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1.
BMC Cancer ; 20(1): 393, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375701

RESUMO

BACKGROUND: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) has been recommended as the first-line therapy for locoregional nasopharyngeal carcinoma (NPC). Due to the different chemotherapeutic drugs used in the IC and CCRT, the results remain controversial. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically retrieved to search potentially eligible clinical trials up to Sep 11, 2019. Eligible studies were registered and prospective randomized controlled clinical trials. RESULTS: From 526 records, nine articles including seven randomized controlled clinical trials were eligible, with a total of 2311 locoregional advanced NPC patients. IC + CCRT had significantly lower risks of death (3-year hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55-0.89, p = 0.003; 5-year HR: 0.77, 95% CI 0.62-0.94, p = 0.01), disease progression (3-year HR: 0.67, 95% CI 0.55-0.80, p < 0.001; 5-year HR: 0.70, 95% CI 0.58-0.83, p < 0.0001), distant metastasis (3-year HR: 0.58, 95% CI 0.45-0.74, p < 0.0001; 5-year HR: 0.69, 95% CI 0.55-0.87, p = 0.001) and locoregional relapse (3-year HR: 0.69, 95% CI 0.50-0.95, p = 0.02; 5-year HR: 0.66, 95% CI 0.51-0.86, p = 0.002) than CCRT. Compared with CCRT, IC + CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade ≥ 3 thrombocytopenia and vomiting during CCRT. CONCLUSION: IC combined with CCRT significantly improved the survival in locoregional advanced NPC patients. Moreover, toxicities were well tolerated during IC and CCRT. Further clinical trials are warranted to confirm the optimal induction chemotherapeutic regimen in the future.

2.
Cell Death Dis ; 11(5): 331, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382038

RESUMO

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

3.
J Cell Physiol ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239704

RESUMO

Current chemotherapy regimens on acute myeloid leukemia (AML) still have some drawbacks, such as intolerance and drug resistance, which calls need for the development of targeted therapy. Signal transducer and activator of transcription 5 (STAT5) is often overexpressed or abnormally activated in leukemia and involved in cell self-renewal, proliferation, and stress adaptation. Overexpressed Aurora A (AURKA) is associated with poor prognosis in tumors, and inhibitors against AURKA are already in clinical trials. However, it has rarely been reported whether AURKA inhibitors restrain STAT5-activated leukemia cells. In this study, we constructed STAT5 constitutively activated (cS5) cells and found that STAT5 promoted cell proliferation and colony formation. Moreover, cS5 cells showed elevated reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, which indicated higher mitochondrial metabolism in cS5 cells. A novel AURKA inhibitor AKI604 was synthesized and showed significant inhibitory effects to the proliferation and colony formation in both STAT5 constitutively activated and nonactivated AML cells. AKI604 induced mitochondrial impairment, leading to the disruption of mitochondrial membrane potential and the elevation of ROS as well as cellular calcium (Ca2+ ) levels. AKI604 could also decline basal oxygen consumption rate and ATP biosynthesis, indicating the damage of oxidative phosphorylation. Furthermore, AKI604 exhibited significant antitumor effect in the HL-60 cS5 xenograft model of the BALB/c nude mice without an obvious influence on mice body weight and other healthy indicators. This study suggested that AKI604 was a potential strategy to overcome STAT5-induced leukemic proliferation in AML treatment by inducing mitochondrial impairment.

4.
Brain Behav Immun ; 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304882

RESUMO

The Psychoneuroimmunology Research Society (PNIRS) created an official Chinese regional affiliate in 2012, designated PNIRSChina. Now, just eight years later, the program has been so successful in advancing the science of psychoneuroimmunology that it has expanded to the whole of Asia-Oceania. In 2017, PNIRSChina became PNIRSAsia-Pacific. Between 2012 and 2019, this outreach affiliate of PNIRS organized seven symposia at major scientific meetings in China as well as nine others in Taiwan, Japan, South Korea, Australia and New Zealand. This paper summarizes the remarkable growth of PNIRSAsia-Pacific. Here, regional experts who have been instrumental in organizing these PNIRSAsia-Pacific symposia briefly review and share their views about the past, present and future state of psychoneuroimmunology research in China, Taiwan, Australia and Japan. The newest initiative of PNIRSAsia-Pacific is connecting Asia-Pacific laboratories with those in Western countries through a simple web-based registration system. These efforts not only contribute to the efforts of PNIRS to serve a truly global scientific society but also to answer the imperative call of increasing diversity in our science.

