| Summary: | 碩士 === 中山醫學大學 === 牙醫學系碩士班 === 103 === Scope: Recent reports have demonstrated that oral cancer stem cells (OCSCs) presented high tumorigenic, chemo-radioresistant, and metastatic properties. CD44 or ALDH1 could be the markers to identify OCSCs. An effective therapeutic approach targeting these OCSCs may help to improve current treatment regimens for oral cancer-related malignancies. The aim of this study was to investigate the chemo-therapeutic effect and regulatory mechanisms of Andrographolide (Andro), a diterpenoid lactone isolated from a plant called Andrographis paniculata, on OCSCs.
Methods: We examined the cytotoxic effect of Andro on normal human oral keratinocyte (NHOK) primary cells and ALDH1+CD44+- OCSCs. ALDH1 activity of OCSCs with Andro treatment was assessed by the Aldefluor assay analysis. Self-renewal, migration, invasiveness, miR-218 expression, and in vivo tumorigenicity of OCSCs with different doses of Andro was presented.
Results: Andro inhibited the proliferation rate of ALDH1+CD44+-OCSCs in a dose-dependent manner, whereas the inhibition on NHOK cells proliferation was limited. We first observed that the treatment of Andro significantly down-regulated the ALDH1 activity, spheres-forming ability, and migration/invasion properties of OCSCs in a dose dependent manner. Using microRNA real-time RT-PCR analysis, Andro significantly increased expression of tumor suppressive miR-218 and identified Bmi1 as the targets of miR-218 in OCSCs. Importantly, in vivo nude mice model showed that Ando treatment by oral gavage to xenograft tumors reduced tumor growth.
Conclusion: From these results, we conclude that the inhibition of tumor aggressiveness in OCSCs by Andro was mediated by up-regulation of miR-218, suggesting that Andro would be a valuable therapeutics clinically in treatment modalities for malignant oral cancer by elimination of properties cancer stem cells properties.
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