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1.
Life Sci ; 241: 117134, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811854

RESUMO

AIMS: Non-small cell lung cancer (NSCLC), characterized by extensive metastasis and poor prognosis, is the most common type of lung cancer. Dysregulation of certain lncRNAs is known to be linked to the tumorigenesis of NSCLC. However, the specific roles in NSCLC for many other lncRNAs, such as linc01088, remain largely unknown. MATERIALS AND METHODS: The expression patterns of linc01088, p21 and EZH2 were examined both in NSCLC tissues and cell lines using RT-qPCR assay. CCK-8, colony formation, immunofluorescence staining, and flow cytometry assays were employed to evaluate the effects of linc01088 on NSCLC cell proliferation properties. RNA immunoprecipitation (RIP) assay was performed to determine the direct binding relationship between linc01088 and zeste homolog 2 (EZH2). Western blot and RT-qPCR analysis were performed to assess p21 level within knockdown of either linc01088 or EZH2. Nude mouse subcutaneous NSCLC models were constructed for further validating the effects and mechanisms of linc01088 in vivo. KEY FINDINGS: linc01088 and EZH2 were highly expressed both in NSCLC tissues and cell lines. Knockdown of linc01088 suppressed the proliferation of NSCLC cells, and prolonged the G1 phase while shortened S and G2-M phases. RIP assay revealed the direct binding relationship between linc01088 and EZH2. Knockdown of either linc01088 or EZH2 induced up-regulation of p21 expression, which subsequently inhibited the tumor growth. SIGNIFICANCE: We demonstrated that linc01088 could promote cell proliferation via binding with EZH2 to repress p21, which aggravates the tumorigenesis of NSCLC. Therefore, linc01088 might be a potential oncogene and target for novel anti-tumor therapies.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/secundário , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Oral Dis ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830347

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of dose-modified docetaxel plus cisplatin and 5-fluorouracil (TPF) in Chinese patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: This Phase III, open-label, multi-center study included Chinese adults with previously untreated TNM Stage III or IV SCCHN (NCT00995293). Patients were randomized (1:1) to induction chemotherapy with TPF (docetaxel 60 mg/m2 and cisplatin 60 mg/m2 on day 1 and 5-FU 750 mg/m2  per day continuous IV infusion on days 1-5) or PF (cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2  per day on days 1-5) every 3 weeks for 3-4 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS in the TPF (n = 108) and PF (n = 111) groups was 400 days and 342 days (HR = 0.75; 95% CI, 0.53─1.06; p = .227), respectively. Overall response rate was higher for TPF versus PF (76.3% vs. 52.9%; p = .001), although this equalized following radiotherapy (75.0% vs. 73.9%). In the TPF and PF groups, ≥1 treatment-emergent adverse event was experienced by 104 (94.5%) and 110 (93.2%) patients, respectively. CONCLUSION: Adding dose-modified docetaxel to PF did not significantly improve PFS but may increase anti-tumor activity in Chinese patients with locally advanced SCCHN.

3.
Mol Genet Genomic Med ; 7(12): e994, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617686

RESUMO

BACKGROUND: Long intergenic noncoding RNAs (lincRNAs) are a series of novel transcribed regions expressed in cancers that may represent candidate biomarkers for lung squamous cell carcinoma (LSqCC) treatment. In this study, we evaluated the lincRNA profile in LSqCC patients and screened valuable lincRNAs for diagnosis and prognosis. METHODS: Transcriptome profiling of 549 samples derived from 501 LSqCC patients were identified in TCGA database. 48 patients had paired primary tumor (PT) and solid normal (SN) tissue samples, while 453 patients had only PT samples. 1,771 lincRNA candidates were evaluated. Paired test (Wilcoxon two-sample paired signed rank tests) was performed in paired PT and SN samples. Logistic regression analysis were performed in independent 453 PT samples and 48 SN samples to screen the significant lincRNAs candidates for malignances. Independent 501 PT samples were further used to screen the significant lincRNAs candidates for prognosis. RESULTS: Among 1,771 lincRNAs, 10 lincRNAs were significant highly-expressed risk candidates in PT samples, and 10 protective lincRNAs candidates were significant lowly-expressed in PT samples. Among 10 highly-expressed risk lincRNAs, a small panel of LINC00487, LINC01927, and C10orf143 (LINC00959) could effectively predict malignancies in paired samples (AUC = 0.7274, 95%CI = (0.6264, 0.8285)). When combined with protective lincRNA candidates LINC02315, LINC00491, and LINC01697, the predictive efficiency was greatly improved in both paired samples (AUC = 0.8030, 95%CI = (0.7250, 0.8810)) and independent samples (AUC = 0.7481, 95%CI= (0.6642, 0.8320)). Additionally, three highly-expressed risk lincRNAs, LINC01031, LINC01088, and LINC01931, were significantly associated with poor prognosis in PT samples, suggesting potential targets for anti-LSqCC treatment. CONCLUSION: Therefore, lincRNAs could be promising biomarkers for predicting malignancies and potential anti-LSqCC targets for drug development.

