Department of Tumor Chemotherapy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Medical Oncology, 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei, China.
Thorac Cancer. 2023 Jul;14(21):2026-2037. doi: 10.1111/1759-7714.14986. Epub 2023 Jun 5.
Lung adenocarcinoma (LUAD) is highly malignant and associated with poor prognoses in patients worldwide. There has been widespread recognition that lncRNAs are tightly linked to LUAD tumorigenesis and development. Here, we identified that the LINC00621 level was increased in LUAD tissues and concerned with the poor prognoses in LUAD patients.
Bioinformatical analysis and RT-qPCR determined the level of LINC00621 in LUAD tissues and cell lines. The admeasurement of the proliferation, migration, and invasion abilities of LUAD cells was utilized in the CCK8 and Transwell formulas. Luciferase reporter assay was used to corroborate the downstream target genes of LINC00621. The phosphorylated SMAD3 protein was tested by Western blotting assay. The impression of LINC00621 knockdown on LUAD tumor growth and metastasis put into effect by murine models. ChIP-qPCR assay was carried out to verify the transcriptional regulation by FOXA1 on LINC00621.
In vitro, the knockdown of LINC00621 significantly reduced the proliferative, migrating, and invasive abilities, the same was true for tumorigenesis and metastasis in vivo. MiR-34a-5p as a straight target of LINC00621 was ascertained, and LUAD patients with inferior miR-34a-5p levels had undesirable prognoses. Furthermore, TGFBR1 is an immediate and functional connection site of miR-34a-5p. Collectively, LINC00621 can sponge miR-34a-5p and upregulate TGFBR1 levels, which further sensitized TGF-β signaling pathway. Finally, it was revealed that FOXA1 transcriptionally upregulated LINC00621.
This study uncovered that FOXA1-induced LINC00621 promotes LUAD progression via the miR-34a-5p/TGFBR1/TGF-β axis, and is one novel therapeutic target that may be used in LUAD treatment.
肺腺癌（LUAD）在全球范围内具有高度恶性和不良预后。人们普遍认识到，lncRNAs 与 LUAD 肿瘤发生和发展密切相关。在这里，我们发现 LINC00621 在 LUAD 组织中的水平升高，并与 LUAD 患者的不良预后有关。
生物信息学分析和 RT-qPCR 确定了 LUAD 组织和细胞系中 LINC00621 的水平。CCK8 和 Transwell 公式用于测量 LUAD 细胞的增殖、迁移和侵袭能力。荧光素酶报告基因测定用于证实 LINC00621 的下游靶基因。Western blotting 测定用于检测磷酸化 SMAD3 蛋白。通过小鼠模型实施 LINC00621 敲低对 LUAD 肿瘤生长和转移的影响。ChIP-qPCR 测定用于验证 FOXA1 对 LINC00621 的转录调控。
在体外，LINC00621 的敲低显著降低了增殖、迁移和侵袭能力，在体内亦然。确定 miR-34a-5p 是 LINC00621 的直接靶标，并且具有较低 miR-34a-5p 水平的 LUAD 患者预后不良。此外，TGFBR1 是 miR-34a-5p 的直接功能连接位点。总之，LINC00621 可以海绵 miR-34a-5p 并上调 TGFBR1 水平，从而进一步敏化 TGF-β 信号通路。最后，揭示了 FOXA1 转录上调 LINC00621。
本研究揭示了 FOXA1 诱导的 LINC00621 通过 miR-34a-5p/TGFBR1/TGF-β 轴促进 LUAD 进展，是 LUAD 治疗中可能使用的一种新的治疗靶点。
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