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Aging (Albany NY) ; 12(1): 156-177, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896739


A promising new strategy for cancer therapy is to target the autophagic pathway. However, comprehensive characterization of autophagy genes and their clinical relevance in cancer is still lacking. Here, we systematically characterized alterations of autophagy genes in multiple cancer lines by analyzing data from The Cancer Genome Atlas and CellMiner database. Interactions between autophagy genes and clinically actionable genes (CAGs) were identified by analyzing co-expression, protein-protein interactions (PPIs) and transcription factor (TF) data. A key subnetwork was identified that included 18 autophagy genes and 22 CAGs linked by 28 PPI pairs and 1 TF-target pair, which was EGFR targeted by RARA. Alterations in the expression of autophagy genes were associated with patient survival in multiple cancer types. RARA and EGFR were associated with worse survival in colorectal cancer patients. The regulatory role of EGFR in 5-FU resistance was validated in colon cancer cells in vivo and in vitro. EGFR contributed to 5-FU resistance in colon cancer cells through autophagy induction, and EGFR overexpression in 5-FU resistant colon cancer was regulated by RARA. The present study provides a comprehensive analysis of autophagy in different cancer cell lines and highlights the potential clinical utility of targeting autophagy genes.

World J Gastroenterol ; 19(37): 6258-64, 2013 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-24115824


AIM: To investigate the stress-induced apoptosis of natural killer (NK) cells and the changes in their killing activity in mouse livers. METHODS: A restraint stress model was established in mice. Flow cytometry was employed to measure the percentage of NK cells and the changes in their absolute number in mouse liver. The cytotoxicity of hepatic and splenic NK cells was assessed against YAC-1 target cells via a 4 h 51Cr-release assay. RESULTS: The restraint stress stimulation induced the apoptosis of NK cells in the liver and the spleen, which decreased the cell number. The number and percentage of NK cells in the spleen decreased. However, the number of NK cells in the liver decreased, whereas the percentage of NK cells was significantly increased. The apoptosis of NK cells increased gradually with prolonged stress time, and the macrophage-1 (Mac-1)(+) NK cells were more susceptible to apoptosis than Mac-1(-) NK cells. Large numbers of Mac-1(-) NK cells in the liver, which are more resistant to stress-induced apoptosis, were observed than the Mac-1(-) NK cells in the spleen. The stress stimulation diminished the killing activity of NK cells in the spleen was significantly decreased, but the retention of numerous Mac-1(-) NK cells in the liver maintained the killing ability. CONCLUSION: Significant stress-induced apoptosis was observed among Mac-1(+) NK cells, but not Mac-1(-) NK cells in the mouse liver. Stress stimulation markedly decreased the killing activity of NK cells in the spleen but remained unchanged in the liver.

Apoptose , Células Matadoras Naturais/patologia , Fígado/patologia , Restrição Física/psicologia , Baço/patologia , Estresse Psicológico/patologia , Animais , Biomarcadores/análise , Células Matadoras Naturais/imunologia , Fígado/imunologia , Antígeno de Macrófago 1/análise , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Estresse Psicológico/imunologia
Cell Biochem Biophys ; 62(1): 41-6, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21833674


The goal of this retrospective study was to determine the effect of para-aortic lymphadenectomy on clinical outcome in patients with stage N+ rectal adenocarcinoma below the peritoneal reflection. A retrospective analysis was performed on the clinical outcome of 181 patients with stage N+ rectal adenocarcinoma below the peritoneal reflection who underwent total mesorectal excision (TME) with total pelvic lymph node (PLN) adenectomy, with or without para-aortic lymph node (PAN) adenectomy. Independent prognostic factors were determined by multivariate Cox regression analysis. Disease-free survival (DFS) was analyzed using Kaplan-Meier curves and the log-rank test. The incidence of PLN metastases was 39.2% (71/181) in all the patients, and the incidence of PAN metastases was 12% (12/100) in patients who received PLN + PAN adenectomies. The patients were divided into two groups: PLN adenectomy (n = 81) and PLN + PAN adenectomy (n = 100). There were no statistically significant differences in clinicopathological factors between the PLN adenectomy and PLN + PAN adenectomy groups. On univariate analysis, the gross tumor type (P = 0.012), histological differentiation (P = 0.013), CEA level (P = 0.019), T stage (P = 0.019), N stage (P < 0.0001), and the number of positive PLN sites (P < 0.0001) were associated with poor DFS. Gross tumor type (P = 0.031), N stage (P = 0.001), and the number of positive PLN sites (P < 0.0001) were independent prognostic factors for DFS as identified by multivariate Cox regression analysis. PLN + PAN adenectomy significantly improved DFS compared to PLN adenectomy alone in patients with noninfiltrating type (P = 0.001), but not in patients with infiltrating type (P = 0.075). PLN + PAN adenectomy significantly improved DFS compared to PLN adenectomy alone in patients with 0 or 1 positive PLN site (P = 0.001, P = 0.009 respectively), but not in patients with ≥2 positive PLN sites (P = 0.095). In the N1 and N2 stage groups, PLN + PAN adenectomy significantly improved DFS compared with PLN adenectomy alone (P = 0.001; P < 0.0001, respectively). Furthermore, mean DFS was longer in the absence of PAN metastasis (P < 0.0001). PAN metastases appear to be associated with reduced DFS. Total PAN adenectomy may improve DFS in patients with noninfiltrating type, stage III rectal cancer below the peritoneal reflection, who have <2 positive PLN sites.

