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Abstract Non-small cell lung cancer (NSCLC) patients harboring EGFR mutation who initially respond to EGFR-TKI will gradually develop acquired resistance. There is still a challenge to treat EGFR-TKI resistant NSCLC patients. Polyphyllin I (PP I), a steroidal saponin isolated from Paris polyphylla., has been exhibited antitumor activities against various carcinomas. However, its mechanism in treating EGFR-TKI resistant NSCLC has not been well elucidated. In this study, we found that PP I suppressed the cell viability and induced apoptosis of gefitinib-resistant NSCLC cells and xenograft models. These therapeutic efficacies were associated with down-regulated level of MALAT1, leading to inactivation of STAT3 signaling pathway. The cell viability inhibition and apoptosis inducing in gefitinib-resistant NSCLC triggered by PP I were abolished by MALAT1 overexpression, while the cell viability inhibition and apoptosis inducing triggered by PP I were potentiated by MALAT1 knockdown. These findings suggest that, in vitro and in vivo, PP I inhibits the viability and induces apoptosis of gefitinib-resistant NSCLC by down-regulating MALAT1 and inactivating STAT3 signaling pathway. Thus, PPI could serve a promising therapeutic agent for the treatment of gefitinib-resistant NSCLC. Highlights • There is still a challenge to treat EGFR-TKI resistant NSCLC. • PP I suppressed the cell viability and induced apoptosis of drug-resistant NSCLC. • PP I might down-regulate MALAT1 expression and inactivate STAT3 signaling pathway. • PP I could serve a promising therapeutic agent for gefitinib-resistant NSCLC. [ABSTRACT FROM AUTHOR]

• Silencing TRIM66 hindered cell malignant phenotype of non-small cell lung cancer; • TRIM66 interacted with MMP9 in non-small cell lung cancer; • MMP9 activated TGF-β/SMAD pathway; • TRIM66/MMP9/TGF-β/SMAD axis promoted non-small cell lung cancer progression. To investigate regulatory function and underlying mechanism of TRIM66 in non-small cell lung cancer (NSCLC). TRIM66 and MMP9 expression in NSCLC cells and tissues was assayed via qRT-PCR and western blot. CCK-8, colony formation, Transwell and flow cytometry assays were conducted to measure cell functional alternations in NSCLC. Western blot was employed to measure expression as well as phosphorylation levels of epithelial-mesenchymal transition-(EMT) and TGF-β/SMAD pathways-related proteins. Co-immunoprecipitation (Co-IP) assay was done to probe interaction between TRIM66 and MMP9. Xenograft in vivo experiment and tumor metastasis model in nude mice were utilized to investigate effects of TRIM66 on tumor growth of NSCLC. TRIM66 and MMP9 were conspicuously highly expressed in NSCLC cells and tissues. High TRIM66 level was markedly correlated with metastasis. Silencing TRIM66 prominently repressed the proliferation, migration and invasion of transfected cells, while inducing cell apoptosis. Whereas forced expression of TRIM66 exerted the opposite effect. The aberrant expression of TRIM66 modulated EMT pathway. TRIM66 also regulated MMP9 expression, and the interaction between them was validated by Co-IP assay. Overexpression of MMP9 could activate TGF-β/SMAD pathway. Rescue experiments manifested that si-MMP9 or SB431542 could partially reverse phenotypes induced by TRIM66. In vivo experiments revealed that silencing TRIM66 could hamper NSCLC tumor growth and metastasis. TRIM66 and MMP9 were up-regulated in NSCLC. TRIM66 facilitated the malignant progression of NSCLC through modulating MMP9-mediated TGF-β/SMAD pathway. [ABSTRACT FROM AUTHOR]