Cervical cancer (CC) is a prevalent malignancy in women, with the feature of metastasis and easy recurrence is responsible for a large proportion of global cancer deaths. Radiotherapy is one of the common treatment tools for CC patients with unresectable tumors. However, radio-resistance in patients could be a major reason for recurrence. Therefore, it is of significance to tunnel the molecular mechanism of radio-resistance in CC. MicroRNAs (miRNAs) are increasingly reported in the regulation of cancer progression and cellular response to radiotherapy and chemotherapy. miR-4429 is a newly discovered miRNA acting as a tumor-suppressor gene in multiple cancers, but its function in CC has never been explored yet. The current study tried to explore the role of miR-4429 in cell radio-sensitivity in CC.First, we validated the downregulation of miR-4429 in CC cells. Importantly, the association of miR-4429 with radio-resistance was validated by identifying the downregulation of miR-4429 in radio-resistant CC cells. Gain-and loss-of-function assays validated that miR-4429 sensitized CC cells to irradiation. Through bioinformatics tools, RAD51 recombinase (RAD51) was identified to be a target for miR-4429. RAD51 is known to be a crucial regulator for DNA damage repair and has been reported to influence cell radio-resistance in cancers, including in CC. Luciferase reporter assay confirmed the interaction between miR-4429 and RAD51. Finally, rescue assays indicated that miR-4429 promoted CC cell radio-sensitivity through RAD51. Consequently, our study showed that miR-4429 sensitized CC cells to irradiation by targeting RAD51, providing a potential therapeutic target for CC patients. K E Y W O R D Scervical cancer, miR-4429, RAD51, radio-resistance
Background: Cervical cancer is a prevalent tumor in women. Here we investigated the synergic effects of Schisandrin B (Sch B), an active compound extracted from the Chinese herb Schisandra Chinensis, in docetaxel (DTX)-induced restriction of growth and invasion of cervical cancer.Methods: Caski cells were treated with Sch B and DTX for 24 hours. In vitro effects were investigated with Cell counting kit-8, western blotting, colony-forming, Transwell, Annexin V-FITC enabled flow cytometry.Then, in vivo experiments were engaged with Sch B (20 mg/kg) and DTX (10 mg/kg) for 30 days, and IHC were applied to validate the effects in vivo. Results: Both Sch B and DTX reduced cell viability, inhibited colony formatting, induced apoptosis, and limited cell invasion. Co-administration of Sch B and DTX more significantly enhanced these changes. The relative levels of HPV infection and tumor progression related proteins p-AKT/AKT, NF-kappaB, Cyclin D1, CDK-4, MMP-9, Notch1, β-catenin and p-p38/p38 were markedly inactivated. The effects of Sch B in cervical cancer were further confirmed in Caski cell-xenograft BALB/c nude mice. Co-administration of Sch B enhanced the anti-tumor effects of DTX in vivo, inhibited tumor formation, increased apoptotic cells, and reduced Ki67 and N-cadherin expression. Conclusions: Altogether, Sch B enhanced the anti-tumor effects of DTX in vitro and in vivo via growth, invasion, and apoptosis regulating. The results supported therapies of co-administering Sch B and DTX to be developed in cervical cancer.
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