Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
Department of Oncology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
Mol Cancer. 2020 May 30;19(1):98. doi: 10.1186/s12943-020-01217-2.
Anti-angiogenic therapy represents a promising strategy for non-small-cell lung cancer (NSCLC) but its application in lung squamous cell carcinoma (SQC) is limited due to the high-risk adverse effects. Accumulating evidence indicates that long noncoding RNAs (lncRNAs) mediate in tumor progression by participating in the regulation of VEGF in NSCLC, which might guide the development of new antiangiogenic strategies.
Differential lncRNA expression in SQC was analyzed in AE-meta and TCGA datasets, and further confirmed in lung cancer tissues and adjacent normal tissues with RT-qPCR and in-situ hybridization. Statistical analysis was performed to evaluate the clinical correlation between LINC00173.v1 expression and survival characteristics. A tube formation assay, chick embryo chorioallantoic membrane assay and animal experiments were conducted to detect the effect of LINC00173.v1 on the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC in vivo. Bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the downstream target of LINC00173.v1. The therapeutic efficacy of antisense oligonucleotide (ASO) against LINC00173.v1 was further investigated in vivo. Chromatin immunoprecipitation and high throughput data processing and visualization were performed to identify the cause of LINC00173.v1 overexpression in SQC.
LINC00173.v1 was specifically upregulated in SQC tissues, which predicted poorer overall and progression-free survival in SQC patients. Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo. Our results further revealed that LINC00173.v1 promoted the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells by upregulating VEGFA expression by sponging miR-511-5p. Importantly, inhibition of LINC00173.v1 via the ASO strategy reduced the tumor growth of SQC cells, and enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo. Moreover, our results showed that squamous cell carcinoma-specific factor ΔNp63α contributed to LINC00173.v1 overexpression in SQC.
Our findings clarify the underlying mechanism by which LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC, demonstrating that LINC00173.v1-targeted drug in combination with cisplatin may serve as a rational regimen against SQC.
抗血管生成治疗是一种有前途的非小细胞肺癌（NSCLC）治疗策略，但由于其高风险的不良反应，在肺鳞癌（SQC）中的应用受到限制。越来越多的证据表明，长链非编码 RNA（lncRNA）通过参与 NSCLC 中 VEGF 的调节来介导肿瘤进展，这可能为新的抗血管生成策略的发展提供指导。
在 AE-meta 和 TCGA 数据集分析 SQC 中的差异 lncRNA 表达，并通过 RT-qPCR 和原位杂交进一步在肺癌组织和相邻正常组织中进行验证。通过统计学分析评估 LINC00173.v1 表达与生存特征之间的临床相关性。通过管形成试验、鸡胚绒毛尿囊膜试验和动物实验检测 LINC00173.v1 对血管内皮细胞增殖和迁移以及 SQC 体内肿瘤发生的影响。通过生物信息学分析、RNA 免疫沉淀和荧光素酶报告基因检测阐明 LINC00173.v1 的下游靶标。进一步通过体内实验研究反义寡核苷酸（ASO）对 LINC00173.v1 的治疗效果。通过染色质免疫沉淀和高通量数据处理和可视化分析确定 SQC 中 LINC00173.v1 过表达的原因。
LINC00173.v1 在 SQC 组织中特异性上调，预测 SQC 患者的总生存期和无进展生存期较差。过表达 LINC00173.v1 促进了血管内皮细胞的增殖和迁移以及 SQC 细胞在体外和体内的肿瘤发生，而沉默 LINC00173.v1 则抑制了其增殖和迁移。我们的结果进一步表明，LINC00173.v1 通过海绵吸附 miR-511-5p 来上调 VEGFA 表达，从而促进血管内皮细胞的增殖和迁移以及 SQC 细胞的肿瘤发生。重要的是，通过 ASO 策略抑制 LINC00173.v1 减少了 SQC 细胞的肿瘤生长，并增强了 SQC 细胞对顺铂的治疗敏感性。此外，我们的研究结果表明，鳞状细胞癌特异性因子 ΔNp63α 有助于 LINC00173.v1 在 SQC 中的过表达。
我们的研究结果阐明了 LINC00173.v1 促进血管内皮细胞增殖和迁移以及 SQC 肿瘤发生的潜在机制，表明 LINC00173.v1 靶向药物联合顺铂可能成为治疗 SQC 的合理方案。
