LncRNA CASC9 facilitates papillary thyroid cancer development and doxorubicin resistance via miR-28-3p/BCL-2 axis and PI3K/AKT signaling pathway.

IF 1.5 4区医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of Cardiothoracic Surgery Pub Date : 2024-11-13 DOI:10.1186/s13019-024-03129-4

Jianping Yu, Chun He, Yun Peng, Yuzhong Wen, Jing Wang

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Abstract

Background: Papillary thyroid cancer (PTC) is a malignant tumor that poses a serious threat to human health. LncRNA CASC9 serves as an oncogene in numerous tumors. The purpose of this study was to explore the mechanism of lncRNA CASC9 regulating doxorubicin (Dox) resistance in PTC.

Methods: The expression of CASC9, miR-28-3p and BCL-2 in PTC tissues or dox-resistant cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot (WB). CCK-8, colony formation assay, flow cytometry and transwell assay were used to measure the semi-inhibitory concentration (IC50) of dox, cell proliferation, apoptosis and migration, respectively. Dual luciferase reporter gene assays were performed to verify the targeting relationship between miR-28-3p and CASC9 or BCL-2. Rescue experiments were applied to verify the mechanism of CASC9. Finally, the role of CASC9 was verified by xenograft modeling in vivo.

Results: We discovered that CASC9 was enhanced in PTC tissues, cells and Dox-resistant cells (BCPAP/Dox and K1/Dox). Furthermore, CASC9 inhibition markedly restrained the proliferation, migration and facilitated apoptosis of Dox cells. In vivo experiments also showed that silencing of CASC9 inhibited tumor growth. Meanwhile, knockdown of CASC9 sensitized PTC cells to Dox. CASC9 enhanced tumor progression by activating the PI3K/AKT signaling pathway. Furthermore, bioinformatics analysis identified miR-28-3p as a downstream target of CASC9. MiR-28-3p inhibitor reversed the impact of CASC9 knockdown in BCPAP/Dox and K1/Dox. Further studies showed that CASC9 positively regulated BCL-2 expression through miR-28-3p. miR-28-3p weakened Dox resistance, proliferation, migration and accelerated apoptosis of PTC cells via BCL-2.

Conclusion: CASC9, as an oncogenic lncRNA, has a promotional effect on Dox resistance and PTC progression via miR-28-3p/BCL-2 axis and PI3K/AKT signaling pathway.

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LncRNA CASC9通过miR-28-3p/BCL-2轴和PI3K/AKT信号通路促进甲状腺乳头状癌的发展和多柔比星耐药性的产生。

背景：甲状腺乳头状癌（PTC甲状腺乳头状癌（PTC）是一种严重威胁人类健康的恶性肿瘤。LncRNA CASC9是多种肿瘤的致癌基因。本研究旨在探讨lncRNA CASC9调控多柔比星（Dox）在PTC中耐药的机制：方法：通过实时定量聚合酶链反应（qRT-PCR）或免疫印迹（WB）检测CASC9、miR-28-3p和BCL-2在PTC组织或多柔比星耐药细胞中的表达。CCK-8、集落形成试验、流式细胞术和透孔试验分别用于测定多克斯的半抑制浓度（IC50）、细胞增殖、凋亡和迁移。通过双荧光素酶报告基因实验来验证 miR-28-3p 与 CASC9 或 BCL-2 的靶向关系。实验还应用了拯救实验来验证 CASC9 的作用机制。最后，通过体内异种移植模型验证了CASC9的作用：结果：我们发现，CASC9在PTC组织、细胞和Dox耐药细胞（BCPAP/Dox和K1/Dox）中增强。此外，抑制 CASC9 能显著抑制 Dox 细胞的增殖、迁移并促进其凋亡。体内实验也表明，沉默 CASC9 可抑制肿瘤生长。同时，敲除 CASC9 可使 PTC 细胞对 Dox 敏感。CASC9通过激活PI3K/AKT信号通路促进肿瘤进展。此外，生物信息学分析发现，miR-28-3p 是 CASC9 的下游靶点。MiR-28-3p抑制剂逆转了CASC9敲除对BCPAP/Dox和K1/Dox的影响。进一步的研究表明，CASC9通过miR-28-3p正向调控BCL-2的表达，miR-28-3p通过BCL-2削弱了PTC细胞对Dox的耐药性、增殖、迁移并加速其凋亡：CASC9作为一种致癌lncRNA，通过miR-28-3p/BCL-2轴和PI3K/AKT信号通路对Dox耐药和PTC进展有促进作用。

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来源期刊

Journal of Cardiothoracic Surgery 医学-心血管系统

CiteScore

2.50

自引率

6.20%

发文量

286

审稿时长

4-8 weeks

期刊介绍： Journal of Cardiothoracic Surgery is an open access journal that encompasses all aspects of research in the field of Cardiology, and Cardiothoracic and Vascular Surgery. The journal publishes original scientific research documenting clinical and experimental advances in cardiac, vascular and thoracic surgery, and related fields. Topics of interest include surgical techniques, survival rates, surgical complications and their outcomes; along with basic sciences, pediatric conditions, transplantations and clinical trials. Journal of Cardiothoracic Surgery is of interest to cardiothoracic and vascular surgeons, cardiothoracic anaesthesiologists, cardiologists, chest physicians, and allied health professionals.