems. In this review, we discuss the research progress of nanomaterials in immunotherapy including nanoparticle-based delivery systems, nanoparticle-based photothermal and photodynamic immunotherapy, nanovaccines, nanoparticle-based T cell cancer immunotherapy and nanoparticle-based bacteria cancer immunotherapy. We also put forward the current challenges and prospects of immunomodulatory therapy.
Background: Hepatocellular carcinoma (HCC) is the predominant histological type of primary liver cancer, which ranks sixth among the most common human tumors. Tumor-associated macrophages (TAMs) are an important component of tumor microenvironment (TME) and the M2 macrophage polarization substantially contributes to tumor growth and metastasis. Long non-coding RNA (lncRNA) MEG3 was reported to restrain HCC development. However, whether MEG3 regulates macrophage phenotypic polarization in HCC remains unclear. Methods: Bone marrow derived macrophages (BMDMs) were treated with LPS/IFNγ and IL4/IL13 to induce the M1 and M2 macrophage polarization, respectively. M2-polarized BMDMs were simultaneously transfected with adenovirus vector overexpressing MEG3 (Adv-MEG3). Subsequently, M2-polarized BMDMs were cultured for 24 h with serum-free medium, the supernatants of which were harvested as conditioned medium (CM). HCC cell line Huh7 was cultured with CM for 24 h. F4/80 + CD68 + and F4/80 + CD206 + cell percentages in M1-and M2-polarized BMDMs were calculated using flow cytometry. Huh7 cell migration, invasion and angiogenesis were determined via Transwell assay and tube formation experiment. Nude mice were implanted with Huh7 cells and Adv-MEG3-transfected M2-polarizd BMDMs, and tumor growth and M2 macrophage polarization markers were assessed. The binding between miR-145-5p and MEG3 or disabled-2 (DAB2) was verified by luciferase reporter assay. Results: MEG3 presented lower expression in HCC tissues than in normal controls, and low expression of MEG3 was correlated to poorer prognosis of HCC patients. MEG3 expression was enhanced during LPS/IFNγ-induced M1 polarization, but was reduced during IL4/IL13-induced M2 polarization. MEG3 overexpression inhibited the expression of M2 polarization markers in both M2polarized BMDMs and mice. Mechanically, MEG3 bound with miR-145-5p to regulate DAB2 expression. Overexpressing MEG3 suppressed M2 polarization-induced HCC cell metastasis and angiogenesis by upregulating DAB2 and inhibited in vivo tumor growth. Conclusion: LncRNA MEG3 curbs HCC development by repressing M2 macrophage polarization via miR-145-5p/DAB2 axis.
As an epitranscriptomic modulation manner, N6‐methyladenosine (m6A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m6A modification affects the fate of RNAs. The potential contributions of m6A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A‐DT as an m6A‐modified RNA and confirmed three m6A sites on FAM111A‐DT. The m6A modification level of FAM111A‐DT was increased in HCC tissues and cell lines, and increased m6A level was correlated with poor survival of HCC patients. m6A modification increased the stability of FAM111A‐DT transcript, whose expression level showed similar clinical relevance to that of the m6A level of FAM111A‐DT. Functional assays found that only m6A‐modified FAM111A‐DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m6A sites on FAM111A‐DT abolished the roles of FAM111A‐DT. Mechanistic investigations found that m6A‐modified FAM111A‐DT bound to FAM111A promoter and also interacted with m6A reader YTHDC1, which further bound and recruited histone demethylase KDM3B to FAM111A promoter, leading to the reduction of the repressive histone mark H3K9me2 and transcriptional activation of FAM111A. The expression of FAM111A was positively correlated with the m6A level of FAM111A‐DT, and the expression of methyltransferase complex, YTHDC1, and KDM3B in HCC tissues. Depletion of FAM111A largely attenuated the roles of m6A‐modified FAM111A‐DT in HCC. In summary, the m6A‐modified FAM111A‐DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC.
As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.
Mesoporous polydopamine nanoparticles (MPDA NPs) are promising nanomaterials that have the prospect of clinical application for multi-strategy antitumor therapy, while the biosecurity of MPDA NPs remains indistinct. Here, transcriptome sequencing (RNA-Seq) was performed to systematically reveal the toxicity of MPDA NPs to five categories of organs after three different exposure routes, including intravenous injection, intramuscular injection, and intragastric administration. Our results uncovered that MPDA NPs could be deposited in various organs in small amounts after intravenous administration, not for the other two exposure routes. The number of differentially expressed genes (DEGs) identified in the heart, liver, spleen, lung, and kidney from the intragastric administration group was from 22 to 519. Similarly, the corresponding number was from 23 to 64 for the intramuscular injection group and was from 11 to 153 for the intravenous injection group. Functional enrichment analyses showed 6, 39, and 4 GO terms enriched for DEGs in intragastric administration, intramuscular injection, and intravenous injection groups, respectively. One enriched pathway was revealed in intragastric administration group, while no enriched pathway was found in other groups. Our results indicated that MPDA NPs produced only slight changes at the transcriptome level in mice, which provided new insights for further clinical application of MPDA NPs.
Background Macrophages are the major components of tumour microenvironment, which play critical roles in tumour development. Long noncoding RNAs (lncRNAs) also contribute to tumour progression. However, the potential roles of lncRNAs in modulating the interaction between cancer cells and macrophages in hepatocellular carcinoma (HCC) are poorly understood. Methods The expression of lncRNA ZNNT1 in tissues and cells was measured using qRT-PCR. The roles of ZNNT1 in HCC cells and macrophages were investigated using in vitro and in vivo assays. The molecular mechanisms of ZNNT1 were explored using qRT-PCR, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, enzyme linked immunosorbent assay, and dual-luciferase reporter assays. Results ZNNT1 was identified as an HCC-related lncRNA, which was upregulated and associated with poor prognosis of HCC. ZNNT1 promoted HCC cellular growth, migration, and invasion, and suppressed apoptosis in vitro. ZNNT1 promoted HCC xenograft growth in vivo. Furthermore, ZNNT1 recruited and induced M2 polarization of macrophages. Mechanistically, ZNNT1 upregulated SPP1 expression and osteopontin (OPN) secretion via sponging miR-181a/b/c/d-5p and miR-33a/b-5p. Functional rescue assays identified OPN as the mediator of the oncogenic roles of ZNNT1 in HCC cells and also the effects of ZNNT1 on macrophages. M2 Macrophages-recruited by ZNNT1 enhanced malignant phenotypes of HCC cells, which was mediated by S100A9 secreted by M2 macrophages. Intriguing, S100A9 secreted by M2 macrophages also upregulated ZNNT1 expression in HCC cells via AGER/NF-κB signaling. Conclusions ZNNT1, OPN, and S100A9 formed a positive feedback loop, which promoted macrophages recruitment and M2 polarization, and enhanced malignant features of HCC cells. The ZNNT1/OPN/S100A9 feedback loop represents potential therapeutic target for HCC.
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