环状 RNA PVT1 通过靶向 miR-455-5p 激活 CXCL12/CXCR4 信号通路来调节甲状腺髓样癌的生长和转移。

circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling.

机构信息

Department of Thyroid and Parathyroid Surgery Center, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China.

出版信息

J Exp Clin Cancer Res. 2021 May 7;40(1):157. doi: 10.1186/s13046-021-01964-0.

DOI:10.1186/s13046-021-01964-0

PMID:33962657

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8106141/

Abstract

BACKGROUND

Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC.

METHODS

Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo.

RESULTS

miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo.

CONCLUSIONS

miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.

摘要

背景

甲状腺髓样癌（MTC）占所有甲状腺癌相关死亡的 13.4%。MTC 的治疗方法非常有限，特别是对于有远端转移的患者。因此，了解 MTC 的发病机制对于寻求新的治疗途径至关重要。在这里，我们研究了 circPVT1/miR-455-5p 在 MTC 中的作用。

方法

使用人 MTC 组织和细胞系。采用 qRT-PCR 和 Western blot 检测 miR-455-5p、circPVT1、CXCL12 和上皮间质转化（EMT）相关蛋白的表达水平。集落形成实验、流式细胞术、Transwell 实验和划痕愈合实验分别用于评估细胞增殖、凋亡、迁移和侵袭能力。双荧光素酶报告基因实验和 RNA 免疫沉淀实验用于验证 circPVT1/miR-455-5p 和 miR-455-5p/CXCL12 的相互作用。裸鼠异种移植模型用于评估 shcircPVT1 和 miR-455-5p 模拟物对体内肿瘤生长和转移的影响。

结果

miR-455-5p 在 MTC 组织和细胞中表达降低，而 circPVT1 表达升高。它们的水平与 MTC 的预后相关。过表达 miR-455-5p 或 sh-circPVT1 抑制 EMT 和 MTC 细胞增殖、迁移和侵袭。miR-455-5p 靶向 CXCL12，而 circPVT1 海绵吸附 miR-455-5p。敲低 CXCL12 或 CXCL12/CXCR4 信号抑制剂逆转了 circPVT1 过表达或 miR-455-5p 抑制剂对 EMT 和 MTC 细胞增殖、迁移和侵袭的影响。敲低 circPVT1 或过表达 miR-455-5p 抑制体内 MTC 肿瘤生长和肺转移。