5.
Oral Oncol ; 104: 104640, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32182550

RESUMO

OBJECTIVES: There is currently no effective salvage therapeutic modality that improves the survival outcomes of patients with recurrent or metastatic nasopharyngeal carcinoma. However, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors may provide clinical benefit for these advanced patients. MATERIALS AND METHODS: The databases, including PubMed, Web of Science, EMBASE and Cochrane Library, were systematically searched up to Nov 5, 2019. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, and drug-related adverse events were extracted and pooled meta-analyzed. RESULTS: From 71 search records, eight studies were included in the systematic review, of which three were eligible for final meta-analysis. In recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy, the pooled ORR was 27% (95% confidence interval [CI] 19-36%), DCR was 63% (95% CI 50-75%), 6 months PFS rate was 49% (95% CI 40-58%), 1-year PFS rate was 25% (95% CI 19-32%), 1-year OS rate was 61% (95% CI 49-72%). The pooled incidences of any grade and grade ≥ 3 drug-related adverse events were 94% and 20% respectively. CONCLUSION: We present the aggregate response rates, survival rates and incidences of drug-related adverse events for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-1/PD-L1 blockage treatment, which could provide useful information for future design of clinical studies. There is a need for more randomized controlled studies with head-to-head comparison of PD-1/PD-L1 inhibitors and traditional chemotherapeutic strategies to enable better recommendations for optimal advanced nasopharyngeal carcinoma treatment.

6.
Photodiagnosis Photodyn Ther ; 29: 101667, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978564

RESUMO

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of non-melanoma skin cancer worldwide. Methyl-5-aminolevulinate (MAL) photodynamic therapy (PDT) is an effective and acceptable treatment for BCC. The purpose of this analysis was to compare the benefit and tolerability of MAL-PDT with other modalities for the treatment of BCC. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched from inception until 5 August 2019. Eligible studies were prospective and retrospective clinical trials of MAL-PDT for superficial and nodular BCC. At least one of the following outcomes were reported: complete response (CR) at 3 months and sustained at 12 months; recurrence at 12 months and sustained at 5 years; cosmetic outcome at ≥ 3 months; adverse events. RESULTS: From 427 search results, 11 articles including seven randomized controlled trials (1339 patients; 1568 lesions) and one retrospective study (108 lesions) were eligible. CR was inferior with MAL-PDT versus surgery (3 months: Risk Ratio [RR]: 0.93, 95 % confidence interval [CI] 0.89-0.97, p = 0.002; 12 months: RR: 0.90, 95 % CI 0.85-0.95, p = 0.0002). Moreover, MAL-PDT had higher 12 months recurrence rate (RR: 10.43, 95 % CI 1.98-55.03, p = 0.006) and more toxicities (RR: 2.12, 95 % CI 1.46-3.09, p < 0.0001) in comparison with surgery. However, MAL-PDT cosmesis was superior to excisional surgery (RR: 1.99, 95 % CI 1.50-2.63, p < 0.00001). Additionally, MAL-PDT was associated with similar CR in comparison with 5-aminolaevulinic acid (ALA)-PDT and ALA nanoemulsion (BF-200 ALA)-PDT, but had higher recurrence rate at 12 months and worse cosmesis compared with BF-200 ALA-PDT, even though the differences were not statistically significant. CONCLUSION: MAL-PDT might not be the best first-line treatment option for BCC, although cosmetic outcome could be good-to-excellent.

