Introduction TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can induce apoptosis in a variety of cancer cells. However, drug resistance of tumor and short half-life seriously affects its clinical targeted therapy. Cabazitaxel (CTX) is a taxane drug, which can induce apoptosis or autophagy by inhibiting the phosphorylation of PI3K/Akt/mTOR and sensitive to some drug-resistant tumors. Therefore, we explored the possibility of developing a mesenchymal stem cell-derived exosomes (MSC-EXO) vector for oral squamous cell carcinoma (OSCC) to deliver CTX/TRAIL combinations. Methods After ultracentrifugation and dialysis, CTX/TRAIL loaded exosomes transfected MSC (MSCT)-derived exosome (EXO) (MSCT-EXO/CTX) were isolated and purified. The expression of CD63, CD9 and TRAIL was detected by BCA to confirm the origin of EXO. High-performance liquid chromatography (HPLC) was used to determine the drug loading of VPF and draw the in vitro release profile. MTT assay, flow cytometry and Western blot were used to detect the antitumor effect of MSCT-EXO/CTX in vitro. Subsequently, the antitumor effect of MSCT-EXO/CTX in vivo was verified by mouse model. Results The diameter of the membrane particles was about 60–150 nm. We have proved that the incorporation and release of CTX in MSCT-EXO can inhibit the activation of PI3K, Akt and mTOR, which is a possible synergistic mechanism of CTX. MSCT-EXO and CTX can induce the apoptosis of SCC25 tumor cells in a dose-dependent manner and exert a good synergistic effect in the proportion range of 10:1–5:1. The inherent activity of MSCT-EXO and the direct effect of MSCT-EXO/CTX on OSCC confirm that MSCT-EXO/CTX makes MSCT-EXO and CTX have an efficient synergistic effect and a highly effective pharmacological inhibition on cancer cells, as verified by the subsequent mouse model. MSCT-EXO/CTX showed the lowest relative tumor volume and the highest tumor inhibition rate (P<0.05) in vivo. Conclusion An MSCT-EXO-based CTX delivery system might be an effective anticancer method.
Background: The miR-144/451a cluster acts as a tumor suppressor in various tumors by synergistically inhibiting the proliferation, migration, and invasion of oral squamous cell carcinoma (OSCC). Aims: To achieve the synergistic delivery of the miR-144/451a cluster for OSCC treatment by constructing chitosan nanoparticles (CAs) camouflaged with macrophage membranes. Study Design: A cell-culture study. Methods: CAs were prepared using the ionic cross-linking method, and biomimetic nanoparticles coloaded with the miR-144/451a cluster (miR-144-source of macrophage-derived exosomes [MEXO]/CA-miR-451a) were prepared using the uptake–efflux method. The MEXO was detected by a bicinchoninic acid assay. The as-prepared biomimetic nanoparticles were then characterized to determine their protective effects on microRNAs (miRNAs). Moreover, the influence of the miR-144-MEXO/CA-miR-451a nanoparticles on the proliferation, migration, and invasion of OSCCs was evaluated. Finally, the effects of the biomimetic system on the expression of calcium-binding protein 39 (CAB39) and migration inhibitory factor (MIF) were detected using the real-time polymerase chain reaction and Western blot. Results: After coating the CAs with MEXO, their particle size increased from 113.1 ± 3.4 nm to 143.2 ± 14 nm, and their surface potential decreased from 26.34 ± 0.4 mV to −10.3 ± 1.6 mV. The expression of the MEXO marker protein was also observed on the biomimetic nanoparticles’ surface. The system can protect miRNAs from RNase A degradation. Compared with the CAs cotransfected with free miR-144/451a cluster, CAs that are coloaded with miR-144-MEXO/CA-miR-451a nanoparticles substantially reduced the viability ( p < 0.001), migration ( p = 0.023), and invasion ( p = 0.004) of OSCC. These findings revealed the successful construction of biomimetic nanoparticles coloaded with the miR-144/451a cluster. CAB39 and MIF expression in OSCC treated with miR-144-MEXO/CA-miR-451a nanoparticles have significantly decreased compared with the miR-144/451a group ( p < 0.05). Thus, the nanoparticles can effectively improve the inhibitory effects of the miR-144/451a cluster on OSCC. Conclusion: This study provided a new idea for the application of gene cotransfection to tumor treatment.
