Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Hum Exp Toxicol. 2023 Jan-Dec;42:9603271231180856. doi: 10.1177/09603271231180856.
Dysregulation of long intergenic non-protein coding RNA 00,641 (LINC00641) is associated with the malignancy progression of multiple cancers, including thyroid carcinoma. The current study aimed to determine the role of LINC00641 in papillary thyroid carcinoma (PTC) and the underlying mechanism. We found that LINC00641 was downregulated in PTC tissues and cells( < 0.05), and overexpression of LINC00641 inhibited PTC cell proliferation and invasion, and induced apoptosis( < 0.05), while silencing LINC00641 promoted the proliferation and invasion in PTC cells, and inhibited cell apoptosis( < 0.05). Furthermore, we found that Glioma-associated oncogene homolog 1 (GLI1) expression was negatively correlated with LINC00641 expression in PTC tissues ( = 0.7649, < 0.0001), and silencing GLI1 inhibited PTC cell proliferation and invasion, and induced apoptosis( < 0.05). Meanwhile, RNA immunoprecipitation (RIP) and RNA pull-down assays confirmed that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) bound to LINC00641 as an RNA binding protein, and overexpression of LINC00641 destabilized GLI1 mRNA by competitively binding to IGF2BP1. Rescue experiments revealed that overexpression of GLI1 restored the inhibitory effect of LINC00641 overexpression on activation of the AKT pathway, as well as PTC cell proliferation and invasion, and counteracted the induction of cell apoptosis by LINC00641 overexpression. Finally, in vivo experimental results showed that overexpression of LINC00641 markedly suppressed tumor growth and reduced expression of GLI1 and p-AKT in xenograft tumor mice( < 0.05). In summary, this study highlighted that LINC00641 plays a critical role in the malignant biological progression of PTC by regulating the LINC00641/IGF2BP1/GLI1/AKT signaling pathway, which may serve as a potential therapeutic target for PTC.
长链非编码 RNA 00641（LINC00641）的失调与多种癌症（包括甲状腺癌）的恶性进展有关。本研究旨在探讨 LINC00641 在甲状腺乳头状癌（PTC）中的作用及其潜在机制。我们发现，LINC00641 在 PTC 组织和细胞中表达下调（ < 0.05），过表达 LINC00641 抑制 PTC 细胞增殖和侵袭，诱导细胞凋亡（ < 0.05），而沉默 LINC00641 促进 PTC 细胞增殖和侵袭，抑制细胞凋亡（ < 0.05）。此外，我们发现Glioma-associated oncogene homolog 1（GLI1）在 PTC 组织中的表达与 LINC00641 的表达呈负相关（ = 0.7649， < 0.0001），沉默 GLI1 抑制 PTC 细胞增殖和侵袭，诱导细胞凋亡（ < 0.05）。同时，RNA 免疫沉淀（RIP）和 RNA 下拉实验证实胰岛素样生长因子 2 mRNA 结合蛋白 1（IGF2BP1）作为 RNA 结合蛋白与 LINC00641 结合，过表达 LINC00641 通过竞争性结合 IGF2BP1 使 GLI1 mRNA 不稳定。挽救实验表明，过表达 GLI1 恢复了 LINC00641 过表达对 AKT 通路激活、PTC 细胞增殖和侵袭的抑制作用，并抵消了 LINC00641 过表达诱导的细胞凋亡。最后，体内实验结果表明，过表达 LINC00641 显著抑制异种移植瘤小鼠的肿瘤生长，降低肿瘤组织中 GLI1 和 p-AKT 的表达（ < 0.05）。综上所述，本研究表明，LINC00641 通过调节 LINC00641/IGF2BP1/GLI1/AKT 信号通路在 PTC 的恶性生物学进展中发挥关键作用，可能成为 PTC 的潜在治疗靶点。