7.
Cancer Genet ; 240: 59-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786363

RESUMO

PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia and its progressive genomic basis over time remains unclear. We aimed to investigate the longitudinal genomic evolution of MPAL from diagnosis to relapse. METHODS: We performed whole genome sequencing (WGS) on bone marrow (BM) samples obtained at the four stages of this disease in a male patient with Philadelphia chromosome positive (Ph+) MPAL, including primary, complete cytogenetic remission (CCR), complete molecular remission (CMR), and relapse stage during the 3 year follow-up period. RESULTS: 156 single-nucleotide variants (SNVs) and indels were detected, which exhibited distinctive evolutionary behaviors. Seventeen mutations disappeared quickly upon DCTER treatment and never came back. Seven mutations, although disappeared initially, reoccurred with the withdrawal of TKI treatment. Notably, ten mutations emerged in spite of the active DCTER chemotherapy. Moreover, copy number loss played critical roles in monitoring MPAL progression, displaying 7, 0, 0, and 383 losses at the stages of primary, CCR, CMR, and relapse respectively. CONCLUSION: This longitudinal genomic investigation of the Ph+ MPAL patient established one MPAL evolution model in which the primary tumor acquired additional variations leading to tumor relapse. Moreover, the event of copy number loss remained a valuable hallmark in the progression of MPAL.

8.
Anal Chem ; 91(20): 13222-13229, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525957

RESUMO

Small-molecule inhibitors of protein kinases attract widespread interest in the field of disease therapy because of their high specificity and ease of administration. However, dissecting the conformational inhibition dynamics of kinase inhibitors is still challenging. Here, simultaneously monitoring the conformational inhibition details and potency of Aurora A kinase inhibitors has been achieved by active isotope dimethyl labeling coupled with mass spectrometry-based quantitative lysine reactivity profiling. The conformational effects of inhibitors on lysine reactivity can be globally quantified to feasibly reveal the regions involved in the kinase dynamic inhibition. The half-maximum disturbance concentrations (DC50 values) of the conformation-specific lysine residues could directly represent the conformational selectivity and potency of kinase inhibitors. Further, K309 is discovered as a novel hotspot contributing to the inhibition of Aurora A kinase via the specific rotation of kinase activation loop. This quantitative lysine reactivity profiling strategy might greatly promote the development of targeted drugs.

9.
Cancer Med ; 8(12): 5673-5686, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31369215

RESUMO

INTRODUCTION: Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients. MATERIALS AND METHODS: Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. RESULTS: Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups. CONCLUSIONS: Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.

10.
J Cell Mol Med ; 23(9): 6442-6453, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359594

RESUMO

Triple-negative breast cancer (TNBC) has a relatively poor outcome. Acquired chemoresistance is a major clinical challenge for TNBC patients. Previously, we reported that kinase-dead Aurora kinase A (Aurora-A) could effectively transactivate the FOXM1 promoter. Here, we demonstrate an additional pathway through which Aurora-A stabilizes FOXM1 by attenuating its ubiquitin in TNBC. Specifically, Aurora-A stabilizes FOXM1 in late M phase and early G1 phase of the cell cycle, which promotes proliferation of TNBC cells. Knock-down of Aurora-A significantly suppresses cell proliferation in TNBC cell lines and can be rescued by FOXM1 overexpression. We observe that paclitaxel-resistant TNBC cells exhibit high expression of Aurora-A and FOXM1. Overexpression of Aurora-A offers TNBC cells an additional growth advantage and protection against paclitaxel. Moreover, Aurora-A and FOXM1 could be simultaneously targeted by thiostrepton. Combination of thiostrepton and paclitaxel treatment reverses paclitaxel resistance and significantly inhibits cell proliferation. In conclusion, our study reveals additional mechanism through which Aurora-A regulates FOXM1 and provides a new therapeutic strategy to treat paclitaxel-resistant triple-negative breast cancer.

11.
Cell Death Dis ; 10(6): 432, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160567

RESUMO

Transcription cofactor Yes-associated protein (YAP) plays an important role in cancer progression. Here, we found that Aurora A kinase expression was positively correlated with YAP in lung cancer. Aurora A depletion suppresses lung cancer cell colony formation, which could be reversed by YAP ectopic overexpression. In addition, activation of Aurora A increases YAP protein abundance through maintaining its protein stability. Consistently, the transcriptional activity of YAP is increased upon Aurora A activation. We further showed that shAURKA suppressed YAP expression in the absence of Lats1/2, indicating that Aurora A regulates YAP independently of Hippo pathway. Instead, Aurora A induced blockage of autophagy to up-regulate YAP expression. Collectively, our findings provide insights into regulatory mechanisms of YAP expression in lung cancer development.

