Hsa_circ_0000520 通过 Lin28a/PTEN/PI3K 信号通路抑制膀胱癌中的血管生成拟态形成和转移。
Hsa_circ_0000520 suppresses vasculogenic mimicry formation and metastasis in bladder cancer through Lin28a/PTEN/PI3K signaling.
机构信息
Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
出版信息
Cell Mol Biol Lett. 2024 Sep 5;29(1):118. doi: 10.1186/s11658-024-00627-0.
BACKGROUND
Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear.
METHODS
Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization.
RESULTS
Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI.
CONCLUSIONS
Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.
背景
血管生成拟态（VM）是抗血管生成治疗产生耐药的潜在原因，与肿瘤的恶性进展密切相关。已有研究表明，非编码 RNA 在恶性肿瘤中 VM 的形成中发挥着重要作用。然而，circRNAs 在膀胱癌 VM 中的作用及其调控机制尚不清楚。
方法
首先，通过 Sanger 测序和 Rnase R 实验鉴定 hsa_circ_0000520 具有环状特征。其次，通过定量实时聚合酶链反应（qRT-PCR）和临床标本的荧光原位杂交（FISH）来探索 hsa_circ_0000520 的潜在临床价值。第三，通过体内和体外实验研究 hsa_circ_0000520 对膀胱癌侵袭、迁移和 VM 形成的作用。最后，通过 RNA 结合蛋白免疫沉淀（RIP）、RNA 下拉、免疫共沉淀（co-IP）、qRT-PCR、Western blot（WB）和荧光共定位实验阐明 hsa_circ_0000520 在膀胱癌恶性进展中的调控机制。
结果
hsa_circ_0000520 被鉴定为环状 RNA，与癌旁组织相比，在膀胱癌中表达水平较低。hsa_circ_0000520 高表达的膀胱癌患者具有更好的生存预后。功能上，hsa_circ_0000520 抑制膀胱癌的侵袭、迁移和 VM 形成。机制上，hsa_circ_0000520 作为支架促进 UBE2V1/UBC13 与 Lin28a 的结合，进而促进 Lin28a 的普遍降解，提高 PTEN mRNA 稳定性，抑制 PI3K/AKT 通路的磷酸化。膀胱癌中 hsa_circ_0000520 的形成受 RNA 结合蛋白 QKI 的调控。
结论
hsa_circ_0000520 抑制膀胱癌的转移和 VM 形成，是膀胱癌诊断和治疗的潜在靶点。
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