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含有微小RNA-146a-5p的子宫颈癌细胞衍生细胞外囊泡通过激活Hippo-YAP信号通路中的WWC2影响肌动蛋白动力学以促进子宫颈癌转移

Cervical Cancer Cells-Derived Extracellular Vesicles Containing microRNA-146a-5p Affect Actin Dynamics to Promote Cervical Cancer Metastasis by Activating the Hippo-YAP Signaling Pathway WWC2.

作者信息

Wang Weiwei, Wu Lipei, Tian Jiale, Yan Wenhui, Qi Chunrun, Liu Wuchao, Xuan Shihai, Shang Anquan

机构信息

Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.

Department of Pathology, Tinghu People's Hospital, Yancheng 224005, China.

出版信息

J Oncol. 2022 Jun 28;2022:4499876. doi: 10.1155/2022/4499876. eCollection 2022.

DOI:10.1155/2022/4499876
PMID:35799607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9256433/
Abstract

Application of extracellular vesicles (EVs) for cancer treatment has been well-documented. We probed into the potential role of cervical cancer cells-secreted EVs by transferring miR-146a-5p in cervical cancer. After characterization of miR-146a-5p expression in clinical cervical cancer tissue samples, gain- and loss-of-function experiments were implemented to test the effect of miR-146a-5p on the invasion, epithelial-mesenchymal transition (EMT), and anoikis in cervical cancer cells. EVs were isolated from high-metastatic cervical cancer cells, after which their effects on the malignant behaviors of low-metastatic cervical cancer cells were assessed in a co-culture system. Luciferase assay was implemented to validate the putative binding relationship between miR-146a-5p and WWC2, followed by further investigation of downstream pathway (Hippo-YAP). Finally, nude mouse lung metastasis model was developed for validation. miR-146a-5p was elevated in cervical cancer tissues and high miR-146a-5p expression promoted the metastatic potential of cervical cancer cells through enhancing their invasiveness and anoikis resistance, and inducing EMT. Furthermore, miR-146a-5p carried by EVs secreted by highly metastatic cervical cancer cells could promote the metastasis of low-metastatic cervical cancer cells. Mechanistically, miR-146a-5p targeted WWC2 to activate YAP, by which it inhibited the phosphorylation of cofilin, and promoted the process of cofilin-mediated depolymerization of F-actin to G-actin. data demonstrated that EVs-carried miR-146a-5p promoted tumor metastasis through the WWC2/YAP axis. Cancer-derived EVs delivered pro-metastatic miR-146a-5p to regulate the actin dynamics in cervical cancer, thereby leading to cancer metastasis. This experiment highlighted an appealing therapeutic modality for cervical cancer.

摘要

细胞外囊泡（EVs）在癌症治疗中的应用已有充分记录。我们通过在宫颈癌中转移miR-146a-5p来探究宫颈癌细胞分泌的EVs的潜在作用。在对临床宫颈癌组织样本中miR-146a-5p的表达进行表征后，进行了功能获得和功能缺失实验，以测试miR-146a-5p对宫颈癌细胞侵袭、上皮-间质转化（EMT）和失巢凋亡的影响。从高转移性宫颈癌细胞中分离出EVs，然后在共培养系统中评估它们对低转移性宫颈癌细胞恶性行为的影响。进行荧光素酶测定以验证miR-146a-5p与WWC2之间的推定结合关系，随后进一步研究下游途径（Hippo-YAP）。最后，建立裸鼠肺转移模型进行验证。miR-146a-5p在宫颈癌组织中升高，高miR-146a-5p表达通过增强宫颈癌细胞的侵袭性和失巢凋亡抗性以及诱导EMT来促进其转移潜能。此外，高转移性宫颈癌细胞分泌的EVs携带的miR-146a-5p可促进低转移性宫颈癌细胞的转移。机制上，miR-146a-5p靶向WWC2以激活YAP，通过这种方式它抑制了丝切蛋白的磷酸化，并促进了丝切蛋白介导的F-肌动蛋白向G-肌动蛋白解聚的过程。数据表明，EVs携带的miR-146a-5p通过WWC2/YAP轴促进肿瘤转移。癌症衍生的EVs传递促转移的miR-146a-5p来调节宫颈癌中的肌动蛋白动力学，从而导致癌症转移。该实验突出了一种有吸引力的宫颈癌治疗方式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/979a18bb38ab/JO2022-4499876.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/c14264d53362/JO2022-4499876.001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/c14264d53362/JO2022-4499876.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/142c2f879d64/JO2022-4499876.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/296f88205f69/JO2022-4499876.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/95ccee74fd74/JO2022-4499876.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/4c0a284d5846/JO2022-4499876.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/8f4e91aea66d/JO2022-4499876.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e02/9256433/979a18bb38ab/JO2022-4499876.007.jpg

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