RESUMO
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RESUMO
Twist related protein 2 (TWIST2) plays an important role in bone development, tumorigenesis, tumour progression and epithelial mesenchymal transition (EMT). At present, there are few reports about the role of TWIST2 in lung cancer, which need to be further explored. Therefore, the purpose of this study is to explore the role and molecular mechanism of TWIST2 in the occurrence and development of lung cancer. The expression of TWIST2 in tissues of patients and cell lines was measured using RT-qPCR and western blotting. MTT and CCK8 assays were used to detect cell proliferation and viability. Western blotting was used to measure the expression of EMT-related proteins, including E-cadherin, N-cadherin, Vimentin and Slug. The results revealed that TWIST2 is lowly expressed in the tissues of lung cancer patients and cell lines. Further studies found that overexpression of TWIST2 significantly induced apoptosis and promoted the expression of E-cadherin, as well as inhibiting the expression of N-cadherin, Vimentin and Slug. More importantly, TWIST2 induced oxidative stress in lung cancer cells. In addition, TWIST2 regulated the FGF21 and AMPK/mTOR signalling pathway, which is involved in the molecular mechanism of the gene in lung cancer cells. We suggest that the mechanism of TWIST2 inhibition of the progression of lung cancer is by regulating the FGF21-mediated AMPK/mTOR signalling pathway.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Transição Epitelial-Mesenquimal , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Pulmonares/patologia , Estresse Oxidativo , Proteínas Repressoras/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Fatores de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Repressoras/genética , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas , Proteína 1 Relacionada a Twist/genéticaRESUMO
BACKGROUND: To investigate the sex-based heterogeneity of immune microenvironmental feature and its impact on the response to first-line PD-1 blockade plus chemotherapy in patients with driver-negative advanced or metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 439 patients with advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy or chemotherapy were identified. Differences in clinical outcomes between female and male patients were determined using Kaplan-Meier curves. Neoantigen burden and five immune microenvironmental markers expression including PD-L1, CD4, CD8, FOXP3, and CD68 were compared between two groups. RESULTS: Of 175 eligible patients, 89 received PD-1 blockade plus chemotherapy and 86 received first-line chemotherapy. Forty five were women (25.7%) and 130 were men (74.3%). Female patients received first-line PD-1 blockade in combination with chemotherapy had dramatically better ORR (85.2% vs. 53.2%; p = 0.009), PFS (23.7 vs. 7.3 months; p = 0.013), and OS (46.2 vs. 20.0 months; p = 0.004) than males. Treatment outcomes were similar between females and males in chemotherapy group. Multivariate analyses showed that sex was the independent prognostic factor for patients received PD-1 blockade combined with chemotherapy. Although female patients had significantly lower tumor mutational and neoantigen burden than males, pretreatment tumor tissues of female patients had markedly higher CD4, CD4/FOXP3, and CD4/FOXP3/PD-L1 expression level than male patients. CONCLUSIONS: Female patients with untreated advanced or metastatic NSCLC would derive a larger benefit from PD-1 blockade in combination with chemotherapy than males. The biological significances of heterogeneity of tumor immune microenvironmental features between them need further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Microambiente Tumoral/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores Sexuais , Adulto , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos Retrospectivos , Fatores de Transcrição ForkheadRESUMO
AIMS: Lung cancer is a key contributor to the cancer-related death throughout the world. FGF21 (fibroblast growth factor 21) has been found to regulate various pulmonary diseases, whereas, the role and mechanism of FGF21 in lung cancer remain unclear. The aim of this research was to explore the expression and function of FGF21 in lung cancer. MAIN METHODS: The mRNA and protein expression of FGF21 were analyzed through qRT-PCR and western blot, respectively. Cell proliferation, apoptosis and migration were analyzed by CCK-8 assay, flow cytometry and wound-healing assay, respectively. ROS, SOD, LDH and CK were examined with respective commercially kit. KEY FINDINGS: FGF21 level was increased in lung cancer tissue samples and cell lines at both mRNA and protein levels. Overexpressing FGF21 promoted cell growth and migration significantly. It also increased SOD and reduced ROS, LDH and CK contents. By contrast, down-regulated FGF21 presented the opposite effect on lung cancer cells. Furthermore, FGF21 may function as a tumor promotor by activating the SIRT1/PI3K/AKT signaling pathway in lung cancer. SIGNIFICANCE: This study demonstrated that FGF21 was a tumor promoter in lung cancer development, serving as a feasible therapeutic target in the treatment of lung cancer.