Hafnium-Based Metal-Organic Framework Nanoparticles as a Radiosensitizer to Improve Radiotherapy Efficacy in Esophageal Cancer.

Radiotherapy is one of the most widely used clinical treatments for tumors, but it faces limitations, such as poor X-ray retention at the tumor site. The use of radiosensitizers containing high Z elements is an effective way to enhance X-ray absorption. Here, we demonstrate a simple one-step method for the synthesis of UiO-66-NH2(Hf) metal-organic framework nanoparticles for use as radiosensitizers in radiotherapy. The UiO-66-NH2(Hf) nanoparticles had a diameter of less than 100 nm and were stable in the physiological environment. UiO-66-NH2(Hf) induced apoptosis by enhancing X-ray absorption, as confirmed by in vitro and in vivo experiments. These characteristics make UiO-66-NH2(Hf) a promising radiosensitizer for esophageal cancer radiotherapy.

Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cell through Wnt/ß-catenin signaling pathway.

BACKGROUND: Esophageal cancer (EC) is a prevalent malignant cancer worldwide. Interestingly, the antimalaria compound artemisinin (ART) is also reported to have anticancer potential, although its underlying mechanism in EC is unclear. In this study, we explored the anticancer role of ART in EC109 and further explored the combination of ART and oxaliplatin (OXA) for their synergetic anticancer functions. METHODS: Human EC cell line EC109 was used. After ART or oxaliplatin (OXA) treatment, cell proliferation, migration, and invasion were measured by MTT, transwell, and scratch wound assays, respectively. Flow cytometry was performed to examine the cell cycle and apoptosis. The mRNA and protein levels were determined using qRT-PCR and western blotting. RESULTS: The migration and invasion abilities of EC109 were suppressed by ART. This was due to the inhibitory effect of ART on the Wnt/ß-catenin signaling pathway. The levels of ß-catenin, c-myc, and survivin were also downregulated by ART. ART inhibits the proliferation of EC109 cells by arresting the cells in the G1-phase of cell cycle. By using LiCl, an activator of the Wnt/ß-catenin pathway, we further verified that the inhibition of the Wnt/ß-catenin pathway was indeed due to ART. Remarkably, ART enhanced the anticancer effects of OXA in EC109 cells. OXA combined with ART was found to be more efficient in decreasing tumor growth compared to the individual drugs. CONCLUSIONS: ART could suppress tumor progression by inhibiting Wnt/ß-catenin signaling pathway, and it may also enhance the antitumor effect of OXA in EC. Thus, ART could be a novel anticancer drug for EC treatment. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: ART could be a novel anticancer drug for esophageal cancer (EC) treatment. WHAT THIS STUDY ADDS: Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cells through the Wnt/ß-catenin signaling pathway.

LINC00657/miR-26a-5p/CKS2 ceRNA network promotes the growth of esophageal cancer cells via the MDM2/p53/Bcl2/Bax pathway.

LncRNA LINC00657 has oncogenic or anti-carcinoma roles in different cancers, and yet its detailed molecular mechanism in esophageal cancer (EC) remains unclear. In addition, competitive endogenous RNA (ceRNA) regulatory lncRNA-miRNA-mRNA networks are critical for tumorigenesis and progression. Hence, the present study explored the roles of LINC00657 in EC and identified its relevant ceRNA network. We first detected the expression of LINC00657 in EC. Then, we applied starBase and TargetScan websites to find miR-26a-5p binding to LINC00657 and obtain CKS2 as a target of miR-26a-5p. The roles of LINC00657, miR-26a-5p or CKS2 in the proliferation, migration, invasion, and apoptosis of EC cells were respectively assessed by CCK-8, wound healing assay, transwell invasion assay, and flow cytometry. The changes of the MDM2/p53/Bcl2/Bax pathway were measured via Western blot. The results revealed that LINC00657 showed an aberrant high expression in EC cells, which promoted the growth of EC cells. Additionally, LINC00657 functioned as a sponge of miR-26a-5p, and LINC00657 negatively mediated miR-26a-5p to regulate the growth of EC cells. Furthermore, CKS2 was observed as a direct target of miR-26a-5p, and CKS2 controlled the growth of EC cells via the MDM2/p53/Bcl2/Bax pathway. Moreover, there was a positive correlation between LINC00657 and CKS2. LINC00657 knockdown inhibited CKS2 expression to suppress the proliferation, migration, and invasion of EC cells and induced apoptosis via regulating the MDM2/p53/Bcl2/Bax pathway. Collectively, LINC00657/miR-26a-5p/CKS2 ceRNA network could promote the progression of EC, which is good for understanding the molecular mechanism of EC and offers novel biomarkers for EC diagnosis and therapy.

