RESUMEN
Non-small cell lung cancer (NSCLC) is a prevalent cancer with unfavorable prognosis. Over the past decade accumulating studies have reported an involvement of lysine-specific histone demethylase 1 (LSD1) in NSCLC development. Here, we aimed to explore whether LSD1 affects the metastasis of NSCLC by mediating Septin 6 (SEPT6) through the TGF-ß1 pathway. RT-qPCR was used to determine LSD1 and SEPT6 expression in NSCLC tissues and cells. Interactions between LSD1, SEPT6, and TGF-ß1 were detected using lentivirus-mediated silencing of LSD1 and overexpression of SEPT6. The role of LSD1 and SEPT6 in mediating the biological behavior of NSCLC cells was determined using the EdU proliferation assay, Transwell assay, and flow cytometry. Thereafter, transplanted cell tumors into nude mice were used to explore the in vivo effects of LSD1 and SEPT6 on metastasis of NSCLC. LSD1 and SEPT6 were overexpressed in NSCLC tissue and cell samples. LSD1 could demethylate the promoter of the SEPT6 to positively regulate SEPT6 expression. LSD1 promoted proliferation, migration, and invasion, while suppressing the apoptosis of NSCLC cells by increasing SEPT6 expression. LSD1-mediated SEPT6 accelerated in vivo NSCLC metastasis through the TGF-ß1/Smad pathway. Collectively, LSD1 demethylates SEPT6 promoter to upregulate SEPT6, which activates TGF-ß1 pathway, thereby promoting metastasis of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Septinas , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Objective: We conducted a phase 2 trial to compare the safety and efficacy of intravenous paclitaxel or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 in untreated advanced gastric cancer. Methods: Participants with untreated advanced gastric cancer were randomly assigned (1:1:1) to: intravenous paclitaxel 135 mg/m2 or intraperitoneal paclitaxel 80 mg/m2 plus mFOLFOX6 omitting bolus fluorouracil; or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2 bolus, fluorouracil 2,400 mg/m2 46-h continuous infusion). Treatment was every 14 days for up to 9 cycles followed by S-1 maintenance. The primary outcome was progression-free survival. Results: Of 90 enrolled participants, 30 in the intravenous paclitaxel group, 29 in the intraperitoneal paclitaxel group, and 30 in the mFOLFOX6 group were included in the analyses. The median progression-free survival was 6.52, 5.83, and 4.55 months, respectively, for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group. The hazard ratios were 0.56 (95% CI: 0.33-0.94; p = 0.026) and 0.56 (95% CI: 0.33-0.96; p = 0.037), respectively, for the intravenous paclitaxel group and the intraperitoneal paclitaxel group vs. the mFOLFOX6 group. The most common grade 3/4 adverse events for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group, respectively, were neutropenia (30.0%, 34.5%, 33.3%), diarrhea (13.3%, 20.7%, 13.3%), and leukopenia (10.0%, 13.8%, 10.0%). No treatment-related death occurred. Conclusion: The findings of this phase 2 trial suggest that adding intravenous paclitaxel or intraperitoneal paclitaxel to mFOLFOX6 for untreated advanced gastric cancer improved progression-free survival with manageable adverse events.