4.
Mol Med Rep ; 20(6): 5064-5074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638226

RESUMO

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non­Hodgkin lymphoma in China. 1,25­Dihydroxyvitamin D3 [1,25(OH)2D3] has been shown to possess significant antitumor potential and is degraded by 25­hydroxyvitamin D­24­hydroxylase (CYP24A1). In the present study, the role of CYP24A1 and autophagy, and their underlying mechanisms in the anticancer effects of 1,25(OH)2D3 in DLBCL cells, were investigated. It was found that the levels of CYP24A1 in DLBCL lymph node tissues were higher than in hyperplasia lymphadenitis tissue. Moreover, the expression of CYP24A1 was positively associated with the Ann Arbor stage and the International Prognostic Index in patients with DLBCL, and negatively associated with the clinical response to treatment. Patients >60 years of age were found to have a higher level of CYP24A1. 1,25(OH)2D3 inhibited the proliferation of the Pfeiffer DLBCL cell line and increased the G1 phase population of Pfeiffer cells. Rapamycin (RAPA) in combination with 1,25(OH)2D3 increased the G1 phase distribution of Pfeiffer cells. Furthermore, RAPA blocked the increase of CYP24A1 and vitamin D receptor (VDR) expression induced by 1,25(OH)2D3. 1,25(OH)2D3 induced the formation of autophagosomes, increased the expression of autophagy related protein light chain (LC)3II/LC3I and reduced the expression of the ubiquitin binding protein P62. In addition, 1,25(OH)2D3 decreased the phosphorylation of AKT and mammalian target of RAPA (mTOR), and downstream targets eukaryotic translation imitation factor 4E­binding protein 1 and ribosomal protein S6 kinase ß­1 in Pfeiffer cells. The results from the present study suggested that CYP24A1 may be a novel prognostic indicator for DLBCL. 1,25(OH)2D3 inhibited proliferation and induced autophagy of Pfeiffer cells. In addition, 1,25(OH)2D3 increased the G1 phase population of Pfeiffer cells. These effects may be mediated by inhibition of the AKT/mTOR/PI3K signaling pathway. RAPA increased the cell cycle arrest induced by 1,25(OH)2D3 by blocking the upregulated expression of CYP24A1 and VDR.

5.
Front Oncol ; 9: 683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403034

RESUMO

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare type of lymphoma with a high incidence in elderly patients, poor drug response, and unfavorable prognosis. Despite advances in genomic profiling and precision medicine in DLBCL, EBV+ DLBCL remain poorly characterized and understood. We include 236 DLBCL patients for EBV-encoded mRNA (EBER) in situ hybridization detection and analyzed 9 EBV+ and 6 EBV negative cases by next-generation sequencing (NGS). We then performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to analyze chromosome rearrangements and gene expressions in 22 EBV+ and 30 EBV negative cases. The EBER results showed a 9.3% (22/236) positive rate. The NGS results revealed recurrent alterations in MYC and RHOA, components of apoptosis and NF-κB pathways. The most frequently mutated genes in EBV+ DLBCL were MYC (3/9; 33.3%), RHOA (3/9; 33.3%), PIM1 (2/9; 22.2%), MEF2B (2/9; 22.2%), MYD88 (2/9; 22.2%), and CD79B (2/9; 22.2%) compared with KMT2D (4/6; 66.7%), CREBBP (3/6; 50.0%), PIM1 (2/6; 33.3%), TNFAIP3 (2/6; 33.3%), and BCL2 (2/6; 33.3%) in EBV-negative DLBCL. MYC and KMT2D alterations stood out the most differently mutated genes between the two groups. FISH detection displayed a lower rearrangement rate in EBV+ cohort. Furthermore, KMT2D expression was highly expressed and associated with poor survival in both cohorts. MYC was only overexpressed and related to an inferior prognosis in the EBV+ DLBCL cohort. In summary, we depicted a distinct mutation profile for EBV+ and EBV-negative DLBCL and validated the differential expression of KMT2D and MYC with potential prognostic influence, thereby providing new perspectives into the pathogenesis and precision medicine of DLBCL.