12.
Aging (Albany NY) ; 11(10): 3333-3347, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31164492

RESUMO

Recently, competing endogenous RNAs (ceRNAs) hypothesis has gained a great interest in the study of molecular biological mechanisms of cancer occurrence and progression. However, studies on leukemia are limited, and there is still a lack of comprehensive analysis of lncRNA-miRNA-mRNA ceRNA regulatory network of AML based on high-throughput sequencing and large-scale sample size. We obtained RNA-Seq data and compared the expression profiles between 407 normal whole blood (GTEx) and 151 bone marrows of AML (TCGA). The similarity between two sets of genes with trait in the network was analyzed by weighted correlation network analysis (WGCNA). MiRcode, starBase, miRTarBase, miRDB and TargetScan was used to predict interactions between lncRNAs, miRNAs and target mRNAs. At last, we identified 108 lncRNAs, 10 miRNAs and 8 mRNAs to construct a lncRNA-miRNA-mRNA ceRNA network, which might act as prognostic biomarkers of AML. Among the network, a survival model with 8 target mRNAs (HOXA9+INSR+KRIT1+MYB+SPRY2+UBE2V1+WEE1+ZNF711) was set up by univariate and multivariate cox proportional hazard regression analysis, of which the AUC was 0.831, indicating its sensitivity and specificity in AML prognostic prediction. CeRNA networks could provide further insight into the study on gene regulation and AML prognosis.

13.
Int J Cancer ; 145(9): 2547-2557, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30919951

RESUMO

The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.


Assuntos
Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Quimiorradioterapia/métodos , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Genoma/genética , Genômica/métodos , Humanos , Pessoa de Meia-Idade , Mutação/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia
14.
EBioMedicine ; 41: 120-133, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799199

RESUMO

BACKGROUND: Differential gene expression patterns are commonly used as biomarkers to predict treatment responses among heterogeneous tumors. However, the link between response biomarkers and treatment-targeting biological processes remain poorly understood. Here, we develop a prognosis-guided approach to establish the determinants of treatment response. METHODS: The prognoses of biological processes were evaluated by integrating the transcriptomes and clinical outcomes of ~26,000 cases across 39 malignancies. Gene-prognosis scores of 39 malignancies (GEO datasets) were used for examining the prognoses, and TCGA datasets were selected for validation. The Oncomine and GEO datasets were used to establish and validate transcriptional signatures for treatment responses. FINDINGS: The prognostic landscape of biological processes was established across 39 malignancies. Notably, the prognoses of biological processes varied among cancer types, and transcriptional features underlying these prognostic patterns distinguished response to treatment targeting specific biological process. Applying this metric, we found that low tumor proliferation rates predicted favorable prognosis, whereas elevated cellular stress response signatures signified resistance to anti-proliferation treatment. Moreover, while high immune activities were associated with favorable prognosis, enhanced lipid metabolism signatures distinguished immunotherapy resistant patients. INTERPRETATION: These findings between prognosis and treatment response provide further insights into patient stratification for precision treatments, providing opportunities for further experimental and clinical validations. FUND: National Natural Science Foundation, Innovative Research Team in University of Ministry of Education of China, National Key Research and Development Program, Natural Science Foundation of Guangdong, Science and Technology Planning Project of Guangzhou, MRC, CRUK, Breast Cancer Now, Imperial ECMC, NIHR Imperial BRC and NIH.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias/genética , Transcriptoma , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resultado do Tratamento
15.
J Clin Invest ; 129(3): 1030-1046, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688660

RESUMO

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Epinefrina/metabolismo , L-Lactato Desidrogenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Estresse Psicológico/metabolismo , Animais , Ácido Ascórbico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
16.
Cell Death Dis ; 9(12): 1172, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518842

RESUMO

Gastric cancer, like most of other cancers, has an uncontrolled cell cycle regulated by cyclins and cyclin-dependent kinases (CDKs). In this study, we reported that gastric cancer cells showed an accelerated G2/M transition promoted by CREPT/RPRD1B and Aurora kinase B (Aurora B). We found that CREPT/RPRD1B and Aurora B were coordinately expressed during the cell cycle in gastric cancer cells. Deletion of CREPT/RPRD1B disturbed the cell progression and extended the length of cell cycle, leading to a significant accumulation of mitotic cells. Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1, which is critical for the regulation of gastric tumorigenesis. Our study provides a mechanism by which gastric tumor cells maintain their high proliferation rate via coordination of Aurora B and CREPT/RPRD1B on the expression of Cyclin B1. Targeting the interaction of Aurora B and CREPT/RPRD1B might be a strategy for anti-gastric cancer therapy in the future.


