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Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 4B and C on p. 1952, and the Transwell invasion assay data in Fig. 2F and 4I, had already appeared in previously published articles written by different authors at different research institutes (a number of which have been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 42: 19461956, 2019; DOI: 10.3892/or.2019.7302].
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An asymmetric total synthesis of the sarpagine alkaloid (-)-normacusine B is presented. Salient features of this synthesis include a photocatalytic nitrogen-centered radical cascade reaction to assemble the tetrahydrocarbolinone skeleton, a titanium-mediated intramolecular amide-alkene coupling to construct the bridged azabicyclo[3.3.1]nonane moiety, and a nickel-catalyzed reductive Heck coupling to assemble the azabicyclo[2.2.2]octane ring system.
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Alcaloides , Alcaloides Indólicos , Ciclización , EstereoisomerismoRESUMEN
Caffeic acid O-methyltransferase from Ligusticum chuanxiong (LcCOMT) showed strict regiospecificity despite a relative degree of preference. Compared with caffeic acid, methyl caffeate was the preferential substrate by its low Km and high Kcat. In this study, we obtained the SAM binary (1.80 Å) and SAH binary (1.95 Å) complex LcCOMT crystal structures, and established the ternary complex structure with methyl caffeate by molecular docking. The active site of LcCOMT included phenolic substrate pocket, SAM/SAH ligand pocket and conserved catalytic residues as well. The regiospecificity of LcCOMT that permitted only 3-hydroxyl group to be methylated arise from the interactions between the active site and the phenyl ring. However, the propanoid tail governed the relative preference of LcCOMT. The ester group in methyl caffeate stabilized the anionic intermediate caused by His268-Asp269 pair, whereas caffeic acid was unable to stabilize the anionic intermediate due to the adjacent carboxylate anion in the propanoid tail. Ser183 residue formed an additional hydrogen bond with SAH and its role was identified by S183A mutation. Ile318 residue might be a potential site for determination of substrate preference, and its mutation led to the change of tertiary conformation. The results supported the selective mechanism of LcCOMT.
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Ligusticum/enzimología , Metiltransferasas/química , Modelos Moleculares , Conformación Proteica , Secuencia de Aminoácidos , Catálisis , Dominio Catalítico , Cinética , Ligusticum/clasificación , Ligusticum/genética , Metiltransferasas/genética , Mutagénesis Sitio-Dirigida , Fenoles/química , Filogenia , Proteínas Recombinantes , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
BACKGROUND Whether nab-paclitaxel plus carboplatin as neoadjuvant therapy can benefit patients with resectable squamous cell carcinoma of the lung remains unclear. This prospective study aimed to investigate outcomes in patients with stage IIIA-N2 squamous cell carcinoma of the lung treated with nab-paclitaxel plus carboplatin as neoadjuvant therapy. MATERIAL AND METHODS Patients with stage IIIA-N2 squamous cell carcinoma of the lung were treated with nab-paclitaxel (100 mg/m², days 1, 8, and 15) and carboplatin (5 mg/(mL·min), day 1) for two 21-day cycles. The patients were followed every 3 months for 2 years and every 6 months after that. The primary endpoint was the downstaging rate. Secondary endpoints included objective response rate (ORR), margin-free (R0) resection, pathologic complete response (pCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Among the 36 enrolled patients, 33 completed neoadjuvant chemotherapy, and 23 underwent surgery. The preoperative ORR was 50.0% (18/36). R0 resection was achieved in 22 (95.7%) of 23 patients. Major pathologic response and pCR were achieved in 8 (34.8%) and 2 (8.7%) patients, respectively. The overall downstaging rate was 47.8% (11/23). The median follow-up was 39.8 (32.5-41.0) months. For patients who underwent surgery, the median PFS and OS were 31.4 (95%CI: 10.4-not reached (NR)) and 45.0 (95%CI: 22.6-NR) months, respectively. The most common adverse events were neutropenia, anemia, and leukopenia. CONCLUSIONS This study preliminarily indicated a favorable effect of nab-paclitaxel plus carboplatin as neoadjuvant therapy without significant adverse events for stage IIIA-N2 squamous cell carcinoma of the lung. Future randomized controlled trials are needed to verify these results.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Pulmonares/terapia , Terapia Neoadyuvante/métodos , Anciano , Albúminas/administración & dosificación , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidad , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/estadística & datos numéricos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/estadística & datos numéricos , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Neumonectomía/estadística & datos numéricos , Supervivencia sin Progresión , Estudios ProspectivosRESUMEN
