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起始识别复合物亚基 1(ORC1)通过靶向 Wnt 信号通路增强肺腺癌细胞的恶性行为。

Origin recognition complex subunit 1 (ORC1) augments malignant behaviors of lung adenocarcinoma cells via targeting Wnt signaling.

机构信息

Department of Medical Oncology, Xuzhou Cancer Hospital, Xuzhou, Jiangsu, China.

出版信息

Bioengineered. 2022 May;13(5):13520-13533. doi: 10.1080/21655979.2022.2078562.

Abstract

It has been reported that origin recognition complex subunit 1 (ORC1) plays an oncogenic role in certain human cancers. Nevertheless, its regulatory function in lung adenocarcinoma (LUAD) progression was poorly understood. In this study, gene and protein levels were measured via RT-qPCR and Western blotting. LUAD cell viability, apoptosis, and metastasis were determined via CCK-8, TUNEL, and Transwell assays. Bioinformatics analyses were performed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. Herein, it was revealed that ORC1 was evidently upregulated and positively correlated to unsatisfactory prognosis in LUAD. Besides, single-sample gene set enrichment analysis (ssGSEA) revealed that ORC1 is negatively associated with 17 immune infiltrating cells and differently expressed in several kinds of immune cells. Also, Gene Ontology (GO) analysis indicated the involvement of ORC1 in several molecular functions. In addition, experiments demonstrated that ORC1 facilitated malignant behaviors of LUAD cells; moreover, animal assays further affirmed that ORC1 promoted LUAD tumor growth . As for the molecular mechanisms involved, it was found that ORC1 depletion inhibited the Wnt pathway in LUAD cells. Furthermore, rescue experiments demonstrated that Wnt signaling activation could abate the impacts of ORC1 knockdown on tumorigenic phenotypes of LUAD cells. In conclusion, our findings demonstrated that ORC1 promoted LUAD progression by regulating the Wnt signaling, indicating ORC1 could be an auspicious biomarker or target for LUAD diagnosis and treatment.

摘要

据报道,起始识别复合物亚基 1(ORC1)在某些人类癌症中发挥致癌作用。然而,其在肺腺癌(LUAD)进展中的调节功能仍知之甚少。在这项研究中,通过 RT-qPCR 和 Western blot 测定基因和蛋白水平。通过 CCK-8、TUNEL 和 Transwell 测定 LUAD 细胞活力、凋亡和转移。使用 Genotype Tissue Expression(GTEx)和 The Cancer Genome Atlas(TCGA)数据库进行生物信息学分析。在此,揭示了 ORC1 在 LUAD 中明显上调,并与不良预后呈正相关。此外,单样本基因集富集分析(ssGSEA)显示 ORC1 与 17 种免疫浸润细胞呈负相关,并在几种免疫细胞中表达不同。此外,基因本体论(GO)分析表明 ORC1 参与了几种分子功能。此外,实验表明 ORC1 促进了 LUAD 细胞的恶性行为;此外,动物实验进一步证实 ORC1 促进了 LUAD 肿瘤的生长。至于涉及的分子机制,发现 ORC1 耗竭抑制了 LUAD 细胞中的 Wnt 通路。此外,挽救实验表明,Wnt 信号激活可以减轻 ORC1 敲低对 LUAD 细胞致瘤表型的影响。总之,我们的研究结果表明,ORC1 通过调节 Wnt 信号促进 LUAD 的进展,表明 ORC1 可能成为 LUAD 诊断和治疗的有前途的生物标志物或靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b703/9275907/6bb0d077fd86/KBIE_A_2078562_UF0001_OC.jpg

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