PLPP1 inhibits Wnt/β-catenin signaling via enhancing Caveolin-1/β-catenin interaction and is negatively regulated by c-Myc in osteosarcoma.
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BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents, characterized by rapid progression and poor prognosis. The molecular mechanisms underlying OS malignancy remain incompletely understood. Phospholipid phosphatase 1 (PLPP1) has recently been implicated in cancer biology, yet its role in OS is largely unknown. METHODS: RNA sequence data from TARGET-OS and GEO cohorts were downloaded and analyzed for assessing the relationship between PLPP1 expression levels and the OS prognosis. PLPP1 expression levels in OS cells and samples were detected using qRT-PCR, WB and immunohistochemistry. The effects of PLPP1 on proliferation, migration, invasion and chemosensitivity of OS cells were evaluated by up- or down-regulated PLLP1 expression. In vivo subcutaneous and tail-vein xenograft models were used to examine tumor growth and metastasis. Then, transcriptome profiling, luciferase reporter assays, co-immunoprecipitation, immunofluorescence and ChIP-PCR were conducted to elucidate the molecular mechanisms. RESULTS: PLPP1 was markedly down-regulated in OS tissues and cell lines. And low expression level of PLPP1 was correlated with poor prognosis, advanced clinical stage and metastasis. Functionally, PLPP1 overexpression inhibited OS cell proliferation, migration, invasion, and enhanced chemotherapy-induced apoptosis; conversely, silencing PLPP1 produced the opposite effects. In vivo, PLPP1 overexpression suppressed tumor growth and lung metastasis. Mechanistically, overexpression of PLPP1 impaired strength of Wnt/β-catenin signaling without altering β-catenin abundance, but instead inhibited β-catenin nuclear import by enhancing Caveolin-1/β-catenin interaction. Furthermore, PLPP1 was transcriptionally repressed by c-Myc, which directly bound to the PLPP1 promoter. Rescue experiments confirmed that c-Myc promoted OS malignancy by repressing PLPP1, thereby activating Wnt/β-catenin signaling. CONCLUSIONS: This study identified PLPP1 as a prognostic suppressor in OS that inhibited β-catenin nuclear import through enhancing Caveolin-1/β-catenin interaction and was transcriptionally repressed by c-Myc. Targeting the c-Myc/PLPP1/β-catenin axis might represent a promising therapeutic strategy for OS. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study revealed the potential of PLPP1 as a novel prognostic biomarker of OS, and suggested its potential for therapeutic applications by specifically activating PLPP1 expression using small-molecule activators.