Abstract
BackgroundCircular RNAs (circRNAs) have important functions in many fields of cancer biology. In particular, we previously reported that the oncogenic circRNA, circPRMT5, has a major role in bladder cancer progression. Therapy based on circRNAs have good prospects as anticancer strategies. While anti-circRNAs are emerging as therapeutics, the specific in vivo delivery of anti-circRNAs into cancer cells has not been reported and remains challenging.MethodsSynthesized chrysotile nanotubes (SCNTs) with a relatively uniform length (~ 200 nm) have been designed to deliver an siRNA against the oncogenic circPRMT5 (si-circPRMT5) inhibit circPRMT5. In addition, the antitumor effects and safety evaluation of SCNTs/si-circPRMT5 was assessed with a series of in vitro and in vivo assays.ResultsThe results showed that SCNTs/si-circPRMT5 nanomaterials prolong si-circPRMT5’s half-life in circulation, enhance its specific uptake by tumor cells, and maximize the silencing efficiency of circPRMT5. In vitro, SCNTs encapsulating si-circPRMT5 could inhibit bladder cancer cell growth and progression. In vivo, SCNTs/si-circPRMT5 inhibited growth and metastasis in three bladder tumor models (a subcutaneous model, a tail vein injection lung metastatic model, and an in situ model) without obvious toxicities. Mechanistic study showed that SCNTs/si-circPRMT5 regulated the miR-30c/SNAIL1/E-cadherin axis, inhibiting bladder cancer growth and progression.ConclusionThe results highlight the potential therapeutic utility of SCNTs/si-circPRMT5 to deliver si-circPRMT5 to treat bladder cancer.
Highlights
Circular RNAs have important functions in many fields of cancer biology
Representative histograms are shown in the upper panel, the lower panel shows the mean ± SD (n = three independent experiments). (C) Confocal laser scanning microscopy (CLSM) images of the uptake of synthetic chrysotile nanotubes (SCNTs)/FAM-si-circPRMT5 by T24 cells at 1, 2, 4, and 8 h
FAM, green signal; DAPI (4′,6-diamidino-2-phenylindole), blue signal; Scale bar = 25 μm. (D) Representative confocal microscopy image showing the co-localization of SCNTs/FAM-si-circPRMT5 with endocytic markers labeled with Alexa Fluor 555
Summary
Circular RNAs (circRNAs) have important functions in many fields of cancer biology. In particular, we previously reported that the oncogenic circRNA, circPRMT5, has a major role in bladder cancer progression. Advances in surgical treatments and new combination chemotherapy protocols have improved median survival, approximately 50% of patients with bladder cancer develop recurrent/metastatic disease within 2 years of diagnosis [3]. Generation sequencing has led to the discovery of circular RNA (circRNAs), which occupy a central position in research into cancer genomics and gene therapy [6, 7]. CircRNAs are a class of circular non-coding RNA molecules that form a covalently closed continuous loop without free caps and poly(A) tails [8, 9], CircRNAs are involved in the regulation of gene expression and, in cancer, they have demonstrated the potential to regulate progression, metastasis, angiogenesis, apoptosis, and proliferation [10, 11]. Our previous study revealed that circPRMT5 is highly expressed in bladder cancer tissue and correlates positively with advanced clinical stage and worse survival in patients with bladder cancer [12]
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