PP4R1 Induced Cancer Stemness by Upregulating the Expression of OCT4 via the MAPK/ERK Pathway in NSCLC

Abstract

Background: Protein phosphatase 4 (PP4) has been reported to be deeply involved in the development of malignancy. Protein phosphatase 4 regulatory subunit 1 (PP4R1) is an indispensable subunit of PP4, but its function in tumors remains unclear. In this study, we investigated the role of PP4R1 in non-small cell lung cancer (NSCLC). Method: Based on clinical samples and clinical data of NSCLC from the cancer genome atlas (TCGA) database, we first explored the role of PP4R1 in NSCLC. Next, we constructed PP4R1-overexpressed NSCLC cell lines (H1299 and A549), and explored the effects of PP4R1 on colony- and sphere-forming capacities. Subsequently, we performed RNA-seq and enrichment analyses, combined with corresponding rescue experiments, to further explore the underlying mechanisms by which PP4R1 affects the progression of NSCLC. Results: PP4R1 was significantly hyper-expressed in cancerous tissues from NSCLC patients, and higher PP4R1 level was negatively related to the overall survival of NSCLC patients. Cellular experiments proved that overexpressing PP4R1 promoted the cell mobility, colony-forming, and sphere-forming abilities of H1299 and A549 cells. Overexpression of PP4R1 led to the hyper-expression of octamer-binding transcription factor 4 (OCT4) and the activation of the mitogen-activated protein kinases/extracellular regulated kinase (MAPK/ERK) signaling pathway. Application of the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, U0126, significantly reversed the activation of ERK and the PP4R1-promoted cell mobility, cell growth, and sphere-forming abilities. Conclusion: In summary, PP4R1 upregulated the expression of OCT4 via the MAPK/ERK signaling pathway, and induced cancer stemness to promote cancer cell progression.