Constitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC). However, the underlying mechanisms of excessive activation of NF-κB signaling remain largely unknown. We used high throughput RNA sequencing to identify differentially expressed circular RNAs (circRNAs) between normal human intestinal epithelial cell lines and CRC cell lines. The identification of protein encoded by circPLCE1 was performed using LC–MS. The function of novel protein was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. A novel protein circPLCE1-411 encoded by circular RNA circPLCE1 was identified as a crucial player in the NF-κB activation of CRC. Mechanistically, circPLCE1-411 promoted the ubiquitin-dependent degradation of the critical NF-κB regulator RPS3 via directly binding the HSP90α/RPS3 complex to facilitate the dissociation of RPS3 from the complex, thereby reducing NF-κB nuclear translocation in CRC cells. Functionally, circPLCE1 inhibited tumor proliferation and metastasis in CRC cells, as well as patient-derived xenograft and orthotopic xenograft tumor models. Clinically, circPLCE1 was downregulated in CRC tissues and correlated with advanced clinical stages and poor survival. circPLCE1 presents an epigenetic mechanism which disrupts NF-κB nuclear translocation and serves as a novel and promising therapeutic target and prognostic marker.

中文翻译：

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一种由circPLCE1编码的新型NF-κB调节因子通过促进RPS3泛素依赖性降解抑制结直肠癌进展

核因子-κB (NF-κB) 信号传导的组成性激活在结直肠癌 (CRC) 的发生和进展中起关键作用。然而，过度激活 NF-κB 信号传导的潜在机制仍然很大程度上未知。我们使用高通量 RNA 测序来鉴定正常人肠上皮细胞系和 CRC 细胞系之间差异表达的环状 RNA (circRNA)。使用 LC-MS 对 circPLCE1 编码的蛋白质进行鉴定。新型蛋白质的功能在体外和体内通过功能获得或损失测定法进行了验证。通过免疫沉淀分析得出机械结果。一种由环状 RNA circPLCE1 编码的新型蛋白质 circPLCE1-411 被确定为 CRC 的 NF-κB 激活的关键参与者。机械地，circPLCE1-411 通过直接结合 HSP90α/RPS3 复合物促进 RPS3 从复合物中解离，从而促进关键 NF-κB 调节因子 RPS3 的泛素依赖性降解，从而减少 CRC 细胞中的 NF-κB 核转位。在功能上，circPLCE1 抑制 CRC 细胞以及患者来源的异种移植物和原位异种移植物肿瘤模型中的肿瘤增殖和转移。临床上，circPLCE1 在 CRC 组织中下调，并与晚期临床分期和较差的生存率相关。circPLCE1 呈现出一种表观遗传机制，可破坏 NF-κB 核转位，并作为一种新的、有前景的治疗靶点和预后标志物。从而减少 CRC 细胞中的 NF-κB 核转位。在功能上，circPLCE1 抑制 CRC 细胞以及患者来源的异种移植物和原位异种移植物肿瘤模型中的肿瘤增殖和转移。临床上，circPLCE1 在 CRC 组织中下调，并与晚期临床分期和较差的生存率相关。circPLCE1 呈现出一种表观遗传机制，可破坏 NF-κB 核转位，并作为一种新的、有前景的治疗靶点和预后标志物。从而减少 CRC 细胞中的 NF-κB 核转位。在功能上，circPLCE1 抑制 CRC 细胞以及患者来源的异种移植物和原位异种移植物肿瘤模型中的肿瘤增殖和转移。临床上，circPLCE1 在 CRC 组织中下调，并与晚期临床分期和较差的生存率相关。circPLCE1 呈现出一种表观遗传机制，可破坏 NF-κB 核转位，并作为一种新的、有前景的治疗靶点和预后标志物。