6.
Transl Oncol ; 12(11): 1496-1503, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446308

RESUMO

BACKGROUND: Seventy percent of intrahepatic cholangiocarcinoma (ICC) patients are inoperable. Treatment for unresectable patients is essential to improve poor survival. AIMS: We aimed to evaluate the prognostic factors for ICC patients, and investigate the potential treatment strategies for unresectable patients. METHODS: ICC patients were identified in SEER registry in 2004-2013. Univariate and multivariate Cox proportional hazard regression analysis were performed to evaluate the effect of treatment strategies. RESULTS: Of 2248 cases diagnosed in 2010-2013 and staged according to the American Joint Committee on Cancer (AJCC) 7th edition, 1706 (76.13%) did not receive cancer-directed surgery. This portion increased compared to those diagnosed between 2004 and 2009 and staged according to the AJCC 6th edition (72.87%). In addition, the percentage of stage 4 cases increased, while stage 3 cases decreased, because AJCC 7th staging system categorized both T4 and N1 patients into stage IV, which were previously categorized into stage III by AJCC 6th staging system. Patients with radiofrequency ablation (RFA) showed a poorer survival in 2004-2009 (P = .0213), but an almost the same survival as patients with tumor resection in 2010-2013 (P = .51), suggesting that RFA performed better in recent years. Lymphadenectomy showed protective effect for unresectable patients. Radiotherapy improved cancer-specific survival in non-surgery patients (P < .0001).The proportion of stage IV patients increased tremendously from 37.4% in 2004-2009 to 58.7% in 2010-2013. Among 1319 stage IV patients (2010-2013), surgery at distant metastatic sites improved cancer-specific survival. CONCLUSIONS: For unresectable tumors, RFA, radiotherapy, lymphadenectomy, and surgery of distant metastases showed significant benefits to improve cancer-specific survival.

7.
Int J Exp Pathol ; 100(1): 32-40, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30912195

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Because the prognosis of DLBCL patients varies considerably, there is an urgent need to identify novel prognostic factors. In this study, we investigated the expression levels of the signalling enzyme 3-phosphoinositide-dependent protein kinase-1 (PDK1), the cell cycle regulatory enzyme Polo-like kinase 1 (PLK1) and the transcription factor (c-Myc) in DLBCL tissues and evaluated their clinical and prognostic significance. PDK1, PLK1 and c-Myc were detected by immunohistochemical staining of paraffin-embedded specimens from 152 DLBCL and 48 lymphadenitis patients. Expression levels were correlated with clinicopathological factors. PDK1, PLK1 and c-Myc were more commonly expressed in DLBCL specimens than in lymphadenitis specimens, and the expression of each protein correlated positively with that of the other two molecules. High PDK1, PLK1 and c-Myc expression, high international prognostic index score, high lactate dehydrogenase levels and late Ann Arbor stage were shown to correlate with shorter overall survival time. A multivariate Cox regression model showed that high expression levels of PLK1 and c-Myc were independent prognostic factors for DLBCL. Our findings indicate that PLK1 and c-Myc expression might be promising predictive biomarkers for DLBCL patients.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/análise , Proteínas de Ciclo Celular/análise , Linfoma Difuso de Grandes Células B/enzimologia , Proteínas Serina-Treonina Quinases/análise , Proteínas Proto-Oncogênicas c-myc/análise , Proteínas Proto-Oncogênicas/análise , Biomarcadores Tumorais/análise , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
8.
Medicine (Baltimore) ; 98(3): e14020, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653108

