环状RNA Hsa_circ_0057521靶向miR-9调控MAPK/ERK信号通路促进甲状腺乳头状癌恶性进展的分子机制研究

The incidence of thyroid cancer has increased dramatically in recent decades, and the prognosis is closely related to the progression of malignancy. It has been demonstrated that PTC progression is associated with persistent activation of signaling pathways, and in which non-coding RNA with its molecular networks play important roles. In this study we have found that the expression of Hsa_circ_0057521 is significantly increased in PTC tissues by using cirRNA gene chip when screening 6 pairs of specimen that including highly invasive PTC and adjacent normal tissues, and this result are verified in PTC tissues and cells by qRT-PCR. Moreover the migration ability of PTC cells was significantly decreased when knocking down the expression of Hsa_circ_0057521. All these results indicate that Hsa_circ_0057521 may be involved in malignant progression of PTC. Further bio-informatics prediction shows that Hsa_circ_0057521 may activate MAPK/ERK signaling pathway by targeting to miR-9. In the follow-up study, we will further verify the role of Hsa_circ_0057521 in the progression of PTC in clinical species and in vitro/vivo experiments, and elucidate the mechanism that Hsa_circ_0057521 promotes progression of PTC by regulating MAPK/ERK pathway via functioning as a sponge of miR-9. Therefore this study will provide new targets for PTC precision diagnosis and treatment, and which is of great significance for improving the prognosis of PTC patients.

甲状腺乳头状癌（PTC）是发病率增长最快的恶性肿瘤，疾病进展导致预后不良。研究显示信号通路级联激活促进PTC恶性进展，其中非编码RNA及其调控网络发挥重要作用。本课题对6对高侵袭性PTC和癌旁正常组织进行环状RNA芯片筛选，并在PTC组织和细胞中验证筛选结果，发现Hsa_circ_0057521表达显著升高，敲减其表达后癌细胞迁移能力明显下降，提示Hsa_circ_0057521促进PTC恶性进展，同时生物信息预测显示Hsa_circ_0057521可以海绵吸附miR-9，下游靶基因富集于MAPK/ERK通路。后续我们将进一步通过临床标本检测、细胞和动物实验验证Hsa_circ_0057521在PTC恶性进展中的作用，并阐明该环状RNA通过靶向miR-9调控MAPK/ERK通路从而促进PTC恶性进展这一分子机制。本研究成果将为PTC精准诊疗提供新靶标，对改善PTC患者预后具有重大意义。

甲状腺乳头状癌（PTC）是发病率增长最快的恶性肿瘤，疾病进展导致预后不良。研究显示环状RNA及其调控网络在调控甲状腺乳头状癌恶性进展中发挥重要作用。本课题前期对高侵袭性PTC和癌旁正常组织进行环状RNA芯片筛选，发现Hsa_circ_0057521表达显著升高，敲减其表达后癌细胞迁移能力明显下降，提示Hsa_circ_0057521可能与甲状腺乳头状癌恶性进展密切相关。本项目旨在明确Hsa_circ_0057521调控甲状腺乳头状癌恶性进展的分子机制。该项目通过基因过表达或表达抑制技术、脂质体转染等体外实验、构建裸鼠成瘤模型，揭示了Hsa_circ_0057521通过海绵吸附miR-9靶向BRAF从而促进甲状腺乳头状癌恶性进展这一分子机制，挖掘出了Hsa_circ_0057521作为甲状腺乳头状癌诊断标志物和治疗靶点的潜能，为开发以Hsa_circ_0057521为靶标治疗复发转移性甲状腺乳头状癌的新措施奠定前期基础，为临床诊断和治疗甲状腺乳头状癌提供新策略。本研究成果以论文形式《Circ_0057521 promotes papillary thyroid carcinoma progression by sponging miR-9/BRAF axis》在投稿中，在本项目的支持下，申请人开展的一系列研究相关论文被期刊Endocrine，Postgraduate Medicine，Endocrine Connections，BMC Endocrine Disorders收录。后续将基于本项目结果的临床应用价值，计划申请并开展相关的临床试验研究。