BACKGROUND: CITED4 belongs to the CBP/p300-interacting transactivator with glutamic acid and aspartic acid-rich tail (CITED) family which is induced by various cytokines and participates in cytokine-induced proliferation and differentiation. CITED4 is induced by HB-EGF in lung cancer cells. However, it is unclear whether and how CITED4 contributes to the invasion and metastasis of lung adenocarcinoma (ADC). METHODS: CITED4 expression in lung adenocarcinoma and its association with disease-free survival (DFS) and overall survival were analyzed based on a cohort of 261 patients. The roles of CITED4 were validated via loss-of-function and gain-of-function experiments. The relationship between CITED4 and CLDN3 was validated by immunohistochemistry, Western blotting, and luciferase reporter assays. The function of the CITED4-CTNNB1-CLDN3 complex was fully validated and described. RESULTS: CITED4 expression was significantly upregulated in ADC tissues and cells and a predictor for DFS. Downregulation of CITED4 attenuated the proliferation and invasion, whereas CITED4 overexpression enhanced these effects. Overexpression and knockdown of CITED4 resulted in the upregulation and downregulation of CLDN3, respectively. Moreover, CITED4 downregulation suppressed CLDN3-mediated ADC cell metastasis in vivo. CITED4 was highly expressed and positively correlated with CLDN3. Mechanistically, CITED4 interacted with CTNNB1 and functioned synergistically to enhance CLDN3 transcription. Importantly, CITED4 induced ADC invasion via a CLDN3-dependent pathway. CITED4 determined the level of CLDN3, which in turn affected the sensitivity of tumors to Clostridium perfringens enterotoxin treatment. CONCLUSIONS: The CITED4-CTNNB1-CLDN3 axis plays a key role in the invasion and metastasis of ADC and provides a novel therapeutic target for lung cancer treatment.
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Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Factores de Transcripción/metabolismo , Adenocarcinoma del Pulmón/genética , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: This study aimed to identify an efficient, simple, and specific method of detecting mutations in the epidermal growth factor receptor (EGFR) gene in isolated lung cancer circulating tumor cells (CTCs) and to improve the ability to obtain tumor tissue clinically. METHODS: EGFR peptide lipid magnetic spheres (EG-P-LMB) were prepared by reverse evaporation, and characterization and cell capture efficiency assessed. The peripheral blood samples of 30 lung cancer patients were isolated and identified with the EG-P-LMB using 20 healthy volunteers as controls. Finally, the isolated CTCs were tested for EGFR gene mutations, and the tissue samples selected for comparison. RESULTS: The prepared magnetic spheres had a smaller particle size and higher stability according to the particle size potential test. Their morphology was homogeneous by atomic force observation, and the UV test showed that there were peptides on the surface. The separation efficiency of EG-P-LMB was greater than 90% in PBS and greater than 80% in the blood simulation system. Compared with the tissue sample results, the positive rate of EGFR gene mutations was 94%. The CTC test results of 27 patients were consistent with the tissue test results of the corresponding patients, and the consistency with the tissue comparison test results was 90% (27/30). CONCLUSIONS: EG-P-LMB can effectively capture CTCs in the peripheral blood of patients with lung cancer. CTC detection can accurately identify mutations in the EGFR gene and improve the ability to obtain tumor tissue in clinical practice. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: EG-P-LMB can effectively capture CTCs in the peripheral blood of patients with lung cancer. CTC detection can accurately identify mutations in the EGFR gene and improve the ability to obtain tumor tissue in clinical practice. WHAT THIS STUDY ADDS: This study added EGFR peptide lipid magnetic spheres to capture CTCs in the blood. Genetic testing was performed and compared with tissues. It solves the problem of clinically difficult tumor tissue sampling.