RESUMO

RATIONALE: Epithelial ovarian carcinoma (EOC) is the most common type of ovarian carcinoma, and the leading cause of female genital tract cancer-related deaths. However, brain metastasis (BM) of EOC is rare, with an incidence of only 1% to 2%. Ovarian clear cell carcinoma (OCCC), accounting for 5% to 25% of all EOC cases, has a poor prognosis compared with other epithelial cell type carcinomas. PATIENT CONCERNS: We retrospectively analyzed the clinical data of a 62-year-old female, who was hospitalized with the main complaint of BM detection for 1 month. She was first diagnosed with ovarian cancer in 2004, and underwent a left oophorectomy. Three years later, the cancer metastasized to the other side, and she underwent a right oophorectomy, followed by 7 courses of platinum-based chemotherapy. She received regular follow-up, and tumor markers and pelvic imaging did not show any signs of progression until July 2012. DIAGNOSIS: Combining the clinical manifestations with the results of radiological and pathological examinations, the findings were consistent with a diagnosis of BM from OCCC. INTERVENTIONS: She received more than 20 courses of chemotherapy since July 2012. The BM was detected in 2016, and she underwent an intracranial lesion resection. OUTCOMES: Unfortunately, the patient went into a coma after the surgery, and passed away 1 month later. LESSONS: For early detection of BM in long-term ovarian cancer, emphasis should be placed on the patient's neurological symptoms and signs as well as serum tumor marker changes. The combination of surgery, radiology, and chemotherapy may achieve long overall survival.


Assuntos
Adenocarcinoma de Células Claras/secundário , Neoplasias Encefálicas/secundário , Neoplasias Epiteliais e Glandulares/secundário , Neoplasias Ovarianas/patologia , Encéfalo/patologia , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Ovário/patologia
9.
Epigenomics ; 11(1): 35-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211623

RESUMO

AIM: To analyze the expression profiles, clinicopathological features and chemotherapeutic efficacies of exosome-derived miRNAs in diffuse large B-cell lymphoma (DLBCL). MATERIALS & METHODS: Next-generation sequencing technique was performed to identify miRNA profiles in exosomes from parental and chemoresistant DLBCL cells. The results were validated by quantitative real-time PCR, and further analyzed by bioinformatics and statistical methods. RESULTS: We identified 37 significantly upregulated and 17 downregulated miRNAs. Of four upregulated miRNAs validated, we found miR-99a-5p and miR-125b-5p were significantly upregulated. Increased levels of exosomal miR-99a-5p and miR-125b-5p in DLBCL patients' serum were associated with shorter progression-free survival time, and they can predict chemotherapeutic efficacy. CONCLUSION: Exosomal miR-99a-5p and miR-125b-5p can serve as biomarkers for DLBCL.


Assuntos
Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , MicroRNAs/genética , Adulto , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Ciclofosfamida , Relação Dose-Resposta a Droga , Doxorrubicina , Exossomos/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prednisona , Prognóstico , Interferência de RNA , Curva ROC , Rituximab , Transcriptoma , Vincristina
10.
Medicine (Baltimore) ; 97(39): e12603, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30278574

RESUMO

The overall survival of breast cancer (BC) patients increased significantly for decades; however, their long-term survival was seriously impaired by subsequent malignancies. This study aimed to investigate the risk factors of subsequent lung / bronchus primary malignancies among BC survivors.A total of 535,941 BC female survivors diagnosed were identified by using SEERStat database in 1973 to 2014. Among them, 9398 had subsequent lung/bronchus malignancies. Clinico-pathological risk factors were evaluated for the development of subsequent lung/bronchus cancer. The main measures were the incidence and risk factors of subsequent lung/bronchus primaries. Logistic regression analysis and survival analysis were performed.Overall, among 535,941 BC survivors, 73,394 (13.69%) patients with subsequent primaries were identified from 1973 to 2014. The overall medium second tumor-free time was 72 months. Estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, human epidermal growth factor receptor-2 (HER2)-positive, radiotherapy, and surgery treatment were protective factors against overall subsequent malignancies, whereas HER2/hormone receptor (HR) subtype triple negative, increasing tumor size, low differentiation grade, and high TNM stage were risk factors associated with overall subsequent malignancies. Surgical implantation reconstruction was risk factor for lung/bronchus cancer. Even though BC patients had a favorite 5-year survival, their long-term survival was affected by subsequent malignancies, especially for lung/bronchus cancer with high mortality.Nearly 13% BC survivors suffered from subsequent malignancies. Increased risk was related to HER2/HR triple negative and advanced TNM stages. Radiotherapy and surgery were protective factors. Our findings may inform the subsequent cancer counseling of female BC survivors.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias Brônquicas/secundário , Neoplasias Pulmonares/secundário , Neoplasias da Mama/terapia , Neoplasias Brônquicas/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Estadiamento de Neoplasias , Fatores de Risco , Programa de SEER , Análise de Sobrevida , Fatores de Tempo , Estados Unidos/epidemiologia
11.
Neoplasia ; 20(10): 1059-1069, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30227305

