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Background Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC). Methods Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms. Results THP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells. Conclusions We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC.

Background Cisplatin resistance is a major challenge for advanced head and neck cancer (HNC). Understanding the underlying mechanisms and developing effective strategies against cisplatin resistance are highly desired in the clinic. However, how tumor stroma modulates HNC growth and chemoresistance is unclear. Results We show that cancer-associated fibroblasts (CAFs) are intrinsically resistant to cisplatin and have an active role in regulating HNC cell survival and proliferation by delivering functional miR-196a from CAFs to tumor cells via exosomes. Exosomal miR-196a then binds novel targets, CDKN1B and ING5, to endow HNC cells with cisplatin resistance. Exosome or exosomal miR-196a depletion from CAFs functionally restored HNC cisplatin sensitivity. Importantly, we found that miR-196a packaging into CAF-derived exosomes might be mediated by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Moreover, we also found that high levels of plasma exosomal miR-196a are clinically correlated with poor overall survival and chemoresistance. Conclusions The present study finds that CAF-derived exosomal miR-196a confers cisplatin resistance in HNC by targeting CDKN1B and ING5, indicating miR-196a may serve as a promising predictor of and potential therapeutic target for cisplatin resistance in HNC.

In recent years, multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise in nanomedicine. In this study, we report the environmentally friendly synthesis of fluorescent carbon nano-dots such as carbon quantum dots (CQDs) by microplasma using o-phenylenediamine. The produced CQDs exhibited a wide absorption peaks at 380–500 nm and emitted bright yellow fluorescence with a peak at 550 nm. The CQDs were rapidly taken up by HeLa cancer cells. When excited under blue light, a bright yellow fluorescence signal and intense reactive oxygen species (ROS) were efficiently produced, enabling simultaneous fluorescent cancer cell imaging and photodynamic inactivation, with a 40% decrease in relative cell viability. Furthermore, about 98% cells were active after the incubation with 400 μg mL−1 CQDs in the dark, which revealed the excellent biocompatibility of CQDs. Hence, the newly prepared CQDs are thus demonstrated to be materials which might be effective and safe to use for in vivo bioimaging and imaging-guided cancer therapy.

Background 5-Fluorouracil (5-FU) is a widely used drug for the therapy of cancer. However, the chemoresistance of tumor cells to 5-FU usually limits its clinical effectiveness. In this study, we explored the role of NLRP3 inflammasome in 5-FU resistance of oral squamous cell carcinoma (OSCC). Methods The mRNA and protein expression levels of NLRP3, Caspase1 and IL-1β in resected OSCC specimens or cell lines were measured respectively by quantitative real time-PCR (qRT-PCR) and western blot. NLRP3 and Ki-67 expression in paraffin-embedded OSCC tissues was determined by immunohistochemistry. The correlation between 5-FU treatment and the expression and activation of NLRP3 inflammasome was further examined by evaluating NLRP3 and IL-1β expression in OSCC cell lines without or with NLRP3 knocked down. Cell viabilities of OSCC cells were determined by the MTT assay. Apoptosis and intracellular reactive oxygen species (ROS) of OSCC cells induced by 5-FU were measured by the flow cytometer. The carcinogen-induced tongue squamous carcinoma mice model was established by continuous oral administration of 4-nitroquinoline 1-oxide in wild-type BALB/c, Nlrp3 −/− and Caspase1 −/− mice. Tumor incidence were observed and tumor area were evaluated. Results In the clinical analysis, expression and activation of NLRP3 inflammasome was clearly increased in OSCC tissues of patients who received 5-FU-based chemotherapy. Multivariate Cox regression analysis revealed that this high expression was significantly correlated with tumor stage and differentiation, and was associated with poor prognosis. Moreover, 5-FU treatment increased expression and activation of NLRP3 inflammasome in OSCC cells in a cell culture system and xenograft mouse model. Silencing of NLRP3 expression significantly inhibited OSCC cell proliferation and enhanced 5-FU-induced apoptosis of OSCC cells. Further investigation showed that intracellular ROS induced by 5-FU promoted the expression and activation of NLRP3 inflammasome and increased the production of interleukin (IL)-1β, which then mediated the chemoresistance. With the carcinogen-induced OSCC model, we found less and later tumor incidence in Nlrp3 −/− and Caspase1 −/− mice than wild-type mice. And greater decrease of tumor area was observed in the gene deficient mice treated with 5-FU. Conclusions Our findings suggest that NLRP3 inflammasome promoted 5-FU resistance of OSCC both in vitro and in vivo, and targeting the ROS/NLRP3 inflammasome/IL-1β signaling pathway may help 5-FU-based adjuvant chemotherapy of OSCC.

Histone lysine demethylase 6a (Kdm6a) mediates the removal of repressive trimethylation from histone H3 lysine 27 (H3K27me3) to activate target gene expression. Obesity is associated with metabolic inflammation, and adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation. However, it is still unclear whether the Kdm6a pathway in ATMs regulates energy homeostasis. Here, we identified Kdm6a as a critical epigenetic switch that modulates macrophage polarisation and further disrupts energy balance. Myeloid-specific Kdm6a knockout in Kdm6a F/Y ; Lyz2-Cre mice significantly reversed the high-fat diet (HFD)-induced M1–M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity. The brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly increased in Kdm6a F/Y ; Lyz2-Cre mice. Furthermore, Kdm6a regulated the Ire1α expression in a demethylase activity-dependent manner and augmented the M2 polarisation of macrophages. Macrophage with higher Kdm6a significantly promotes adipogenesis in white adipocyte and inhibits thermogenesis in beige adipocytes. These results suggest that the Kdm6a in macrophages drives obesity and metabolic syndrome by impairing BAT activity and WAT differentiation.

