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MicroRNAs are a group of endogenous small non-coding RNAs commonly dysregulated in tumorigenesis, including glioblastoma (GBM), the most malignant brain tumor with rapid proliferation, diffuse invasion, and therapeutic resistance. Accumulating evidence has manifested that miR-1258 exerts an inhibitory role in many human cancers. However, the expression pattern of miR-1258 and its potential function in GBM tumorigenesis remain unclear. In this study, we reported that miR-1258 expression decreased with the ascending pathological grade of glioma, which indicated an unfavorable prognosis of patients. Functional assays revealed an inhibitory effect of miR-1258 on malignant proliferation, therapeutic resistance, migration, and invasion of GBM in vitro. Moreover, xenograft models also suggested a repression effect of miR-1258 on gliomagenesis. Mechanistically, miR-1258 directly targeted E2F1 in 3’-untranslated regions and attenuated E2F1-mediated downstream gene PCNA and MMP2 transcriptions. Furthermore, restoration of E2F1 expression in GBM cells effectively rescued the tumor-suppressive effect of miR-1258. Our studies illustrated that miR-1258 functioned as a tumor suppressor in GBM by directly targeting E2F1, subsequently inhibiting PCNA and MMP2 transcriptions, which contributed to new potential targets for GBM therapy and other E2F1-driven cancers.

Sorafenib is a first-line chemotherapy drug for advanced hepatocellular carcinoma (HCC), but the drug resistance appeared over time. Hypoxia and acidosis are common features of the microenvironment, which contribute to the drug resistance. Here, we verified that metformin could enhance the sensitivity of HCC cells to sorafenib under hypoxia. Furthermore, metformin altered the pH levels and reversed the acidification of extracellular environment. Mechanistically, metformin promoted the ubiquitination and degradation of NHE1, a sodium-hydrogen exchanger-1, which altered the pH regulation and decreased the sensitivity of HCC cells to chemotherapy. Finally, lung metastasis mice model, subcutaneous xenograft mice model, and orthotopic recurrence mice model were used to confirm the synergistic effects of metformin in vivo. In conclusion, metformin might be a promising adjuvant therapy to enhance the effectiveness of sorafenib in HCC patients.