ABSTRACT
The microRNA miR-130a-3p (miR-130a-3p) has anti-tumor activity against numerous cancer types. Further, miR-130a-3p may target Wnt signaling, which is a critical pathway regulating tumorigenesis. Functions of miR-130a-3p in colorectal cancer (CRC) and contributions of Wnt1 pathway modulation, however, have not been examined, hence the exploration on these two aspects. In this study, in comparison with normal controls, both CRC tissue and multiple CRC cell lines showed downregulated miR-130a-3p. MiR-130a-3p overexpression contributed to a decrease in CRC cell proliferation. Additionally, its overexpression also caused reduced expression of WNT Family Member 1 (WNT1) and downstream WNT pathway factors c-myc and cyclin D1. Dual-luciferase assay revealed WNT1 as a direct target of miR-130a-3p, and further the inhibitory effect of miR-130a-3p on c-myc and cyclin D1 was proved to be reversed by overexpressed WNT1. Collectively, miR-130a-3p inhibits CRC growth by directly targeting WNT1, and miR-130a-3p and WNT1 pathway-associated factors are defined as potential targets for CRC treatment.
Subject(s)
Colorectal Neoplasms/pathology , Down-Regulation , MicroRNAs/genetics , Wnt1 Protein/genetics , 3' Untranslated Regions , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colorectal Neoplasms/genetics , Cyclin D1/genetics , Female , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice , Neoplasm Transplantation , Proto-Oncogene Proteins c-myc/geneticsABSTRACT
PURPOSE: Using antibodies to block the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway as an immunotherapy has achieved great success in the clinical treatment of various types of carcinoma. However, the efficacy is limited because of tumor-mediated immune immunosuppression and evasion. This study demonstrated that inhibiting the PI3K pathway with (-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) quinic acid (QA), a new compound from endophytic fungus Penicillium citrinum of Avicennia marina, enhanced the therapeutic efficacy of anti-PD-L1 antibody against esophageal tumors. MATERIALS AND METHODS: mEC25 cells were injected into C57BL/6 mice to establish a syngeneic esophageal tumor model. Tumor infiltration lymphocytes (TILs) were analyzed by flow cytometry. Gene and protein expression was detected by qPCR and western blot, respectively. Moreover, the therapeutic effects of QA combining with anti-PD-L1 antibody were evaluated in the tumor model. RESULTS: These data demonstrated that inhibition of PI3K with QA could overcome immunosuppression and promote the response of T-lymphocytes, resulting in the restoration of cytotoxic T cell-mediated tumor control. QA and anti-PD-L1 combination therapy significantly delayed tumor growth. CONCLUSIONS: Our results provide a scientific basis to develop combination therapies involving anti-PD-L1 and PI3K inhibitors to improve responses in patients with esophageal cancer.