Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma.
Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma.
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DOI：
10.1186/s13046-022-02560-6
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发表时间：
2023-01-10
影响因子：
11.3
通讯作者：
Liu, Zhen
中科院分区：
文献类型：
--
作者：
Tao, Xingyu;Li, Yang;Fan, Songqing;Wu, Liyang;Xin, Jianyang;Su, Yun;Xian, Xiaoyang;Huang, Yingying;Huang, Rongquan;Fang, Weiyi;Liu, Zhen
LINC 00173已被报告为小细胞肺癌（SCLC）和肺鳞状细胞癌（LUSC）的顺铂（顺式二氨二氯铂，DDP）化疗耐药诱导剂。本研究旨在显示LINC 00173作为肺腺癌（LUAD）中DDP化疗敏感性诱导因子的反向数据。LINC 00173从基因表达综合数据库（GSE 43493）中筛选。采用原位杂交和定量逆转录-聚合酶链反应检测LINC 00173在LUAD组织和细胞系中的表达水平。采用集落形成、细胞存活率、半数抑制浓度、流式细胞术和异种移植小鼠模型评价LINC 00173对LUAD化疗敏感性的影响。应用LINC 00173介导miR-1275/PROCA 1/ZFP 36 L2轴损害BCL 2 mRNA稳定性的机制，并进行免疫共沉淀、染色质免疫沉淀、RNA反义纯化、RNA免疫沉淀和荧光素酶报告基因测定。DDP耐药LUAD患者LINC 00173表达下调与预后不良相关。此外，LINC 00173表达在DDP耐药LUAD细胞和DDP处理的人LUAD组织中显著降低。抑制LINC 00173的表达可增强LUAD细胞对DDP的体内外耐药性，而恢复LINC 00173的表达可使LUAD细胞对DDP的化疗敏感性明显恢复。机制上，DDP耐药LUAD细胞激活PI 3 K/AKT信号并进一步提高c-Myc表达。c-Myc作为一种致癌转录因子，与LINC 00173的启动子结合，抑制其表达。降低的LINC 00173表达减弱了致癌miR-1275的吸附，下调了miR-1275靶基因PROCA 1的表达。PROCA 1通过募集ZFP 36 L2与BCL 2的3′端非翻译区结合，降低BCL 2 mRNA的稳定性，激活凋亡信号，从而发挥潜在的抑瘤作用，诱导细胞凋亡和DDP化疗敏感性。这项研究证明了LINC 00173的一种新的关键作用。在LUAD中，它被DDP激活的PI 3 K/AKT/c-Myc信号转录抑制，通过调节miR-1275抑制PROCA 1/ZFP 36 L2诱导的BCL 2降解，从而促进DDP获得性化疗耐药，从而导致凋亡信号减少。这些数据与先前描述的LINC 00173在SCLC或LUSC中的作用不一致，这表明LINC 00173可以在肺癌的不同病理亚型中发挥微调的DDP耐药作用。这项研究表明，LINC 00173的表达减少可能作为LUAD中DDP获得性耐药的指标。在线版本包含补充材料，可通过10.1186/s13046-022-02560-6获得。
LINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small-cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). This study aimed to display reverse data for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD). LINC00173 was screened from the Gene Expression Omnibus database (GSE43493). The expression level of LINC00173 in LUAD tissues and cell lines was detected using in situ hybridization and quantitative reverse transcription–polymerase chain reaction. Colony formation, cell viability, half-maximal inhibitory concentration, flow cytometry, and xenograft mouse model were used to evaluate the role of LINC00173 in the chemosensitivity of LUAD to DDP. The mechanism of LINC00173 in DDP resistance by mediating miR-1275/PROCA1/ZFP36L2 axis to impair BCL2 mRNA stability was applied, and co-immunoprecipitation, chromatin immunoprecipitation, RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays were performed. LINC00173 downregulation in patients with DDP-resistant LUAD was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 expression in LUAD cells enhanced DDP chemoresistance in vivo and in vitro, while restored LINC00173 expression in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated the c-Myc expression. The c-Myc, as an oncogenic transcriptional factor, bound to the promoter of LINC00173 and suppressed its expression. The reduced LINC00173 expression attenuated the adsorption of oncogenic miR-1275, downregulating the expression of miR-1275 target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3′ untranslated region of BCL2, reducing the stability of BCL2 mRNA and thus activating the apoptotic signal. This study demonstrated a novel and critical role of LINC00173. It was transcriptionally repressed by DDP-activated PI3K/AKT/c-Myc signal in LUAD, promoting DDP-acquired chemotherapeutic resistance by regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, which led to apoptotic signal reduction. These data were not consistent with the previously described role of LINC00173 in SCLC or LUSC, which suggested that LINC00173 could play fine-tuned DDP resistance roles in different pathological subtypes of lung cancer. This study demonstrated that the diminished expression of LINC00173 might serve as an indicator of DDP-acquired resistance in LUAD. The online version contains supplementary material available at 10.1186/s13046-022-02560-6.
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