LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Jiarong Chen, Aibin Liu, Zhihui Wang, Bin Wang, Xingxing Chai, Wenjie Lu, Ting Cao, Ronggang Li, Minyan Wu, Zhuming Lu, Wenguang Pang, Lin Xiao, Xiangmeng Chen, Yan Zheng, Qiong Chen, Jincheng Zeng, Jun Li, Xin Zhang, Dong Ren, Yanming Huang
• Journal: Molecular cancer (Mol Cancer) Vol. 19 Issue 1 Pg. 98 (05 30 2020) ISSN: 1476-4598 [Electronic] England
• PMID: 32473645 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• MIRN511 microRNA, human
• MicroRNAs
• RNA, Long Noncoding
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• long noncoding RNA LINC00173, human

Topics

• Adenocarcinoma of Lung (blood supply, genetics, pathology)
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Squamous Cell (blood supply, genetics, pathology)
• Cell Proliferation
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (blood supply, genetics, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Neovascularization, Pathologic (genetics, pathology)
• Prognosis
• RNA, Long Noncoding (genetics)
• Survival Rate
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xenograft Model Antitumor Assays