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CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p
Molecular Cancer ( IF 27.7 ) Pub Date : 2022-07-15 , DOI: 10.1186/s12943-022-01615-8
Yong Xi 1 , Yaxing Shen 2 , Donglei Wu 3 , Jingtao Zhang 4 , Chengbin Lin 1 , Lijie Wang 1 , Chaoqun Yu 1 , Bentong Yu 4 , Weiyu Shen 1
Affiliation  

Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis. Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq. CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI. Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.

中文翻译:

CircBCAR3通过海绵化miR-27a-3p加速食管癌肿瘤发生和转移

环状 RNA (circRNA) 已被证明有助于食管癌的进展。通过生物信息学分析,预测 CircBCAR3 (hsa_circ_0007624) 在食管癌中差异表达。我们研究了 circBCAR3 在食管癌发生中的致癌作用和生物发生。使用功能丧失测定法探索了 circBCAR3 对癌细胞增殖、迁移、侵袭和铁死亡的功能。异种移植小鼠模型用于揭示 circBCAR3 对异种移植物生长和肺转移的影响。通过生物信息学分析研究了circBCAR3的上游和下游机制,并通过RNA免疫沉淀和荧光素酶报告基因分析证实。使用 RNA-seq 鉴定了缺氧诱导的食管癌细胞中失调的基因。CircBCAR3在食管癌组织和细胞中高表达,体外缺氧时其表达增加。circBCAR3的沉默在体外抑制了食管癌细胞的增殖、迁移、侵袭和铁死亡,并在体内抑制了小鼠食管异种移植物的生长和转移。circBCAR3 敲低挽救了缺氧诱导的食管癌细胞迁移和铁死亡的促进作用。机制上,circBCAR3 可以通过竞争性内源性 RNA 机制与 miR-27a-3p 相互作用,从而上调 transportin-1 (TNPO1)。此外,我们的研究表明,剪接因子 quaking (QKI) 是 circBCAR3 的正调节因子,通过靶向 BCAR3 前体 mRNA 中 hsa_circ_0007624 形成的外显子侧翼的内含子。缺氧上调 E2F7 以转录激活 QKI。我们的研究表明,剪接因子 QKI 促进 circBCAR3 的生物发生,通过与 miR-27a-3p 结合上调 TNPO1 加速食管癌肿瘤发生。这些数据表明circBCAR3是治疗食管癌的潜在靶点。缺氧诱导 E2F7 的上调,其在食管癌细胞中转录激活 QKI。QKI 通过并列环化外显子来增加 circBCAR3 的形成。CircBCAR3 与 miR-27a-3p 结合以促进 TNPO1 表达。CircBCAR3 通过 miR-27a-3p 促进食管癌细胞的增殖、迁移、侵袭和铁死亡。其通过与 miR-27a-3p 结合上调 TNPO1 加速食管癌肿瘤发生。这些数据表明circBCAR3是治疗食管癌的潜在靶点。缺氧诱导 E2F7 的上调,其在食管癌细胞中转录激活 QKI。QKI 通过并列环化外显子来增加 circBCAR3 的形成。CircBCAR3 与 miR-27a-3p 结合以促进 TNPO1 表达。CircBCAR3 通过 miR-27a-3p 促进食管癌细胞的增殖、迁移、侵袭和铁死亡。其通过与 miR-27a-3p 结合上调 TNPO1 加速食管癌肿瘤发生。这些数据表明circBCAR3是治疗食管癌的潜在靶点。缺氧诱导 E2F7 的上调,其在食管癌细胞中转录激活 QKI。QKI 通过并列环化外显子来增加 circBCAR3 的形成。CircBCAR3 与 miR-27a-3p 结合以促进 TNPO1 表达。CircBCAR3 通过 miR-27a-3p 促进食管癌细胞的增殖、迁移、侵袭和铁死亡。QKI 通过并列环化外显子来增加 circBCAR3 的形成。CircBCAR3 与 miR-27a-3p 结合以促进 TNPO1 表达。CircBCAR3 通过 miR-27a-3p 促进食管癌细胞的增殖、迁移、侵袭和铁死亡。QKI 通过并列环化外显子来增加 circBCAR3 的形成。CircBCAR3 与 miR-27a-3p 结合以促进 TNPO1 表达。CircBCAR3 通过 miR-27a-3p 促进食管癌细胞的增殖、迁移、侵袭和铁死亡。
更新日期:2022-07-15
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