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare and special type of non-Hodgkin lymphoma. The treatment of PCNSL is comprehensive, combining surgery, radiotherapy, and chemotherapy. However, the outcome is poor because of its high invasiveness and rate of recurrence. We analyzed 22 cases of PCNSL using next-generation sequencing (NGS) to detect 64 candidate genes. We used immunohistochemical methods to analyze gene expression in 57 PCNSL samples. NGS showed that recurrent mutations in KMT2D and CD79B, components of the NF-κB pathway, accounted for 65% of total mutations in PCNSL samples. The most frequent mutated gene was PIM1 (77.27%, 17/22), followed by MYD88 (63.64%, 14/22), CD79B (69.09%, 13/22), and KMT2D (50.00%, 11/22). Mutations of the CD79B gene were associated with an inferior progression-free survival (PFS), and GNA13 gene mutations were associated with a shorter PFS and overall survival (OS) in PCNSL patients (P < .05). PIM1 and MYD88 were highly expressed in PCNSL patients and were related to their OS time. MYD88 overexpression might be an independent and poor prognostic predictor of OS time. In summary, we identified highly recurrent genetic lesions in CD79B and KMT2D, components of the NF-κB pathway, in PCNSL and validated the expression of PIM1 and MYD88 related to poor survival, thereby providing novel insights into the pathogenesis and precision medicine of PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , Mutação , Adolescente , Adulto , Idoso , Antígenos CD79/genética , Neoplasias do Sistema Nervoso Central/mortalidade , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas de Neoplasias/genética , Prognóstico , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas c-pim-1/metabolismo
12.
Cell Signal ; 52: 137-146, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30223016

RESUMO

YES is a member of the SRC family kinase (SFK) group of non-receptor tyrosine kinases, which are implicated in multiple key cellular processes involved in oncogenesis. Antitubulin agents have been widely used as chemotherapeutics for cancer patients and these drugs arrest cells in mitosis, leading to subsequent cell death. In the present study, we define a mechanism for phospho-regulation of YES that is critical for its role in response to antitubulin agents. Specifically, we found that YES is phosphorylated at multiple sites on its N-terminal unique domain by the cell cycle kinase CDK1 during antitubulin drug-induced mitotic arrest. Phosphorylation of YES occurs during normal mitosis. Deletion of YES causes arrest in prometaphase and polyploidy in a p53-independent manner. We further show that YES regulates antitubulin chemosensitivity. Importantly, mitotic phosphorylation is essential for these effects. In support of our findings, we found that YES expression is high in recurrent ovarian cancer patients. Finally, through expression profiling, we documented that YES phosphorylation affects expression of multiple cell cycle regulators. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YES during antitubulin chemotherapeutic treatment and suggest YES as a potential target for the treatment of antitubulin-resistant cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Resistencia a Medicamentos Antineoplásicos , Mitose/efeitos dos fármacos , Nocodazol/farmacologia , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-yes/metabolismo , Moduladores de Tubulina/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Nocodazol/uso terapêutico , Paclitaxel/uso terapêutico , Fosforilação , Proteínas Proto-Oncogênicas c-yes/genética , Moduladores de Tubulina/uso terapêutico
13.
Medicine (Baltimore) ; 97(26): e11332, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29953024

