Plakophilin-2 Promotes Lung Adenocarcinoma Development via Enhancing Focal Adhesion and Epithelial–Mesenchymal Transition

BACKGROUND: Lung cancer is one of the most aggressive tumors with high incidence and mortality, which could be classified into lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). Overexpression of Plakophilin-2 (PKP2) has been reported in multiple malignancies. However, the expression and function mechanism of PKP2 in LUAD remain illusive. METHODS: Real-time PCR (RT-PCR) was conducted to assess the expression of PKP2 in LUAD cells and tissues. An integrated analysis of PKP2 expression in The Cancer Genome Atlas (TCGA) was further performed. The effect of PKP2 on cell proliferation and invasion potential were then evaluated with loss-of-function assays in vitro. Xenograft nude mouse models were used to determine the role of PKP2 in LUAD tumorigenicity in vivo. Bioinformatics prediction, immunohistochemistry and Western blot were performed to examine whether PKP2 promoted LUAD development via enhancing focal adhesion and epithelial–mesenchymal transition. RESULTS: PKP2 expression was highly expressed in LUAD tissues compared with that in normal tissues and predicated poor prognosis of LUAD patients. TCGA LUAD cohort analysis also showed that high expression of PKP2 indicated unfavorable outcomes in LUAD patients. PKP2 expression was also upregulated in lung cancer cells. Functionally, knockdown of PKP2 suppressed lung cancer cell proliferation and invasion in vitro, while inhibited xenograft lung tumor development in vivo. Mechanistically, we demonstrated that high expression of PKP2 in LUAD was correlated with enhanced EMT and focal adhesion. Knockdown of PKP2 inhibited the expression of EMT-related Vimentin and N-cadherin and focal adhesion-associated expression of BMP4, ICAM1, and VCAM1 in xenograft tumors and lung cancer cells. CONCLUSION: In summary, our findings indicate that PKP2 functions as an oncogene in LUAD, which could be utilized as a novel diagnostic and therapeutic marker for LUAD treatment.