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Receptores ErbB/metabolismo , Neoplasias Pulmonares/genética , Péptidos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Células Neoplásicas Circulantes/patologíaRESUMEN
OBJECTIVES: Recent genomic studies suggest the biological significance of theãcylindromatosis (CYLD) gene in thymic epithelial tumors (TETs). CYLD is a crucial regulator of immune response, and we previously reported that CYLD mutation is associated with high PD-L1 expression in thymic carcinoma. Therefore, we wanted to explore the role and mechanism of CYLD in regulating PD-L1 expression in TETs. MATERIALS AND METHODS: The role of CYLD in PD-L1 expression was assessed by knockdown of CYLD in TET cells upon stimulation with interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α) or polyinosinic-polycytidylic acid (poly I:C). The molecular mechanism was investigated through analysis of downstream molecules in the STAT1/IRF1 pathway. Moreover, the clinical correlation between low CYLD and high PD-L1 expression, and the clinical impact of CYLD expression were evaluated in tissue microarrays of 105 TET cases. RESULTS: CYLD knockdown significantly enhanced the expression of PD-L1 in presence of IFN-γ stimulation in most TET cell lines. However, this phenomenon was not observed in presence of TNF-α stimulation. CYLD knockdown upregulated IFN-γ mediated activation of the STAT1/IRF1 axis, which in turn induced PD-L1 expression. Interestingly, we found a significant association between low CYLD expression and ≥ 50 % PD-L1 expression (p = 0.001). In addition, the average proportion of tumor cells exhibiting PD-L1 staining was significantly higher in the low CYLD expression group (24.7 %) than in the high CYLD expression group (5.2 %) (p = 0.005). There was no correlation between CYLD expression and the frequency of pre-existing paraneoplastic auto-immune diseases. In advanced stages (III/IV), the low CYLD expressing group had numerically worse survival than the high CYLD group (log-rank p = 0.089). CONCLUSIONS: Our findings provide insight into the mechanism of regulation of PD-L1 expression by CYLD in TET cells. Tumors with low CYLD expression could be potential targets for PD-1/PD-L1 inhibitors.
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Neoplasias Pulmonares , Neoplasias Glandulares y Epiteliales , Neoplasias del Timo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Enzima Desubiquitinante CYLD/genética , Regulación hacia Abajo , Humanos , Interferón gamma/metabolismo , Neoplasias del Timo/genéticaRESUMEN
Although digestive resistance of Kunitz protease inhibitors has been reported extensively, the molecular mechanism is not well established. In the present study, the first X-ray structure of Cassia obtusifolia trypsin inhibitor (COTI), a member of Kunitz protease inhibitors, was solved at a resolution of 1.9 Å. The structure adopted a classic ß-trefoil fold with the inhibitory loop protruding from the hydrophobic core. The role of Phe139, a unique residue in Kunitz protease inhibitors, and Arg63 in the COTI structure was verified by F139A and R63E mutants. COTI was a specific inhibitor of bovine trypsin and the result was also verified by COTI-trypsin complex formation. Meanwhile, COTI showed equivalent inhibitory activity with that of soybean trypsin inhibitor against bovine trypsin and midgut trypsin from Pieris rapae. The F139 and R63E mutants further indicated that inhibitory specificity and efficiency of COTI were closely related to the global framework, the conformation and the amino acid composition of reactive loop. Finally, a midgut trypsin from P. rapae (PrSP40), which might be involve in the food digestion, was proposed to be a potential target of COTI and might be a promising target for future crop-protection strategy. The results supported the digestive resistance of COTI.
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Mariposas Diurnas/metabolismo , Cassia/química , Extractos Vegetales/química , Proteínas de Plantas/química , Inhibidores de Tripsina/química , Secuencia de Aminoácidos , Animales , Sitios de Unión , Bovinos , Cristalización , Digestión , Modelos Moleculares , Mutación , Unión Proteica , Conformación Proteica , Glycine max/química , Tripsina/metabolismo , Inhibidores de Tripsina/metabolismoRESUMEN
BACKGROUND: Adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasing considered for the tailored management of resectable non-small cell lung cancer (NSCLC). This study aimed to analyze the survival and toxicity profile of patients with EGFR mutation-positive NSCLC treated with adjuvant icotinib. METHODS: This was a single-center retrospective study of patients with EGFR mutation-positive NSCLC who underwent R0 (microscopically margin-negative) resection and received adjuvant icotinib between November 2011 and December 2017. The outcomes included 2-year disease-free survival (DFS) rate, 3-year overall survival (OS) rates, DFS, OS, and adverse events (AEs). RESULTS: A total of 86 patients receiving adjuvant icotinib were included. Their mean age was 59.7±10.0 years, and 26 (30.2%) patients were male. The 2-year DFS rate was 86.7%, and the 3-year OS rate was 95.3% with adjuvant icotinib. DFS (P=0.044) and OS (P=0.003) are better in stage I/II disease than in stage III disease. There seems no differences in DFS and OS between patients with low or high preoperative CEA levels (cutoff of 5 ng/mL), patients with exon 19 or 21 EGFR mutation or patients with or without smoking history. The most common AEs with adjuvant icotinib were rash (83.7%) and diarrhea (19.8%). One (1.2%) patient-reported grade ≥3 AEs. No treatment-related death occurred. CONCLUSIONS: For patients with EGFR mutation-positive NSCLC, adjuvant icotinib might be associated with a promising survival benefit, with an acceptable toxicity profile.