RESUMO

RATIONALE: Multiple primary neoplasms (MPNs) are rare. Most MPNs are double, and triple primary neoplasms are extremely rarer. Here, we describe a case of a 66-year-old man diagnosed with metachronous triple primary neoplasms with primary prostate cancer, lung cancer and colon cancer. PATIENT CONCERNS: The patient complained of dysuria in January 2015, and he underwent transurethral resection of the prostate. The pathological results showed acinar adenocarcinoma of prostate with a Gleason score of 3+3. In January 2017, he complained of lower abdominal pain, then he took an enteroscopy examination, found a mass in the sigmoid colon, and positron emission tomography/computed tomography examination showed masses in the sigmoid colon and right upper lobe of the lung. Biopsy of the colon showed moderately differentiated adenocarcinoma with Kirsten rat sarcoma viral oncogene homolog exon 2 mutation, and biopsy of the lung showed moderately differentiated adenocarcinoma with epidermal rowth factor receptor exon 21 mutation. DIAGNOSES: Metachronous triple primary neoplasms with primary prostate cancer, lung cancer and colon cancer. INTERVENTIONS: The patient underwent surgical resection of the right upper lobe of the lung, postoperative stage was T1bN0M0 (stage IA). After 8 cycles of chemotherapy with modified FOLFOX6 regimen (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil 400 mg/m on day 1, followed by 5-fluorouracil 2400 mg/m intravenous infusion over 46 hours every 2 weeks), the patient underwent radical resection of colon cancer, and he finished the remaining 4 cycles of modified FOLFOX6 regimen chemotherapy in November 2017. OUTCOMES: The patient takes examination every three months, and the results show no recurrence. LESSONS: When considering MPNs, thorough surveillance by new screening methods is required to detect a second or even third neoplasm at an early stage.


Assuntos
Neoplasias Pulmonares/patologia , Neoplasias da Próstata/patologia , Neoplasias do Colo Sigmoide/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Neoplasias do Colo Sigmoide/tratamento farmacológico , Neoplasias do Colo Sigmoide/cirurgia
14.
J Cancer ; 9(9): 1598-1606, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760798

RESUMO

Background: Chemotherapy and radiotherapy are critical for treating early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTL); however, the optimal therapy sequence remains unclear. Therefore, we performed this study to compare the efficacy of L-asparaginase/pegaspargase-based sequential versus sandwich chemoradiotherapy for patients newly diagnosed with stage IE-IIE ENKTL. Methods: Patients were categorized into sequential (N = 111) and sandwich (N = 104) groups. Chemotherapy regimens included GELOX, SMILE, and VLP. The median radiotherapy dose was 55.0 Gy (range, 40.0-63.0 Gy). Adverse events, treatment responses, and survival outcomes were analyzed. Results: Patients' clinical characteristics were largely comparable between the 2 groups; however, the sandwich group comprised a larger number of Ann Arbor stage IIE patients. Local invasion was the most significant predictor of overall survival (OS); local invasion and Ann Arbor stage were significant predictors of progression-free survival (PFS). There were no significant differences in the complete response rate (85.6% vs. 89.4%, p = 0.396), 3-year OS (77.5% vs. 80.8%, p = 0.636), or 3-year PFS rates (74.8% vs. 76.9%, p = 0.806) in the sequential vs. sandwich groups, respectively. The incidence of grade 3/4 hematological toxicities was higher in the sandwich group than in the sequential group (27.9% vs. 15.3%, respectively, p = 0.025). The response rates and survival outcomes in stage IE and IIE patients did not differ between sequential and sandwich groups. Conclusions: In the era of L-asparaginase/pegaspargase, both sequential and sandwich chemoradiotherapy are safe and similarly effective in patients with newly diagnosed stage IE-IIE ENKTL.

