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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

UHRF1, an epigenetic factor, is implicated in various cellular processes of tumorigenesis. However, the modulation of UHRF1 expression in human bladder cancer at post‐transcriptional levels remains unclear. Here, we report that miR‐124 suppresses expression of UHRF1 to affect the progression of human bladder cancer through competitive binding of the same region of its 3′‐UTR. We show that compared with corresponding normal tissues, UHRF1 is upregulated and miR‐124 is downregulated in bladder cancer tissues, demonstrating an inverse correlation of miR‐124 and UHRF1. Quantitative PCR and western blot assay demonstrated that over‐expression of miR‐124 resulted in the suppression of UHRF1. Furthermore, luciferase assay revealed that miR‐124 could control the fate of target gene UHRF1 mRNA by binding 3′‐UTR. The rescue experiment confirmed that miR‐124 exerted its biological functions by targeting UHRF1. miR‐124 over‐expression significantly attenuated cellular proliferation, migration, invasion and vasculogenic mimicry in vitro, and tumor growth in vivo. UHRF1 siRNA showed significant inhibitory effects on bladder cancer cells. Collectively, our study demonstrates that miR‐124 can impair the proliferation or metastasis of human bladder cancer cells by down‐regulation of UHRF1.

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