Assuntos
Aurora Quinase B/genética , Proteínas de Ciclo Celular/genética , Ciclina B1/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Animais , Aurora Quinase B/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina B1/metabolismo , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Fosforilação , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Mol Clin Oncol ; 9(6): 622-628, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30546891

RESUMO

Metastatic cystic lesions may be considered as target lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. However, cystic lesions are considered as non-measurable according to RECIST 1.0. Krukenberg tumors are cystic metastases from gastric cancer. The aim of the present case report was to address the question of whether a Krukenberg tumor can be considered as a target lesion. A 30-year-old female patient was diagnosed with stage IV gastric cancer 6 months after parturition. Subsequently, the patient received two courses of oxaliplatin/capecitabine plus trastuzumab (OCT) treatment. The response evaluation was considered as stable disease. However, after four courses of OCT, the cystic target lesion in the right pelvic cavity exhibited an increase in diameter of >40%. After one more cycle of OCT, contrast-enhanced magnetic resonance imaging (MRI) revealed that the diameter of the cystic mass lesion had decreased by >35% and a further two cycles of treatment were administered. After the last OCT cycle, the levels of the tumor markers cancer antigen (CA) 125, CA19-9 and CA153 had markedly increased, although the cystic mass had decreased in size. Eventually, positron emission tomography-computed tomography (PET/CT) was used to assess the efficacy of treatment. A new lesion was identified, indicating progressive disease. The present case demonstrated that the Krukenberg tumor may be considered as a non-target lesion. In addition, tumor markers and PET/CT yielded results complementary to those of contrast-enhanced MRI in the therapeutic assessment of advanced gastric cancer.

18.
EBioMedicine ; 38: 113-126, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30429088

RESUMO

BACKGROUND: Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer. METHODS: Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms. FINDINGS: Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival. CONCLUSIONS: Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy.


Assuntos
Processamento Alternativo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , PTEN Fosfo-Hidrolase/genética , Tolerância a Radiação/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular Tumoral , Biologia Computacional , Quebras de DNA de Cadeia Dupla , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/radioterapia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cell Death Dis ; 9(11): 1120, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389909

RESUMO

Estrogen receptor ß (ERß) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERß is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERß decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERß and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERß expression. ERß depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERß is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERß expression. Collectively, our findings reveal that ERß-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.


Assuntos
Receptor beta de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , /genética , Animais , Antineoplásicos/farmacologia , Aspirina/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Retroalimentação Fisiológica , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia
20.
Oncotarget ; 9(62): 31945-31957, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30174788

RESUMO

Anaplastic thyroid cancer (ATC), an undifferentiated subtype of thyroid cancer, is one of the most malignant endocrine cancer with low survival rate, and resistant to chemotherapy and radiation therapy. Here we found that UHRF1 was highly expressed in human ATC compared with normal tissue and papillary thyroid cancer (PTC). Knockdown of UHRF1 inhibited proliferation of ATC in vitro and in vivo. Consistently, overexpression of UHRF1 promoted the proliferation of thyroid cancer cells. Moreover, UHRF1 suppression induced differentiation of three-dimensional (3D) cultured ATC cells and down-regulated the expression of dedifferentiation marker (CD97). The stem cell markers (Sox2, Oct4 and Nanog) were suppressed simultaneously. In addition, UHRF1 knockdown reduced the transcription of cytokines (IL-8, TGF-α and TNF-α), which might relieve the inflammatory reaction in ATC patients. This study demonstrated a role of UHRF1 in ATC proliferation, dedifferentiation and inflammatory reaction, presenting UHRF1 as a potential target in ATC therapy.

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