15.
Med Sci Monit ; 24: 2683-2692, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29712887

RESUMO

BACKGROUND This study compared clinical outcomes and adverse events between L-asparaginase/pegaspargase-based short-course and long-course chemoradiotherapy in newly diagnosed stage IE-IIE extranodal natural killer/T cell lymphoma, nasal type (ENKTL). MATERIAL AND METHODS Patients were categorized into a short-course (2-4 chemotherapy cycles, median: 4, n=153) and long-course group (5-6 cycles, median: 6, n=83). The chemotherapy regimens included GELOX, SMILE, and VLP. The radiotherapy dose was 40-63 Gy (median: 55 Gy). Adverse events, treatment responses, and survival outcomes between the 2 groups were compared. RESULTS Ann Arbor stage IIE and short-course chemotherapy adversely affected overall survival (OS). Ann Arbor stage IE favorably affected progression-free survival (PFS). Grade 3-4 hematological toxicities were higher in the long-course group (25.3% vs. 14.4%, p=0.038). Ann Arbor stage was the single different clinical feature between the 2 groups, and independently affected survival outcomes. In subgroup analysis of stage IE, there was no difference in response rates and survival outcomes between the 2 groups. In subgroup analysis of stage IIE, the recurrence and death rates were significantly lower in the long-course group (6.1% vs. 23.2%, p=0.015; 12.2% vs. 39.3%, p=0.002; respectively), and the 3-year OS and PFS rates were much longer in the long-course group (87.8% vs. 62.5%, p<0.001; 83.7% vs. 57.1%, p=0.001; respectively). CONCLUSIONS When radiotherapy was combined with L-asparaginase/pegaspargase-based chemotherapy to treat early-stage ENKTL patients, 2-4 cycles of chemotherapy might be sufficient for stage IE patients, while stage IIE patients might require 5+ cycles.


Assuntos
Quimiorradioterapia , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/terapia , Quimiorradioterapia/efeitos adversos , Feminino , Humanos , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
16.
J Zhejiang Univ Sci B ; 19(3): 171-182, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29504311

RESUMO

The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of oncogenic proteins is needed for the benefit to cancer patients. The lipid raft marker proteins, flotillin-1 and flotillin-2, were first found in goldfish retinal ganglion cells during axon regeneration. They have since been found in a variety of cells, mainly on the inner surface of cell membranes, and not only act as a skeleton to provide a platform for protein-protein interactions, but also are involved in signal transduction, nerve regeneration, endocytosis, and lymphocyte activation. Previous studies have shown that flotillins are closely associated with tumor development, invasion, and metastasis. In this article, we review the functions of flotillins in relevant cell processes, their underlying mechanisms of action in a variety of tumors, and their potential applications to tumor molecular diagnosis and targeted therapy.


Assuntos
Proteínas de Membrana/fisiologia , Neoplasias/etiologia , Regeneração Nervosa , Animais , Diferenciação Celular , Endocitose , Humanos , Proteínas de Membrana/química
17.
Biomater Sci ; 6(5): 1099-1108, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528079

RESUMO

Treatment of spinal cord injury (SCI) remains a clinical challenge worldwide because of the complicated inhibitory microenvironment formed post-injury, reduced axonal regenerative ability of spinal cord neurons, and scarcity of endogenous neurogenesis within the lesion center. Taxol, in addition to stabilizing microtubules, has shown potential for decreasing axonal degeneration and reducing scar formation after SCI in rodents. In this study, we further verified the therapeutic effects and clinical potential of Taxol on restriction of scar formation and promotion of neuronal regeneration and functional recovery after severe spinal cord transection in a large animal (canine) model. A linear-ordered collagen scaffold (LOCS) combined with Taxol was implanted into the injury site after the complete removal of 1 cm of spinal tissue. Afterwards, diligent nursing and multi-system rehabilitation were carried out during a half-year period of observation. The results showed that LOCS + Taxol implantation markedly promoted motor-evoked potentials and locomotion recovery. Moreover, histological analysis demonstrated that LOCS + Taxol implantation significantly increased neurogenesis and axon regeneration to reconnect the spinal cord stumps. Additionally, reduced glial scar formation was observed within the lesion site. Thus, LOCS + Taxol implantation treatment is a promising combinatorial therapy for the treatment of acute long-distance spinal cord defects.