Prognostic value of PAX9 in patients with esophageal squamous cell carcinoma and its prediction value to radiation sensitivity.

Abnormal paired box 9 (PAX9) expression is associated with tumorigenesis, cancer development, invasion and metastasis. The present study investigated the prognostic significance of PAX9 in esophageal squamous cell carcinoma (ESCC) and its role in predicting radiation sensitivity. A total of 52.8% (121/229) ESCC tissues were positive for PAX9. The 1­, 3­ and 5­year disease­free survival (DFS) rates were 72.2, 35.2 and 5.6%, respectively, and the overall survival (OS) rates were and 86.1, 44.4, and 23.1%, respectively, in PAX9­positive tumors. In PAX9­negative tumors, the one­, three­ and five­year DFS rates were 76.9, 47.9 and 24.0%, and the OS rates were 90.9, 57.9 and 38.8%, respectively. Univariate analysis revealed that PAX9, differentiation, T stage, lymph node metastasis, and tumor­node­metastasis stage were associated with OS. Multivariate analysis of DFS and OS revealed that the hazard ratios for PAX9 were 0.624 (95% CI: 0.472­0.869, P=0.004) and 0.673 (95% CI: 0.491­0.922, P=0.014), respectively. Patients that received adjuvant therapy exhibited significant differences in the 5­year DFS (P<0.001) and OS (P<0.001). PAX9­positive ESCC patients who received post­surgery radiotherapy had a significantly greater 5­year DFS (P=0.011) and OS (P=0.009) than patients who received surgery only. Thus, PAX9 may be an independent prognostic factor for the surgical treatment of ESCC and a possible predictor of radiation sensitivity.

Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors.

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13 µM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 µM, respectively.

Targeted lung cancer therapy: preparation and optimization of transferrin-decorated nanostructured lipid carriers as novel nanomedicine for co-delivery of anticancer drugs and DNA.

PURPOSE: Nanostructured lipid carriers (NLC) represent an improved generation of lipid nanoparticles. They have specific nanostructures to accommodate drugs/genes, and thus achieve higher loading capacity. The aim of this study was to develop transferrin (Tf)-decorated NLC as multifunctional nanomedicine for co-delivery of paclitaxel (PTX) and enhanced green fluorescence protein plasmid. METHODS: Firstly, Tf-conjugated ligands were synthesized. Secondly, PTX- and DNA-loaded NLC (PTX-DNA-NLC) was prepared. Finally, Tf-containing ligands were used for the surface decoration of NLC. Their average size, zeta potential, drug, and gene loading were evaluated. Human non-small cell lung carcinoma cell line (NCl-H460 cells) was used for the testing of in vitro transfection efficiency, and in vivo transfection efficiency of NLC was evaluated on mice bearing NCl-H460 cells. RESULTS: Tf-decorated PTX and DNA co-encapsulated NLC (Tf-PTX-DNA-NLC) were nano-sized particles with positive zeta potential. Tf-PTX-DNA-NLC displayed low cytotoxicity, high gene transfection efficiency, and enhanced antitumor activity in vitro and in vivo. CONCLUSION: The results demonstrated that Tf-PTX-DNA-NLC can achieve impressive antitumor activity and gene transfection efficiency. Tf decoration also enhanced the active targeting ability of the carriers to NCl-H460 cells. The novel drug and gene delivery system offers a promising strategy for the treatment of lung cancer.