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Feiyanning formula modulates the molecular mechanism of osimertinib resistance in lung cancer by regulating the Wnt/β-catenin pathway.

ABSTRACT: Feiyanning Formula (FYN), a Chinese herbal formula derived from summarized clinical experience, is proven to have anti-tumor effects in lung cancer patients. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), can improve progression-free survival and overall survival of patients but drug resistance is inevitable. The current study evaluated the effects of FYN in osimertinib-resistant HCC827OR and PC9OR cells. FYN preferentially inhibited the proliferation and migration of HCC827OR and PC9OR cells. Moreover, FYN and osimertinib exhibited synergistic inhibitory effects on proliferation and migration. Real-time qPCR (RT-qPCR) and western blotting results indicated that FYN downregulated gene and protein levels of GSK3β and SRFS1, which are enriched in the Wnt/β-catenin pathway. Besides, FYN inhibited tumor growth and exhibited synergistic effects with osimertinib in vivo. Collectively, the results suggested that FYN exerted an anti-osimertinib resistance effect via the Wnt/β-catenin pathway.

SUBMITTER: Sang S

PROVIDER: S-EPMC9745155 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Feiyanning formula modulates the molecular mechanism of osimertinib resistance in lung cancer by regulating the Wnt/β-catenin pathway.

Sang Shuliu S Sun Chenbing C Ding Rongzhen R Jiang Jingjie J Han Yang Y Gan Shanshan S Bi Ling L Gong Yabin Y

Frontiers in pharmacology 20221129

Feiyanning Formula (FYN), a Chinese herbal formula derived from summarized clinical experience, is proven to have anti-tumor effects in lung cancer patients. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), can improve progression-free survival and overall survival of patients but drug resistance is inevitable. The current study evaluated the effects of FYN in osimertinib-resistant HCC827OR and PC9OR cells. FYN preferentially inhibited the pr ...[more]

PMID: 36523489

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Project description:BackgroundOsteosarcoma, the most prevalent primary bone malignancy in children and adolescents, exhibits high heterogeneity. The CGREF1 gene encodes a novel 301 amino acid classical secreted protein that contains the presumed N-terminal signaling peptide and EF hand motif. However, its role in osteosarcoma remains unclear.MethodsTumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized for bioinformatics analysis. Western blot and immunohistochemistry (IHC) techniques were employed to detect the expression of relevant proteins. siRNA, lentivirus, and plasmid technologies were applied to modulate gene expression. The downstream pathway of CGREF1 was identified through RNA sequencing analysis. Cell counting kit-8 (CCK-8) assay, colony formation assay, flow cytometry, wound healing assay, and Transwell assay were conducted for in vitro functional experiments. In vivo experiments involved subcutaneous tumor formation in nude mice.ResultsOur analysis of public databases and clinical samples revealed that CGREF1 is highly expressed in osteosarcoma and is associated with poor prognosis. Knockdown of CGREF1 impeded cell cycle progression and suppressed the proliferation of osteosarcoma cells. Conversely, upregulation of CGREF1 exhibited an opposing pattern. The RNA-seq data from 143B cells was subjected to analysis, revealing that the differentially expressed genes were predominantly enriched in the Wnt signaling pathway. Further experimental results demonstrated that CGREF1 affects activation of the Wnt pathway by regulating GSK3/β-catenin signaling, thereby affecting proliferation ability of osteosarcoma cells. Finally, experiments using subcutaneous transplanted tumor models in nude mice showed that CGREF1 knockdown inhibited tumor growth in vivo by inhibiting the Wnt/β-catenin signaling pathway.ConclusionThe expression of CGREF1 was significantly upregulated in osteosarcoma and correlated with unfavorable prognosis. CGREF1 exerted a regulatory effect on the proliferation of osteosarcoma cells both in vitro and in vivo through modulation of the wnt/β-catenin signaling pathway. In the future, targeting CGREF1 could potentially offer a novel therapeutic strategy for treating osteosarcoma.

Dataset Information

Feiyanning formula modulates the molecular mechanism of osimertinib resistance in lung cancer by regulating the Wnt/β-catenin pathway.

Publications

Feiyanning formula modulates the molecular mechanism of osimertinib resistance in lung cancer by regulating the Wnt/β-catenin pathway.

Similar Datasets

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