PHLDA3 promotes lung adenocarcinoma cell proliferation and invasion via activation of the Wnt signaling pathway

• Published in: Laboratory investigation Vol. 101; no. 9; pp. 1130 - 1141
• Main Authors: Lei, Lei, Wang, Yuan, Li, Zhi-Han, Fei, Liang-Ru, Huang, Wen-Jing, Zheng, Yi-Wen, Liu, Chen-Chen, Yang, Mai-Qing, Wang, Zhao, Zou, Zi-Fang, Xu, Hong-Tao
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.09.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/95; 14/35; 631/67/1612/1350; 631/80/86/2365; 82/51; 82/80; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Amino acids; Cell growth; Cell Line, Tumor; Cell migration; Cell Proliferation; Correlation; Female; Homology; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Invasiveness; Kinases; Laboratory Medicine; Lung - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Mesenchyme; Middle Aged; Neoplasm Invasiveness - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathology; Plasmids; Pleckstrin; Regulatory mechanisms (biology); Signal transduction; Signaling; siRNA; Wnt protein; Wnt Signaling Pathway - genetics; Wound healing
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00608-3

The PHLDA3 gene encodes a small 127 amino acid protein with a pleckstrin homology (PH)-only domain. The expression and significance of PHLDA3 in lung cancer remain unclear. Here, we investigated the role of PHLDA3 in tumor proliferation and invasion in lung adenocarcinoma. Immunohistochemistry and immunoblotting analyses were used to assess PHLDA3 expression in lung cancer tissues, and its correlation with clinicopathological factors in lung cancer. Plasmids encoding PHLDA3 and small interfering RNA against PHLDA3 were used to regulate the expression of PHLDA3 in lung cancer cells. Furthermore, the effects of PHLDA3 on lung cancer cell proliferation and invasion were investigated using the MTS, colony formation, Matrigel invasion, and wound healing assays. Co-immunoprecipitation analysis and inhibitors of both the Wnt signaling pathway and GSK3β were used to explore the regulatory mechanisms underlying the role of PHLDA3 in lung cancer cells. PHLDA3 was found to be overexpressed in lung cancer tissues, and its expression was correlated with poor outcomes in lung adenocarcinoma patients. PHLDA3 expression promoted the proliferation, invasion, and migration of lung cancer cells. Overexpression of PHLDA3 activated the Wnt signaling pathway and facilitated epithelial–mesenchymal transition. Inhibition of Wnt signaling pathway activity, using XAV-939, reversed the effects of PHLDA3 overexpression in lung cancer cells; moreover, PHLDA3 could bind to GSK3β. Inhibition of GSK3β activity, using CHIR-99021, restored the proliferative and invasive abilities of PHLDA3 knockdown cells. Our findings demonstrate that PHLDA3 is highly expressed in lung adenocarcinomas and is correlated with poor outcomes. Furthermore, it promotes the proliferation and invasion of lung cancer cells by activating the Wnt signaling pathway. This paper demonstrates that PHLDA3 is highly expressed in lung adenocarcinomas and correlates with poor outcome. PHLDA3, in conjunction with GSK3β, promotes the proliferation and invasion of lung cancer cells by activating the Wnt signaling pathway, and facilitates epithelial–mesenchymal transition.