The function and mechanism of PSMD14 in promoting progression and resistance to anlotinib in osteosarcoma.

BACKGROUND:Osteosarcoma is a rare bone malignancy that frequently affects adolescents and poses formidable obstacles in its advanced stages. Studies revealed that PSMD14 may be a viable osteosarcoma treatment target. However, PSMD14's function and mechanism in osteosarcoma remain unknown. This study aimed to examine the function and mechanism of PSMD14 in the biological behavior of osteosarcoma and its role in anlotinib resistance. METHODS:Western blotting, qRT-PCR, and immunohistochemistry (IHC) studies were used to examine PSMD14 levels. The role of PSMD14 in the malignant phenotype of osteosarcoma and its molecular pathway was explored by a series of studies, including Western blotting, cell amplification assay, transwell assay, and tumor growth. Furthermore, a series of in vitro investigations were done to determine the effect of PSMD14 on anlotinib-resistant osteosarcoma cell lines. RESULTS:PSMD14 expression was elevated in osteosarcoma tissues compared to normal tissues. Overexpression of PSMD14 was associated with osteosarcoma patients' pathological grade and clinical stage, and PSMD14 was an independent poor prognostic factor. PSMD14 knockdown inhibits in vitro cell proliferation, migration, invasion, and in vivo tumor growth. PSMD14 knockdown has the potential to downregulate the PI3K/Akt/mTOR pathway, which was regarded as one of the key mechanisms promoting tumor growth. PSMD14 was likewise overexpressed in anlotinib-resistant OS cell lines, and its knockdown not only reduced the proliferation, migration, and invasion of subline cells and triggered cell apoptosis. Importantly, combination therapy with anlotinib enhanced these effects. CONCLUSIONS:PSMD14 is substantially expressed in osteosarcoma and may be an independent risk factor associated with poor prognosis. It can promote tumor progression and anlotinib resistance in osteosarcoma and may promote osteosarcoma progression by modulating PI3K/AKT/mTOR signaling pathway.