CPSF4 promotes tumor-initiating phenotype by enhancing VEGF/NRP2/TAZ signaling in lung cancer.

Abstract

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer.

• Authors: YingQiu Song, Kai Sun, LiLan Gong, LinLi Shi, Tao Qin, ShuSen Wang, WuGuo Deng, WangBing Chen, FeiMeng Zheng, GuiLing Li
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 40 Issue 1 Pg. 62 (Dec 26 2022) ISSN: 1559-131X [Electronic] United States
• PMID: 36567417 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Neuropilin-2
• Vascular Endothelial Growth Factor A
• CPSF4 protein, human
• Cleavage And Polyadenylation Specificity Factor
• Transcriptional Coactivator with PDZ-Binding Motif Proteins

Topics

• Humans
• Cell Line, Tumor
• Lung Neoplasms (genetics, metabolism)
• Neuropilin-2 (genetics)
• Phenotype
• Signal Transduction
• Vascular Endothelial Growth Factor A (genetics)
• Cleavage And Polyadenylation Specificity Factor (metabolism)
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• Carcinogenesis (genetics)
• Gene Expression Regulation, Neoplastic