Assuntos
Colágeno/química , Regeneração Tecidual Guiada/métodos , Paclitaxel/química , Traumatismos da Medula Espinal/cirurgia , Regeneração da Medula Espinal , Tecidos Suporte/química , Animais , Cães , Potencial Evocado Motor , Feminino , Neurônios Motores/fisiologia
18.
Int J Oncol ; 52(6): 1787-1800, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29568859

RESUMO

Three-dimensional (3D) culture has been increasingly used to investigate tumor cell biology for improved simulation of the natural developing environment. However, the way in which 3D culture affects the gene expression and biological functions of glioma cells remains to be fully elucidated. In the present study, 3D culture environments were established using collagen scaffolds with different pore sizes, followed by the comparison of gene expression profiles and associated biological functions of glioma cells, including the U87, U251 and HS683 cell lines, in 3D collagen scaffolds with conventional two-dimensional (2D) cultured cells. Finally, the possible signaling pathways regulating these differences were investigated. It was found that the 3D collagen scaffold culture upregulated the expression of genes associated with stemness, cell cycle, apoptosis, epithelia-mesenchymal transition, migration, invasion and glioma malignancy, and induced the corresponding functional changes. Apoptotic pathways, the Wnt pathway, Sonic Hedgehog pathway and Notch pathway, may be involved in the regulation of these changes. The aperture size of the collagen-scaffold did not appear to affect the gene expression or functions of the glioma cells. The results of the study suggested that the 3D collagen scaffold enhanced the malignancy of glioma cells and may be a promising in vitro platform for investigations of glioma.


Assuntos
Neoplasias Encefálicas/genética , Técnicas de Cultura de Células/métodos , Colágeno/farmacologia , Redes Reguladoras de Genes , Glioma/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tecidos Suporte/química
19.
Oncol Rep ; 39(3): 1261-1268, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29399699

RESUMO

Previously we showed that aldehyde dehydrogenase 1A1 (ALDH1A1) is a new mediator for resistance of DLBCL to CHOP and a facility predictor of clinical prognosis. In the present study, knockdown and inhibitor of ALDH1A1 were applied to identify the role of ALDH1A1 in Raji cells. CCK-8 and clone formation assay were applied to determine the CHOP sensitivity and clone formation ability. Caspase colorimetric assay and Annexin V/FITC staining was performed to determine the degree of apoptosis. Western blot analysis was used to detect the NF-κB/STAT3 signaling proteins and apoptotic-associated proteins. Real-time quantitative PCR (RT-PCR) was used to identify the differential expression of ALDH1A1 between NHL patients and healthy donors. We demonstrated that inhibition of ALDH1A1 increased the sensitivity of Raji cells to CHOP, as indicated by increased cytotoxicity, reduced clonogenicity, activated caspase-3/-9, decreased NF-κB/STAT3 signaling and increased pro-apoptosis signaling, ad increased apoptosis rate. Moreover, we found high ALDH1A1 expression was associated with poor prognosis in NHL patients. Our data revealed the critical role of ALDH1A1 in NHL and provides a theoretical basis for the use of ALDH1A1 inhibitors in NHL patients.


Assuntos
Aldeído Desidrogenase/fisiologia , Linfoma de Células B/enzimologia , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Doxorrubicina/farmacologia , Humanos , Linfoma de Células B/mortalidade , NF-kappa B/metabolismo , Prednisona/farmacologia , Prognóstico , Retinal Desidrogenase , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Vincristina/farmacologia
20.
Oncol Rep ; 39(1): 45-52, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115528

RESUMO

Phospholipase C (PLC) is a pivotal enzyme in the phosphoinositide pathway that promotes the second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), to participate in eukaryotic signal transduction. Several PLC isozymes are associated with cancer, such as PLC-ß1, PLC-δ1, PLC-ε and PLC-γ1. However, the role of PLC-δ3 (PLCD3) in nasopharyngeal carcinoma (NPC) has not been investigated to date. In our previous study, we demonstrated that flotillin2 (Flot2) plays a pro-neoplastic role in NPC and is involved in tumour progression and metastasis. In the present study, we screened the interacting proteins of Flot2 using the yeast two-hybrid (Y2H) method and verified the interaction between PLCD3 and Flot2 by co-immunoprecipitation. We also investigated the biological functions of PLCD3 in NPC. Inhibition of PLCD3 expression impaired the malignant potential of 5-8F, a highly metastatic NPC cell line, by restraining its growth, proliferation, mobility and migration. The present study demonstrated that PLCD3 may be an oncogenic protein in NPC and that it plays an important role in the progression of NPC partially by interacting with Flot2.


Assuntos
Carcinoma/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Fosfolipase C delta/genética , Fosfolipase C delta/metabolismo , Carcinoma/genética , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , Técnicas do Sistema de Duplo-Híbrido , Regulação para Cima
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