Adenocarcinoma/cirurgia , Aorta/cirurgia , Excisão de Linfonodo , Neoplasias Retais/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pelve/cirurgia , Peritônio/patologia , Peritônio/cirurgia , Prognóstico , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Regressão , Estudos Retrospectivos
Artigo em Chinês | MEDLINE | ID: mdl-15599032


Effects of phosphorus deficiency on alternative respiratory pathway and its relation with O(-.)(2) production were investigated in two lines of suspension-cultured tobacco cells which have different tolerances to P deficiency. Oxford cells were shown to be much more tolerant than K326. There were no apparent differences in inorganic and total phosphorous content between the two cell lines. The capacity and activity of alternative respiratory pathway were decreased by P deficiency in K326 cells but were little influenced in Oxford cells. Under either P-deficient or sufficient condition, the capacity and activity of alternative respiratory pathway were always higher in Oxford than in K326. When mitochondria were isolated and used for the same study, similar results were obtained as described above. The expression of AOX at protein level was induced by P deficiency in both lines to similar extents. O(-.)(2) content in K326 cells was significantly higher under P deficiency but little affected in Oxford. It is suggested that alternative respiratory pathway may be associated with tolerance of tobacco cells to P deficiency and may play a role in scavenging reactive oxygen species.

Consumo de Oxigênio , Fósforo/deficiência , Tabaco/metabolismo , Divisão Celular , Proteínas Mitocondriais , Oxirredutases/análise , Fósforo/análise , Proteínas de Plantas , Superóxidos/metabolismo , Suspensões , Tabaco/citologia
Acta Biochim Biophys Sin (Shanghai) ; 36(4): 290-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15253155


The dependence of glycolate oxidase apoprotein (apoGO) activity on flavin analogs was surveyed in 9 higher plants from 7 families. Activities of all apoGOs depended not only on flavin mononucleotide (FMN) but also on flavin adenine dinucleotide (FAD), but not on riboflavin. The kinetic analysis showed that FMN was the optimum cofactor for apoGO from leaves of Brassica campestris. In plant kingdom, FMN, FAD and riboflavin are three flavin analogs with very similar structure, and they could coexist and be inter-converted from each other, so the question is how the apoprotein of glycolate oxidase (GO) recognized these flavin analogs. No inhibition effect of riboflavin on the activity of apoGO with FMN or FAD was found and no obvious quenching of riboflavin or apoGO protein fluorescence was detected with the addition of apoGO or riboflavin, respectively. These results indicated that riboflavin did not bind to apoGO tightly like FMN and FAD. Inorganic phosphate (Pi) did inhibit the activity of GO, and kinetic analysis revealed that this inhibition was caused by the competitive binding to apoGO between Pi and FMN. This competitive binding was further confirmed by the inhibition of Pi to the quenching of FMN and apoGO protein fluorescence with apoGO and FMN, respectively. It was suggested that the 5'-phosphate group of FMN or FAD may play a key role in the recognition and binding of riboflavin analog cofactors with apoGO.

Oxirredutases do Álcool/química , Apoproteínas/química , Mononucleotídeo de Flavina/metabolismo , Flavinas/química , Plantas/enzimologia , Oxirredutases do Álcool/isolamento & purificação , Oxirredutases do Álcool/metabolismo , Apoproteínas/genética , Apoproteínas/isolamento & purificação , Apoproteínas/metabolismo , Ligação Competitiva , Brassica/enzimologia , Mononucleotídeo de Flavina/química , Flavina-Adenina Dinucleotídeo/química , Flavina-Adenina Dinucleotídeo/metabolismo , Cinética , Fosfatos/metabolismo , Folhas de Planta/química , Sensibilidade e Especificidade , Espectrometria de Fluorescência