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Exosomes are critical mediators of intercellular communication in the tumor microenvironment. Exosomal circular RNAs (circRNAs) can act as biomarkers and play crucial roles in many cancers, including non-small cell lung cancer (NSCLC). The aim of this study was to explore the functions and regulatory mechanism of exosomal circ_0007385 in NSCLC. The expression levels of circ_0007385, microRNA-1253 (miR-1253), family with sequence similarity 83, member A (FAM83A) mRNA were determined by quantitative real-time PCR (qRT-PCR). Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (Edu), and colony formation assays were utilized to determine cell proliferation ability. Sphere formation efficiency was determined by sphere formation assay. All protein levels were detected by western blot assay. Exosomes were detected using transmission electron microscopy analysis. Size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-1253 and circ_0007385 or FAM83A was confirmed by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Mice xenograft model was established to verify the function of circ_0007385 in vivo. Circ_0007385 was upregulated in NSCLC tissues and cells. Knockdown of circ_0007385 inhibited NSCLC cell proliferation and stemness, while exosomal circ_0007385 facilitated NSCLC cell proliferation and stemness. In addition, miR-1253 was a direct target of circ_0007385, and miR-1253 reversed the inhibitory effects of circ_0007385 on cell proliferation and stemness in NSCLC cells. Moreover, FAM83A was a direct target of miR-1253, and miR-1253 suppressed NSCLC cell proliferation and stemness by targeting FAM83A. Furthermore, circ_0007385 knockdown inhibited tumor growth in vivo. Exosomal circ_0007385 promoted NSCLC cell proliferation and stemness by regulating miR-1253/FAM83A axis.

As a novel orally active multitarget small molecule inhibitor, CS2164 has shown broad antitumor activities against several human tumor xenograft models in immune-compromised mice. However, the ability of CS2164 to modulate antitumor immunity in an immune-competent mouse tumor model remains undefined, although antiangiogenic treatment has been reported to affect immune cell infiltration and remodel the tumor immune microenvironment. In the present study, the subcutaneous and ascites hepatocellular carcinoma (HCC) models in syngeneic Balb/c mice established by inoculation of an H22 hepatoma cell line were utilized to investigate the antitumor and immunomodulatory effects of CS2164. Although the antitumor effects of CS2164 were validated in both subcutaneous and ascites HCC models in syngeneic mice, CS2164 treatment consistently modulated immune cell populations, both in the periphery and in tumor microenvironments, with upregulation of CD4+ and CD8+ T cells in the spleen, but downregulation of immunosuppressive populations including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages in the spleen and tumor tissues. Furthermore, CS2164 increased the relative gene expression and protein production of several proinflammatory cytokines in tumor-related ascites. These results indicate that CS2164 exerts an antitumor effect associated with its immunomodulatory activities in mouse HCC models, and may also provide evidence for the immunotherapy potentiation of CS2164 in future cancer treatment.