Circular RNA circ-TNPO3 inhibits clear cell renal cell carcinoma metastasis by binding to IGF2BP2 and destabilizing SERPINH1 mRNA.
Circular RNA circ-TNPO3 inhibits clear cell renal cell carcinoma metastasis by binding to IGF2BP2 and destabilizing SERPINH1 mRNA.
复制标题
环状 RNA circ-TNPO3 通过与 IGF2BP2 结合并破坏 SERPINH1 mRNA 的稳定性来抑制透明细胞肾细胞癌转移
DOI：
10.1002/ctm2.994
复制
发表时间：
2022-07
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
透明细胞肾细胞癌（ccRCC）是泌尿道的常见恶性肿瘤。预后不良的主要原因是缺乏早期诊断和转移。越来越多的研究表明，环状RNA（circRNA）在癌症的发生和发展中起着关键作用。然而，circRNA在ccRCC中的作用仍然不确定。采用circRNA芯片（n = 4）检测ccRCC组织中差异表达的circRNA。基于截止标准选择候选circRNA，例如circRNA表达丰度、circRNA大小和不同引物的设计。通过定量真实的-时间（qRT）-PCR（n = 110）检测ccRCC组织中的循环转运蛋白-3（TNPO 3）水平。通过RNase R测定、qRT-PCR和荧光原位杂交（FISH）鉴定了circ-TNPO 3的特征和亚细胞定位。然后，我们通过体外和体内功能实验探讨了circ-TNPO 3在ccRCC中的生物学作用。应用RNA pull-down、RNA免疫沉淀、生物信息学分析、RNA-FISH测定和拯救测定来验证circ-TNPO 3、胰岛素样生长因子2 mRNA结合蛋白2（IGF 2BP 2）和丝氨酸蛋白酶抑制剂家族H成员1（SERPINH 1）之间的相互作用，以揭示circ-TNPO 3的潜在分子机制。我们检测到与匹配的相邻正常组织相比，ccRCC中的circ-TNPO 3明显下调（n = 110）。在具有远处转移、较高的世界卫生组织/国际泌尿病理学家学会（WHO/ISUP）分级和更晚期的肿瘤T分期的ccRCC患者中发现较低的circ‐ TNPO 3表达。在体外和体内，circ-TNPO 3显著抑制ccRCC细胞的增殖和迁移。从机制上讲，我们阐明了circ-TNPO 3直接与IGF 2BP 2蛋白结合，然后使SERPINH 1 mRNA不稳定。此外，IGF 2BP 2/SERPINH 1轴负责circ‐ TNPO 3抑制ccRCC转移的功能。上皮剪接调节蛋白1（ESRP 1）可能参与circ‐ TNPO 3的生物发生。Circ-TNPO 3可以通过直接结合IGF 2BP 2蛋白和使SERPINH 1 mRNA不稳定来抑制ccRCC进展和转移。Circ‐ TNPO 3可能作为ccRCC治疗的潜在靶点。Circ‐ TNPO 3在ccRCC中显著下调。Circ‐ TNPO 3可通过直接结合IGF 2BP 2蛋白并使SERPINH 1 mRNA失稳，进而调节SERPINH 1 ‐SNAIL/SLUG轴来抑制ccRCC转移。ESRP 1通过靶向侧翼内含子参与circ‐ TNPO 3的生物发生。
Clear cell renal cell carcinoma (ccRCC) is a common malignant tumour of the urinary tract. The major causes of poor prognosis are the lack of early diagnosis and metastasis. Accumulating research reveals that circular RNAs (circRNAs) can play key roles in the development and the progression of cancer. However, the role of circRNAs in ccRCC is still uncertain. The circRNAs microarray (n = 4) was performed to investigate the circRNAs with differential expression in ccRCC tissues. The candidate circRNA was selected based on the cut‐off criteria, such as circRNA expression abundance, circRNA size and the design of divergent primers. The circ‐transportin‐3 (TNPO3) levels in ccRCC tissues were tested by quantitative real‐time (qRT)‐PCR (n = 110). The characteristics and subcellular localization of circ‐TNPO3 were identified via RNase R assay, qRT‐PCR and fluorescence in situ hybridization (FISH). Then, we explored the biological roles of circ‐TNPO3 in ccRCC via the function experiments in vitro and in vivo. RNA pull‐down, RNA immunoprecipitation, bioinformatic analysis, RNA‐FISH assays and rescue assays were applied to validate the interactions between circ‐TNPO3, insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2) and serpin family H member 1 (SERPINH1) to uncover the underlying molecular mechanisms of circ‐TNPO3. We detected the obvious downregulation of circ‐TNPO3 in ccRCC compared to matched adjacent normal tissues (n = 110). The lower circ‐TNPO3 expression was found in ccRCC patients with distant metastasis, higher World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) grade and more advanced tumour T stage. In vitro and in vivo, circ‐TNPO3 significantly suppressed the proliferation and migration of ccRCC cells. Mechanistically, we elucidated that circ‐TNPO3 directly bound to IGF2BP2 protein and then destabilized SERPINH1 mRNA. Moreover, IGF2BP2/SERPINH1 axis was responsible for circ‐TNPO3's function of inhibiting ccRCC metastasis. Epithelial splicing regulatory protein 1 (ESRP1) was probably involved in the biogenesis of circ‐TNPO3. Circ‐TNPO3 can suppress ccRCC progression and metastasis via directly binding to IGF2BP2 protein and destabilizing SERPINH1 mRNA. Circ‐TNPO3 may act as a potential target for ccRCC treatment. Circ‐TNPO3 is significantly downregulated in ccRCC. Circ‐TNPO3 can suppress ccRCC metastasis by directly binding to IGF2BP2 protein and destabilizing SERPINH1 mRNA, in turn, regulating the SERPINH1‐SNAIL/SLUG axis. ESRP1 is involved in the biogenesis of circ‐TNPO3 by targeting the flanking intron.
登录
查看更多内容
YTHDF2通过识别METTL3介导的m(6)A修饰促进UBXN1 mRNA降解，从而激活NE-kappa B并促进胶质瘤的恶性进展
影响因子：
28.5
作者：
Chai RC;Chang YZ;Chang X;Pang B;An SY;Zhang KN;Chang YH;Jiang T;Wang YZ
通讯作者：
Wang YZ
影响因子：
14.9
作者：
Hong H;An O;Chan THM;Ng VHE;Kwok HS;Lin JS;Qi L;Han J;Tay DJT;Tang SJ;Yang H;Song Y;Bellido Molias F;Tenen DG;Chen L
通讯作者：
Chen L
circTP63 作为 ceRNA 通过上调 FOXM1 促进肺鳞状细胞癌进展
影响因子：
16.6
作者：
Cheng, Zhuoan;Yu, Chengtao;Qin, Wenxin
通讯作者：
Qin, Wenxin
CircRNA cRAPGEF5 通过 miR-27a-3p/TXNIP 通路抑制肾细胞癌的生长和转移。
影响因子：
9.7
作者：
Chen, Qiong;Liu, Tao;Wang, Linhui
通讯作者：
Wang, Linhui
影响因子：
8
作者：
Bell, Jessica L.;Waechter, Kristin;Muehleck, Britta;Pazaitis, Nikolaos;Koehn, Marcel;Lederer, Marcell;Huettelmaier, Stefan
通讯作者：
Huettelmaier, Stefan