环状 RNA6834 通过稳定 ANHAK 和调节 miR-873-5p/TXNIP 轴抑制非小细胞肺癌的进展。
Circ6834 suppresses non-small cell lung cancer progression by destabilizing ANHAK and regulating miR-873-5p/TXNIP axis.
机构信息
Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China.
Department of Oncology, Gaochun Hospital Affiliated to Jiangsu University, Nanjing, 211300, China.
出版信息
Mol Cancer. 2024 Jun 18;23(1):128. doi: 10.1186/s12943-024-02038-3.
BACKGROUND
Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear.
METHODS
In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments.
RESULTS
Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells.
CONCLUSION
In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.
背景
环状 RNA（circRNAs）在癌症的进展和转移中发挥重要作用。然而，circRNAs 在非小细胞肺癌（NSCLC）中的表达谱和生物学作用仍不清楚。
方法
在这项研究中，我们通过 RNA-seq 鉴定了 NSCLC 中的一种新型 circRNA，hsa_circ_0006834（称为 circ6834），并研究了 circ6834 在 NSCLC 进展中的生物学作用。最后，通过标记 RNA 亲和纯化（TRAP）、western blot、RNA 免疫沉淀、双荧光素酶报告基因检测和挽救实验揭示了 circ6834 的分子机制。
结果
我们的结果表明，circ6834 在 NSCLC 肿瘤组织和细胞系中下调。circ6834 的过表达抑制了 NSCLC 细胞的体外和体内生长和转移，而 circ6834 的敲低则产生相反的效果。我们发现 TGF-β 处理降低了 circ6834 的表达，这与 NSCLC 细胞中 QKI 的减少有关，并且 circ6834 拮抗了 TGF-β 诱导的 EMT 和 NSCLC 细胞的转移。机制上，circ6834 与 AHNAK 蛋白结合，AHNAK 蛋白是 TGF-β/Smad 信号通路的关键调节因子，并通过增强 TRIM25 介导的泛素化和降解来抑制其稳定性。此外，circ6834 作为 miR-873-5p 的 miRNA 海绵，并上调 TXNIP 基因表达，共同抑制了 NSCLC 细胞中的 TGF-β/Smad 信号通路。
结论
总之，circ6834 是一种肿瘤抑制性 circRNA，通过与 TGF-β/Smad 信号通路形成负反馈调节环来抑制 NSCLC 的进展，代表了 NSCLC 的一种新的治疗靶点。
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