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The ligand/receptor pair CC motif chemokine ligand 20 (CCL20)/CC motif chemokine receptor 6 (CCR6) is considered to be highly activated in lung cancer and significantly accelerates lung cancer progression through activation of ERK signaling. In addition, it has been shown that long noncoding RNAu50535 (lncRNAu50535) upregulates CCL20 expression and facilitates cancer progression in colorectal cancer (CRC). However, the effects of lncRNAu50535 in lung cancer progression and whether lncRNAu50535 regulates CCL20/CCR6/ERK signaling in lung cancer remain illdefined. Therefore, the aim of the present study was to investigate the effects of lncRNAu50535 on CCL20/CCR6/ERK signaling in lung cancer progression. The results demonstrated that lncRNAu50535 expression was upregulated in lung cancer tissues and cell lines compared with normal tissues and cells. Knockdown of lncRNAu50535 decreased lung cancer cell proliferation and migration, induced G0/G1 phase arrest and promoted cell apoptosis. Western blot and luciferase reporter gene assays demonstrated that lncRNAu50535 overexpression increased the translation and transcription of CCL20. In addition, knockdown of lncRNAu50535 decreased CCL20, CCR6 and pERK levels. The effects of lncRNAu50535 on cell proliferation and cell apoptosis were weakened when CCL20 was silenced. Overall, the present study demonstrated that lncRNAu50535 may function as an oncogene in lung cancer progression by regulating CCL20/ERK signaling.
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Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas , ARN Largo no Codificante/genética , Regulación hacia Arriba , Células A549 , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Trasplante de Neoplasias , Receptores CCR6/genética , Receptores CCR6/metabolismoRESUMEN
BACKGROUND: To assess the potential prognostic value of the albumin to alkaline phosphatase ratio (AAPR) in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: The log-rank and Kaplan-Meier analyses were performed to detect differences in survival levels between different groups. A model of Cox proportional hazards was used to perform univariate and multivariate survival analyses. Comparisons of receiver operating characteristic (ROC) curves and the likelihood ratio test (LRT) were also utilized to compare the prognostic abilities of different systems for overall survival (OS) prediction. RESULTS: The optimal cut-off value of the preoperative AAPR was 0.64. A decreased AAPR was associated with several clinicopathological and clinicolaboratory variables related to cancer progression. The preoperative AAPR of patients was positively correlated with the poor prognosis of NSCLC. In multivariate analyses, the preoperative AAPR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.001) and overall survival (OS; P = 0.003). The LRT showed that the AAPR tumor-node-metastasis (TNM) system presented a significantly larger χ2 value (112.4 vs. 89.2, respectively, P < 0.01) and a relatively smaller Akaike information criterion (AIC) value (2955 vs. 2977, respectively, P < 0.01) than the TNM staging system. CONCLUSION: Preoperative AAPR was a potentially valuable prognostic factor in NSCLC patients who underwent surgery. Our results further showed that the AAPR-TNM system was superior to the current TNM staging system.
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Fosfatasa Alcalina/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Albúmina Sérica Humana/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Curva ROC , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response. METHODS: We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and -resistant preclinical models. RESULTS: Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC. CONCLUSIONS: Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/administración & dosificación , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Ratones , Ratones Desnudos , Mitosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Distribución Aleatoria , Carcinoma Pulmonar de Células Pequeñas/enzimología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.14822.].
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Pieris rapae, a serious Lepidoptera pest of cultivated crucifers, utilizes midgut enzymes to digest food and detoxify secondary metabolites from host plants. A recombinant trypsin inhibitor (COTI) from nonhost plant, Cassia obtusifolia, significantly decreased activities of trypsin-like proteases in the larval midgut on Pieris rapae and could suppress the growth of larvae. In order to know how COTI took effect, transcriptional profiles of P. rapae midgut in response to COTI was studied. A total of 51,544 unigenes were generated and 45.86% of which had homologs in public databases. Most of the regulated genes associated with digestion, detoxification, homeostasis, and resistance were downregulated after ingestion of COTI. Meanwhile, several unigenes in the integrin signaling pathway might be involved in response to COTI. Furthermore, using comparative transcriptome analysis, we detected differently expressing genes and identified a new reference gene, UPF3, by qRT-polymerase chain reaction (PCR). Therefore, it was suggested that not only proteolysis inhibition, but also suppression of expression of genes involved in metabolism, development, signaling, and defense might account for the anti-insect resistance of COTI.
