Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Hubei Key Laboratory of Tumour Biological Behaviours, Wuhan, 430071, China.
J Exp Clin Cancer Res. 2023 Nov 27;42(1):319. doi: 10.1186/s13046-023-02887-8.
It has been demonstrated that circularRNA (circRNAs) plays a critical role in various cancers. While the potential molecular mechanism of circRNAs in the progression of colorectal cancer (CRC) remains uncertain.
Differentially expressed circRNAs were identified by RNA sequencing. RT-qPCR detected the expression of circ_0009092, miR-665, and NLK in CRC tissues and cells. Functions of circ_0009092 on tumor cell proliferation, migration, and invasion were investigated by a series of in vitro assays. The underlying mechanism of circ_0009092 was explored by bioinformatics analysis, RNA immunoprecipitation (RIP) and luciferase assays. A co-culture assay in vitro was performed to detect the affection of circ_0009092 on macrophage recruitment in the tumor microenvironment (TME). A xenograft mouse model was used to explore the effect of circ_0009092 on tumor growth.
Circ_0009092 was downregulated in CRCand predicted a good prognosis. Overexpression of circ_0009092 reduced tumor cell EMT, proliferation, migration, and invasion in vitro and in vivo. Mechanistically, circ_0009092 elevated the NLK expression via sponging miR-665 and suppressed the Wnt/β-catenin signaling pathway. EIF4EA3 induced circ_0009092 expression in CRC cells. In addition, NLK regulates phosphorylation and O-GlcNAcylation of STAT3 by binding to STAT3, thereby inhibiting CCL2 expression, in which it inhibits macrophage recruitment in the tumor microenvironment (TME).
EIF4A3 suppressed circ_0009092 biogenesis, whichinhibits CRC progression by sponging miR-665 to downregulate NLK. Circ_0009092/miR-665/NLK suppressed tumor EMT, proliferation, migration, and invasion by acting on the Wnt/β-catenin signaling pathway. NLK directly interacted with STAT3 and decreased the CCL2 expression, inhibiting the recruitment of tumor-associated macrophages (TAMs) in the TME. Our study provided novel insights into the roles of circ_0009092 as a novel promising prognostic and therapeutic target in CRC.
已经证明环状 RNA（circRNAs）在各种癌症中发挥着关键作用。然而，circRNAs 在结直肠癌（CRC）进展中的潜在分子机制尚不清楚。
通过 RNA 测序鉴定差异表达的 circRNAs。实时定量 PCR（RT-qPCR）检测 CRC 组织和细胞中 circ_0009092、miR-665 和 NLK 的表达。通过一系列体外实验研究 circ_0009092 对肿瘤细胞增殖、迁移和侵袭的影响。通过生物信息学分析、RNA 免疫沉淀（RIP）和荧光素酶测定探讨 circ_0009092 的潜在机制。体外共培养实验检测 circ_0009092 对肿瘤微环境（TME）中巨噬细胞募集的影响。建立异种移植小鼠模型探讨 circ_0009092 对肿瘤生长的影响。
circ_0009092 在 CRC 中表达下调，预测预后良好。过表达 circ_0009092 可降低肿瘤细胞 EMT、体外和体内增殖、迁移和侵袭。机制上，circ_0009092 通过海绵 miR-665 上调 NLK 表达，抑制 Wnt/β-catenin 信号通路。EIF4EA3 诱导 CRC 细胞中 circ_0009092 的表达。此外，NLK 通过与 STAT3 结合调节 STAT3 的磷酸化和 O-GlcNAc 化，从而抑制 CCL2 的表达，抑制肿瘤微环境（TME）中巨噬细胞的募集。
EIF4A3 抑制 circ_0009092 的生物发生，通过海绵 miR-665 下调 NLK 抑制 CRC 进展。circ_0009092/miR-665/NLK 通过作用于 Wnt/β-catenin 信号通路抑制肿瘤 EMT、增殖、迁移和侵袭。NLK 直接与 STAT3 相互作用，降低 CCL2 的表达，抑制 TME 中肿瘤相关巨噬细胞（TAMs）的募集。我们的研究为 circ_0009092 作为 CRC 中一种有前途的新型预后和治疗靶点提供了新的见解。
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