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1.
Clin Cancer Res ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694833

RESUMO

PURPOSE: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. EXPERIMENTAL DESIGN: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced-stage incurable disease who received first line chemotherapy. RESULTS: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 LCNEC patients were classified into small cell lung cancer (SCLC)-like and non-small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival (OS) than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared to pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared to etoposide-platinum or pemetrexed-platinum in NSCLC-like LCNEC patients. CONCLUSIONS: Genomic subtyping has potentials in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.

2.
J Environ Manage ; 253: 109687, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31666211

RESUMO

Stream losses are extensively observed due to human activities in the world, and the patterns of stream loss vary in different land use types. However, relationship between stream loss pattern and land use covers is poorly understood. We select the lower Taihu watershed (LTWS) within Yangtze River Delta (YRD), which is dominated by agricultural and urban covers and a typical case of most urbanized watersheds in China. In this study, we measured the stream loss of LTWS from 1960s to 2010s and investigated its relation to different land use covers and impervious area percentage (IAP) in order to figure out the main factor of stream loss in this area. The results show that urban area has tripled with fractional contribution from 10.3% to 33.18% in the form of conversion from agriculture to urban area during 1990-2015. 12.5% of all the streams are lost and 1st-order streams contribute most (91.8%) to the total stream loss. Urban cover contribute most (76%) to total streams loss compared to other land use types. We find that 1st-order streams have highest stream loss intensity, which is mainly caused by urban expansion, but preferred protections are given to highest-order streams. The linear model of correlation of pixel-level streams loss and IAP shows that the streams loss is statistically significant positive with IAP of cells (R2 = 0.91). Tradeoffs between city expansion and river network make small channels sacrifice for the urbanization. Urgent measures including legislation must be taken to protect small streams during urbanization nowadays and in future.

3.
Ecotoxicol Environ Saf ; 184: 109633, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31518825

RESUMO

Soil organic matter (SOM) could immobilize most of metals, but it could promote the migration of a small part of metals in special environments. Heavy rainfall and drought makes wetlands affected by the alternation of drought and flood, altering the mobility of metals. Few studies have been conducted on the changes of binding characteristics of metals onto SOM which derived from different water conditions and rhizospheric environments. The objective of this paper was to explore the sequential differences of spectral variations of fluorescent groups and UV-Vis groups of metals onto SOM which derived from different water managements and rhizospheric environments. The method adopted was mainly two-dimensional correlation analysis (2DCOS). The results showed that flooding samples contained more aromatic substances compared to draining samples, which could promote metal binding. The binding characteristics were shown in the following: (1) Cd2+ and Zn2+ could react with aromatic substances, react with functional groups in SOM, and promote the formation of new groups such as carboxyl; (2) both Zn2+ and Cd2+ could bind with functional groups on proteins but relatively reductive environment can weaken the binding ability of Cd2+; (3) the protein-like or fulvic-like groups gave the fastest responses and then came the amide and carboxyl groups in nearly all flooding samples; (4) in flooding samples, Cd2+ was most easily to bind with fulvic-like groups, while Zn2+ was most easily to bind with protein-like groups. This work is conducive to the long-term management of heavy metal pollutants in wetlands.

4.
Breast Cancer Res ; 21(1): 89, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391072

RESUMO

BACKGROUND: Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment. METHODS: The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed. RESULTS: Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability. CONCLUSIONS: miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management.

5.
Cell Death Dis ; 10(8): 603, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399556

RESUMO

The Hippo-TAZ signaling has emerged as a fundamental regulator underlying cancer stem cells (CSCs) stemness which intricately associates with local recurrence and metastatic spreading in head neck squamous cell carcinoma (HNSCC). However, the precise downstream targets of TAZ responsible for HNSCC CSCs maintenance remain largely underexplored. Here, we identified Sex determining region Y box 2 (SOX2) as a putative downstream target of TAZ to promote CSCs maintenance and tumorigenicity in HNSCC. Both TAZ and SOX2 were significantly enriched in CSCs subpopulation (CD44+CD133+) isolated from Cal27 and Fadu cells via fluorescence-activated cell sorting. TAZ knockdown significantly reduced expression of SOX2 at both mRNA and protein levels, whereas its ectopic overexpression markedly increased its abundance in HNSCC cells. Moreover, reintroduction of ectopic SOX2 abolished, at least in part, the reduced tumorsphere formation and tumorigenicity in vivo induced by TAZ knockdown. Mechanistically, transcriptional complex formed by TAZ and TEAD4 was recruited to two binding sites in SOX2 promoter, which in turn facilitated transcription of SOX2 in HNSCC cells. In addition, the abundance of TAZ and SOX2 was positively correlated in HNSCC clinical samples, and both upregulations of TAZ and SOX2 associated with the worst survival. Taken together, our data reveal a previously unknown mechanistic linkage between TAZ and SOX2 and identify SOX2 as a direct downstream target of TAZ in modulating CSCs self-renewal and maintenance in HNSCC. These findings suggest that targeting TAZ-SOX2 axis might be a promising therapeutic strategy for HNSCC.