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Mariposas Diurnas/enzimología , Cassia/metabolismo , Proteínas de Plantas/metabolismo , Transcriptoma , Inhibidores de Tripsina/metabolismo , Animales , Mariposas Diurnas/crecimiento & desarrollo , Tracto Gastrointestinal/enzimología , Perfilación de la Expresión Génica , Larva/enzimología , Larva/crecimiento & desarrollo , Proteínas Recombinantes/metabolismoRESUMEN
PinX1 has been identified as a suppressor of telomerase enzymatic activity. However, the tumour-suppressive roles of PinX1 in different types of human cancers are unclear. PinX1 expression status and its correlation with clinicopathological features in non-small-cell lung cancer (NSCLC) have not been investigated. Accordingly, in this study, we aimed to evaluate the roles of PinX1 in NSCLC. PinX1 expression status was examined by immunohistochemistry using tissue microarray from a total of 158 patients. Correlations among PinX1 expression, clinicopathological variables, and patient survival were analysed. Furthermore, we overexpressed PinX1 in NSCLC cells and tested telomerase activity using real-time quantitative telomeric repeat amplification protocol (qTRAP) assays. Proliferation and migration of NSCLC cells were examined using the MTS method, wound healing assays, and transwell assays, respectively. Our results showed that negative PinX1 expression was associated with a poor prognosis in NSCLC. Sex, smoking status, lymph gland status, subcarinal lymph node status, pathological stage, and PinX1 expression were related to survival. PinX1 was not an independent prognostic factor in NSCLC. PinX1 overexpression inhibited proliferation and migration in NSCLC cells by suppressing telomerase activity. Our findings suggested that PinX1 could be a potential tumour suppressor in NSCLC and that loss of PinX1 promoted NSCLC progression.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/genética , Proteínas Supresoras de Tumor/genética , Células A549 , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Ciclo Celular , Movimiento Celular/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The clinical characteristics of metastatic lung tumors are not well understood. To explore the surgical indications, surgical modes, and factors that influence postoperative outcomes, we analyzed clinical data from 42 patients with metastatic lung tumors who received surgical treatment at Tianjin Medical University Cancer Institute and Hospital between January 2000 and January 2014. Gender, age, nature of resections, surgical mode, smoking index, disease-free intervals (DFIs), number of metastatic lesions, and lymph node metastases were analyzed. Patients were followed for 6 to 98 months. We found that surgical treatment is feasible for resectable metastatic lung tumors, though postoperative radiochemotherapy had no significant effect on postoperative survival rates among patients with metastatic lung tumors. No patients died perioperatively. The 1-year, 3-year, and 5-year survival rates after surgical resection of metastatic lung tumors were 88.1%, 45.7%, and 34.6%, respectively. Univariate analysis indicated that DFIs and lymph node metastasis correlated with patient prognoses, while multivariate analysis indicated these two variables were independent prognostic factors. Thus surgical treatment may be indicated, depending on patients' specific condition, to lengthen DFIs in patients with metastatic lung tumors with or without evident lymph node metastasis.
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Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Adulto , Anciano , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Resultado del Tratamiento , Carga TumoralRESUMEN
OBJECTIVES: To clone and characterize a novel bi-functional α-amylase/subtilisin inhibitor (LASI) from the rhizome of Ligusticum chuanxiong, a traditional Chinese medicine. RESULTS: The LASI showed strong homology with members of the Kunitz trypsin inhibitor family. Its putative amino acid sequence has a 40 % identity with that of the α-amylase/subtilisin inhibitor from rice. LASI gene without signal peptide was expressed in E. coli Rosetta. After purification, the recombinant LASI protein was inhibitory against not only α-amylase from porcine pancreas, Helicoverpa armigera, Spodoptera litura and Plutella xylostella, but also subtilisin A, but not against trypsin or chymotrypsin. In addition, the expression level of LASI in rhizome was higher than that in leaf and LASI expression was enhanced by salt, chilling and drought treatment. CONCLUSIONS: This is the first member of the Kunitz-protease inhibitor family identified in traditional Chinese medicine and it might be involved in the plant defense responses against lepidopterous pests, microorganisms and abiotic stresses.