With the great success of coronavirus disease (COVID-19) messenger ribonucleic acid (mRNA) vaccines, mRNA therapeutics have gained significant momentum for the prevention and treatment of various refractory diseases. To function efficiently in vivo and overcome clinical limitations, mRNA demands safe and stable vectors and a reasonable administration route, bypassing multiple biological barriers and achieving organ-specific targeted delivery of mRNA. Nanoparticle (NP)-based delivery systems representing leading vector approaches ensure the successful intracellular delivery of mRNA to the target organ. In this review, chemical modifications of mRNA and various types of advanced mRNA NPs, including lipid NPs and polymers are summarized. The importance of passive targeting, especially endogenous targeting, and active targeting in mRNA nano-delivery is emphasized, and different cellular endocytic mechanisms are discussed. Most importantly, based on the above content and the physiological structure characteristics of various organs in vivo, the design strategies of mRNA NPs targeting different organs and cells are classified and discussed. Furthermore, the influence of administration routes on targeting design is highlighted. Finally, an outlook on the remaining challenges and future development toward mRNA targeted therapies and precision medicine is provided.

Background The lncRNA LINC00460 plays crucial roles in several epithelial cancers, although its mechanisms of action differ greatly in different cellular contexts. In this study, we aimed to determine the potential clinical applications of LINC00460 and elucidate the mechanisms by which LINC00460 affects the development and progression of head and neck squamous cell carcinoma (HNSCC). Methods The biological functions of LINC00460 were assessed in several epithelial cancer cell lines. The subcellular localization of LINC00460 was evaluated by cell nuclear/cytoplasmic fractionation and fluorescence in situ hybridization. RNA pull-down assays, LS-MS/MS analysis, and RNA and chromatin immunoprecipitation assays were performed to identify the molecular mechanism by which LINC00460 promotes HNSCC progression. The clinical pathological features of LINC00460 and PRDX1 were evaluated in HNSCC tissues and paired adjacent normal tissues. Results LINC00460 enhanced HNSCC cell proliferation and metastasis in vitro and in vivo and induced epithelial–mesenchymal transition (EMT). LINC00460 primarily localized within the cytoplasm of HNSCC cells, physically interacted with PRDX1 and facilitated PRDX1 entry into the nucleus. PRDX1 promoted the transcription of LINC00460, forming a positive feedback loop. In addition, PRDX1 also promoted the transcription of EMT-related genes (such as ZEB1, ZEB2 and VIM) through enrichment on gene promoters in the nucleus. LINC00460 effectively induced HNSCC cell EMT in a PRDX1-dependent manner, and PRDX1 mainly mediated the EMT-promoting effect of LINC00460. High levels of LINC00460 and PRDX1 expression were positively associated with lymph metastasis, pathological differentiation and tumor size in HNSCC patients. Conclusions LINC00460 promoted EMT in HNSCC cells by facilitating PRDX1 entry into the nucleus. LINC00460 and PRDX1 are promising candidate prognostic predictors and potential targets for cancer therapy for HNSCC.

Background Head and neck cancer (HNC) is one of the most common deadly diseases worldwide. An increasing number of studies have recently focused on the malignant functions of cancer-associated fibroblasts (CAFs) in numerous cancers. However, the underlying mechanisms by which CAF-derived exosomes promote tumor progression need to be further elucidated. This study aims to determine whether the loss of specific miRNAs in CAF-derived exosomes may be involved in the malignant transformation of HNC. Methods MiRNA array and real-time PCR assays were used to analyze the differential expression of miRNAs in exosomes from normal fibroblasts (NFs) and CAFs. Cell proliferation, EdU incorporation, colony formation, apoptosis, cell cycle distribution and xenograft assays were performed to examine the effects of miR-3188 on HNC in vitro and in vivo. Real-time PCR, western blotting and luciferase reporter assays were used to identify the target genes of miR-3188. Furthermore, tumor-bearing mouse models were used to prove the potential therapeutic value of miR-3188-loaded exosomes in HNC. Results Our results showed that miR-3188 expression is reduced in exosomes and their parental CAFs from HNC tissues. In addition, miR-3188 can be transferred from fibroblasts to HNC cells by exosomes. Further exploration demonstrated that exosomal miR-3188 can influence the proliferation and apoptosis of HNC cells by directly targeting B-cell lymphoma 2 (BCL2) in vitro and in vivo. More importantly, we also found that miR-3188-loaded exosomes significantly inhibited tumor growth in vivo . Conclusions Our findings revealed that CAF-derived exosomes contain lower miR-3188 levels than NFs, and the loss of miR-3188 in exosomes contributes to the malignant phenotypes of HNC cells through the derepression of BCL2. Furthermore, these data suggest the potential therapeutic value of exosomal miR-3188 for inhibiting HNC growth.

The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.

Background Epithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT. Methods The expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo . Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC). Results MiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3′UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo . Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens. Conclusions Down-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy.