Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again. Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed. MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

Ezrin is a cytoskeletal protein involved in tumor growth and invasion. However its prognostic value for survival in patients with solid tumor remains controversial. Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Twenty-seven eligible trials involving 4693 patients were ultimately identified. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive Ezrin expression had an impact on overall survival (OS) [1.95, 95% confidence interval (CI) 1.60–2.39; P<0.001] in all eligible studies and progress free survival (PFS): (2.30 95% CI 1.0–3.61; P = 0.001). Similar results were also observed in subgroup analysis, according to tumor types, regions, patients' number and publication year. Our findings suggested that Ezrin protein expression might be a factor for a poor prognosis in patients with solid tumor. So large well-designed prospective studies are now needed to confirm the clinical utility of Ezrin as an independent prognostic marker.

Background: Melanoma accounts for more than 80% of deaths from all dermatologic cancers, mainly due to its widespread metastasis. High intensity focused ultrasound (HIFU) is a promising technique for cancer therapy. Here, we investigated the efficacy of HIFU against melanoma and the underlying mechanisms. Methods: A melanoma allograft mouse model was established to examine the tumor progression and survival rate. Anti-tumor immunity was determined by measuring cytokines, regulatory T cells (Tregs), Th17 cells and CD8+ effector T cells. Western blot, qPCR, RNAi and luciferase assay were performed to confirm the expression and regulation of microRNA (miR)-9-5p and transforming growth factor beta (TGF-β). Results: HIFU exposure significantly suppressed melanoma growth and metastasis by activating interferon gamma (IFN-γ) secretion, inhibiting Tregs and Th17 cells, and stimulating CD8+ effector T cells. TGF-β was a direct target of miR-9-5p. The anti-tumor effect of HIFU might be mediated through the miR-9-5p/TGF-β pathway. Conclusion: HIFU activates anti-tumor response and alters tumor microenvironment, which may serve as a potential therapeutic strategy for melanoma treatment.

Purpose: Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma. Materials and Methods: We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells’ antitumor activity and the production of IL-12 and IFN-γ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival. Results: In vitro assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-γ. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment. Conclusion: Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.