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Inhibidores Enzimáticos/metabolismo , Ligusticum/metabolismo , Rizoma/metabolismo , Subtilisina/antagonistas & inhibidores , alfa-Amilasas/antagonistas & inhibidores , Clonación Molecular , Inhibidores Enzimáticos/farmacologíaRESUMEN
We demonstrate that loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT), which is visualized by the repression of E-cadherin and up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens. In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SDH5 in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, our data indicate that SDH5 functions as a critical protein in regulating EMT by modulating the glycogen synthase kinase (GSK)-3ß-ß-catenin signaling pathway. These results reveal a critical role for SDH5 in EMT and suggest that SDH5 may be a prognostic biomarker and potential therapeutic target for lung cancer metastasis.
Asunto(s)
Glucógeno Sintasa Quinasa 3/metabolismo , Neoplasias Pulmonares/patología , Proteínas Mitocondriales/metabolismo , Succinato Deshidrogenasa/metabolismo , beta Catenina/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Xenoinjertos , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Desnudos , Microscopía Confocal , Proteínas Mitocondriales/genética , Metástasis de la Neoplasia , Unión Proteica , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Interferencia de ARN , Transducción de Señal , Succinato Deshidrogenasa/genética , Carga Tumoral , beta Catenina/genéticaRESUMEN
PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is considered as one of the most important treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, not all patients benefit from this therapy because of primary or acquired resistance, both of which are usually caused by the activation of alternative signaling pathways. Thus, a combination of different signaling pathway inhibitors is a promising strategy. We used the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with gefitinib in NSCLC cell lines to analyze the efficacy of this combination regimen and the underlying molecular mechanism. METHODS: Acquired gefitinib-resistant cell lines, together with EGFR wild-type and mutant primary gefitinib-resistant NSCLC cell lines, were treated with everolimus alone, gefitinib alone, or the combination of the two drugs, and the effects were evaluated using cell proliferation assays. The effects of everolimus and gefitinib on the EGFR pathway in NSCLC cell lines were determined by Western blot analysis. RESULTS: Combined treatment resulted in synergistic antitumor effects in gefitinib-resistant cells A549 and H1975. The combination index (CI) of cells increased with increasing dose of everolimus. Everolimus demonstrated no apparent inhibition of phosphorylated Akt (p-Akt) and phosphorylated p44/42 MAPK (p-MAPK) in H1650 cells. Additionally, in gefitinib-resistant cell lines, the combination of gefitinib and everolimus not only showed stronger inhibition of phosphorylated mTOR and phosphorylated p70S6K expression than either drug alone but also reduced the levels of p-Akt and p-MAPK in both cell lines. CONCLUSIONS: Our data showed that the combination of everolimus and gefitinib exhibits dose-dependent synergism in primary and acquired gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of everolimus to enhance the efficacy of gefitinib in EGFR-TKI-resistant patients with NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Sirolimus/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inhibidores , Everolimus , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/administración & dosificación , Transducción de Señal , Sirolimus/administración & dosificación , Sirolimus/farmacologíaRESUMEN
OBJECTIVES: To investigate the relationship between the epithelial growth factor receptor (EGFR) mutation status and clinicopathological factors, and to analyze the mutation on the effect in non-small cell lung cancer (NSCLC) after surgery. METHODS: The NSCLC patients who were resected and detected EGFR gene from March 2009 to March 2011 were retrospectively reviewed. The relationship between EGFR mutation status and clinicopathological factors, tumor markers, prognostic was analyzed. RESULTS: The mutation and the wild group had 169 and 214 patients respectively. EGFR mutation in female, non-smoking, adenocarcinoma and less than 60 years old accounted for 63.91%, 61.54%, 88.76% and 62.13% with statistical significance compared with male (χ(2) = 53.490, P = 0.000), smoking (χ(2) = 48.568, P = 0.000), non-adenocarcinoma (χ(2) = 105.560, P = 0.000) and more than 60 years old (χ(2) = 6.057, P = 0.017). Disease free survival (DFS) of the wild group was better than mutation group (χ(2) = 11.329, P = 0.001). In addition, there were some relations between mutation status and excision repair cross complementing (ERCC1) protein, carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) and Cyfra21-1. ERCC1(+) (χ(2) = 6.739, P = 0.012), SCC(χ(2) = 16.839, P = 0.000) and Cyfra21-1(χ(2) = 6.638, P = 0.013) more than normal value was common in wild group. Increased CEA was common in mutation group (χ(2) = 5.436, P = 0.023). CONCLUSIONS: EGFR mutation is commonly found in female, non-smoking, adenocarcinoma and less than 60 years old NSCLC patients. The wild group obtains better DFS than mutation group. Tumor markers may predict the mutation status, which need further research.