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Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN
Cellular Oncology ( IF 6.6 ) Pub Date : 2021-01-10 , DOI: 10.1007/s13402-020-00500-0
Guang Shan 1 , Xike Zhou 2, 3 , Juan Gu 2, 3 , Daoping Zhou 4 , Wei Cheng 4 , Huaiguo Wu 4 , Yueping Wang 4, 5 , Tian Tang 4, 6 , Xuedong Wang 3, 4
Affiliation  

Objective

Exosomes derived from cancer-associated fibroblasts (CAFs) are known as important drivers of tumor progression. Previously, microRNA (miR)-148b-3p has been found to be upregulated in bladder cancers as well as in body fluids (blood, urine) of bladder cancer patients. Here, we aimed to explore the role of CAF-derived exosome miR-148b-3p in bladder cancer progression and chemosensitivity.

Methods

Transwell, MTT, flow cytometry and colony formation assays were applied to assess the effects of CAF-derived exosomes on bladder cancer cell metastasis, epithelial-mesenchymal transition (EMT) and chemosensitivity. A dual luciferase reporter assay was employed to evaluate the targeting relationship between miR-148b-3p and PTEN. Gain- and loss- of function assays were conducted to explore the roles of miR-148b-3p and PTEN in the behavior of bladder cancer cells. The role of PTEN in the metastasis, EMT and chemosensitivity of bladder cancer cells was assessed both in vivo and in vitro.

Results

We found that CAF-derived exosomes promoted the metastasis, EMT and drug resistance of bladder cancer cells. We also found that CAF-derived exosomes could directly transport miR-148b-3p into bladder cancer cells. In a xenograft mouse model we found that CAF-derived exosomes increased miR-148b-3p expression levels and promoted tumor proliferation, metastasis and drug resistance. PTEN was validated as a target of miR-148b-3p. Concordantly, we found that PTEN overexpression inhibited EMT, metastasis and chemoresistance in bladder cancer cells, reversing the tumor promoting effects of miR-148b-3p via the Wnt/β-catenin pathway.

Conclusions

Our results suggest that miR-148b-3p downregulation in CAF-derived exosomes, thereby inhibiting the Wnt/β-catenin pathway and promoting PTEN expression, may offer potential opportunities for bladder cancer treatment.



中文翻译:

癌症相关成纤维细胞中下调的外泌体 microRNA-148b-3p 通过下调 Wn​​t/β-catenin 通路和上调 PTEN 增强膀胱癌细胞的化学敏感性

客观的

源自癌症相关成纤维细胞 (CAF) 的外泌体被认为是肿瘤进展的重要驱动因素。此前,已发现 microRNA (miR)-148b-3p 在膀胱癌以及膀胱癌患者的体液(血液、尿液)中上调。在这里,我们旨在探索 CAF 衍生的外泌体 miR-148b-3p 在膀胱癌进展和化学敏感性中的作用。

方法

应用 Transwell、MTT、流式细胞术和集落形成测定来评估 CAF 衍生的外泌体对膀胱癌细胞转移、上皮-间质转化 (EMT) 和化学敏感性的影响。采用双荧光素酶报告基因测定来评估 miR-148b-3p 和 PTEN 之间的靶向关系。进行了功能获得和损失测定以探索 miR-148b-3p 和 PTEN 在膀胱癌细胞行为中的作用。在体内体外评估了 PTEN 在膀胱癌细胞转移、EMT 和化学敏感性中的作用。

结果

我们发现 CAF 衍生的外泌体促进了膀胱癌细胞的转移、EMT 和耐药性。我们还发现 CAF 衍生的外泌体可以直接将 miR-148b-3p 转运到膀胱癌细胞中。在异种移植小鼠模型中,我们发现 CAF 衍生的外泌体增加了 miR-148b-3p 的表达水平并促进了肿瘤的增殖、转移和耐药性。PTEN 被验证为 miR-148b-3p 的靶标。一致地,我们发现 PTEN 过表达抑制了膀胱癌细胞中的 EMT、转移和化学抗性,逆转了 miR-148b-3p 通过 Wnt/β-catenin 途径的肿瘤促进作用。

结论

我们的研究结果表明,CAF 衍生的外泌体中 miR-148b-3p 下调,从而抑制 Wnt/β-catenin 通路并促进 PTEN 表达,可能为膀胱癌治疗提供潜在机会。

更新日期:2021-01-10
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