The abnormal expression of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) is closely related to several tumor diagnosis and progression, such as endometrial carcinoma and ovarian cancer. However, the role of MEG3 in oral squamous cell carcinoma (OSCC) is rarely reported. The current study aimed to evaluate the expression of lncRNA MEG3 in OSCC tissues and cell lines and its effect on the biological behavior of OSCC cell lines. The expression of lncRNA MEG3 in the OSCC tissues and cell lines was detected by reverse transcription-quantitative (RT-q) PCR. The relationship between MEG3 expression and the clinicopathologic characteristics and prognosis of patients with OSCC was analyzed. The lncRNA MEG3 overexpression plasmid and control plasmid were transfected into SCC25 and CAL27 cell lines using the lipofectin method. MTT assay was performed to detect the growth and proliferation of the cell lines. Transwell chamber test was used to detect changes in cell migration and invasion. Flow cytometry was employed to detect changes in apoptosis. Western blotting and RT-qPCR were conducted to detect the expression of the p53 gene. The expression of lncRNA MEG3 in the OSCC tissues and cell lines was significantly compared with normal tissues and cell lines, respectively. The expression level of MEG3 was related to clinical stage, lymph node metastasis, distant metastasis and survival status. Overexpression of lncRNA MEG3 inhibited the proliferation, migration, and invasion of SCC25 and CAL27 cell lines, induced apoptosis and promoted the expression of p53 gene. lncRNA MEG3 played the role of a tumor inhibitor gene and significantly inhibited the biological activity of OSCC cell lines, which may provide a novel idea for molecular targeted therapy of OSCC.
Long non-coding RNAs (lncRNAs) have been consistently demonstrated to be involved in oral squamous cell carcinoma (OSCC) as either tumor oncogenes or tumor suppressors. However, the underlying mechanisms of OSCC tumorigenesis and development have not yet been fully elucidated. The expression profiles of mRNAs and lncRNAs in OSCC were analyzed by a microarray assay. To verify the results of the microarray, 10 differentially expressed lncRNAs were randomly selected and measured by quantitative RT-PCR (qRT-PCR). Gene Ontology (GO) and metabolic pathway analyses were performed to analyze gene function and identify enriched pathways. Subsequently, two independent algorithms were used to predict the target genes of the lncRNAs. We identified 2,294 lncRNAs and 1,938 mRNAs that were differentially expressed in all three OSCC tissues by a microarray assay. Through the construction of co-expression networks of differentially expressed genes, 4 critical lncRNAs nodes were identified as potential key factors in the pathogenesis of OSCC. Expression of the 4 critical lncRNA nodes was not associated with age, sex, smoking or tumor location (P>0.05) but was positively correlated with clinical stage, lymphatic metastasis, distant metastasis and survival status (P<0.05). Kaplan-Meier analysis demonstrated that low expression levels of these 4 critical lncRNA nodes contributed to poor median progression-free survival (PFS) and overall survival (OS) (P<0.05). GO and pathway analyses indicated that the functions and enriched pathways of many dysregulated genes are associated with cancer. Potential target genes of dysregulated lncRNAs were enriched in 43 metabolic pathways, with cancer pathways being the primary enrichment pathways. In summary, we analyzed the profile of lncRNAs in OSCC and identified the functions and enriched metabolic pathways of both dysregulated mRNAs and the target genes of dysregulated lncRNAs, providing new insights into molecular markers and therapeutic targets for OSCC.
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