Liu Yiqian, Zhang Ling, Wang Jian, Xu Jiali, Xu Jing, Xie Mengyan, Wang Rong
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Oncology, Jintan Hospital Affiliated to Jiangsu University, Changzhou, China.
Cancer Biol Ther. 2025 Dec;26(1):2510041. doi: 10.1080/15384047.2025.2510041. Epub 2025 May 26.
Abnormally expressed long non-coding (lnc)RNAs are closely associated with the pathogenesis of non-small cell lung cancer (NSCLC); thus, the present study aimed to investigate the potential role of SNHG12 in NSCLC. Transmission electron microscopy and nanoparticle tracking analysis were conducted to verify NSCLC cell-derived small extracellular vesicles (sEVs). MicroRNA (miRNA/miR) and mRNA expression levels were determined using reverse transcription-quantitative PCR, while protein expression levels were determined using western blot analysis and immunofluorescence. In addition, potential binding sites between miR-326 and SNHG12/SLC7A11 were verified using a dual-luciferase reporter assay. Cell behavior was detected using flow cytometry, colony formation, wound healing and Transwell assays, and xenograft experiments were conducted to confirm the roles of SNHG12 in NSCLC. H&E staining was used for histological analysis, and each experiment was repeated three times. Results of the present study demonstrated that NSCLC-derived SNHG12 promoted type-2 tumor-associated macrophage (TAM2) polarization. However, the decrease of SNHG12 expression in EVs reduced TAM2 polarization, weakened NSCLC cell proliferation, migration and invasion, and promoted tumor cell ferroptosis. Moreover, results of the present study revealed that SNHG12 knockdown markedly suppressed tumor growth and the metastasis of NSCLC. In addition, SNHG12 upregulated SLC7A11 expression via binding to miR-326. Overexpressed SLC7A11 promoted tumor aggressiveness and suppressed the ferroptosis of NSCLC cells. Collectively, results of the present study revealed that SNHG12 suppressed ferroptosis and promoted the metastasis of NSCLC, further demonstrating that high SNHG12 expression levels may be indicative of poor clinical outcomes for patients with NSCLC. Thus, the present study highlighted that the SNHG12/miR-326/SLC7A11 axis may exhibit potential as a novel target for the treatment of NSCLC.
异常表达的长链非编码（lnc）RNA与非小细胞肺癌（NSCLC）的发病机制密切相关；因此，本研究旨在探讨SNHG12在NSCLC中的潜在作用。进行了透射电子显微镜和纳米颗粒跟踪分析以验证NSCLC细胞衍生的小细胞外囊泡（sEVs）。使用逆转录定量PCR测定微小RNA（miRNA/miR）和mRNA表达水平，而使用蛋白质免疫印迹分析和免疫荧光测定蛋白质表达水平。此外，使用双荧光素酶报告基因测定法验证了miR-326与SNHG12/SLC7A11之间的潜在结合位点。使用流式细胞术、集落形成、伤口愈合和Transwell测定法检测细胞行为，并进行异种移植实验以证实SNHG12在NSCLC中的作用。苏木精-伊红染色用于组织学分析，每个实验重复三次。本研究结果表明，NSCLC来源的SNHG12促进2型肿瘤相关巨噬细胞（TAM2）极化。然而，EVs中SNHG12表达的降低减少了TAM2极化，减弱了NSCLC细胞的增殖、迁移和侵袭，并促进了肿瘤细胞铁死亡。此外，本研究结果显示，SNHG12基因敲低明显抑制了NSCLC的肿瘤生长和转移。此外，SNHG12通过与miR-326结合上调SLC7A11表达。过表达的SLC7A11促进肿瘤侵袭性并抑制NSCLC细胞的铁死亡。总体而言，本研究结果显示，SNHG12抑制铁死亡并促进NSCLC转移，进一步证明高SNHG12表达水平可能预示NSCLC患者的临床预后较差。因此，本研究强调SNHG12/miR-326/SLC7A11轴可能具有作为NSCLC治疗新靶点的潜力。