6.
Int J Cancer ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304591

RESUMO

Immune infiltrates have been increasingly recognized as robust prognostic factors for human cancer. Here, we developed and validated a seven-immune-feature-based prognostic score (7IFBPS) for patients with oral squamous cell carcinoma (OSCC) after curative resection. Fourteen immune features regarding detailed locations and densities of seven types of tumor-infiltrating immune cells (TIIs) were characterized in clinical samples from 269 eligible patients in three independent cohorts by immunohistochemistry coupled with digital quantitation. Optimal cutoff values for individual immune features were yielded using X-tile software. The 7IFBPS was constructed by Kaplan-Meier and Cox regression model in training cohort and verified in testing, validation and combined cohorts. Concordance index (C-index), receiver operating characteristics and calibration curves were employed to define the performance of 7IFBPS in prognostic prediction. High CD3 IM (invasive margin), CD3 CT (center of tumor), CD8 CT, CD45RO IM, CD45RO CT, FOXP3 IM and FOXP3 CT significantly associated with improved survival. The 7IFBPS score was calculated using the formula: 1.041 × CD3 IM + 1.24 × CD3 CT + 1.701 × CD8 CT + 1.127 × CD45RO IM + 1.348 × CD45RO CT + 1.089 × FOXP3 IM + 1.483 FOXP3 CT. High 7IFBPS significantly associated with improved survival in all cohorts and served as an independent prognostic predictor. The C-index of 7IFBPS for predicting survival was 0.668 (95% CI, 0.609-0.726). Calibration curves for survival probability showed good agreement between prediction by 7IFBPS and actual observation. Collectively, our findings established the 7IFBPS as a novel powerful prognostic classifier for resectable OSCC. It holds potentials to be incorporated into current prognostic regime to better patient stratification.

7.
Nat Commun ; 10(1): 3163, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320640

RESUMO

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

8.
Theranostics ; 9(12): 3485-3500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281492

RESUMO

Background: Liver is the most common metastatic site in advanced colorectal cancer. Most patients with colorectal cancer liver metastasis (CRLM) do not benefit from current treatment. Patient-derived xenografts (PDXs) with defined molecular signatures are attractive models for preclinical studies. Methods: Successfully established PDXs were evaluated to elucidate their fidelity of patients' biologic characteristics (pathologic, genetic and protein properties, together with chemosensitivity). The genomic variations of PDXs were analyzed by next-generation sequencing to explore the underlying molecular mechanism of metastasis and potential therapeutic targets. Results: CRLM (N=73) showed a significantly higher successful PDX establishment rate than primary specimens (N=26; 76.7% vs. 57.7%). CRLM PDXs recapitulated the pathologic, genetic and protein properties of parental tumors, as well as chemosensitivity. Frequent altered genes in PDXs showed high consistency compared to patients' genomic alterations and were enriched in MAPK, ErbB, cell cycle, focal adhesion pathways for CRLM PDXs, whereas primary tumor-derived PDXs only exhibited genomic variations involving ErbB and cell cycle. The genetic alterations showed high concordance between paired PDXs from primary and metastatic tissues, except for recurrent gene mutations (ARID1A, CDK8, ETV1, STAT5B and WNK3) and common copy number gains in chromosomes 20q (e.g., SRC/AURKA). Several potential drug targets such as KRAS, HER2, and FGFR2 were validated using corresponding inhibitors. Additionally, PDX models could also be used in screening efficient regimens for patients with no druggable alterations. Conclusion: This study has successfully established and validated a large panel of molecularly annotated platforms from patients with CRLM for preclinical studies.

9.
J Cell Biochem ; 120(10): 18266-18277, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31172583

RESUMO

Long noncoding RNAs (lncRNAs) have been recognized as novel biomarkers and therapeutic targets in human cancer including head-neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the expression of a novel lncRNA WW domain containing transcription regulator 1 antisense RNA 1 (WWTR1-AS1) as well as its clinical significance and biological roles in HNSCC. The expression level of endogenous WWTR1-AS1 in primary HNSCC and paired adjacent nontumor mucosa was evaluated by quantitative reverse-transcription polymerase chain reaction. The correlations were assessed between WWTR1-AS1 expression and clinical data such as clinicopathological parameters and patient survival. Further, the molecular mechanisms of WWTR1-AS1 underlying HNSCC progression were detected by loss-of-function assay in vitro and bioinformatics analysis. Aberrant overexpression of WWTR1-AS1 in HNSCC samples showed a significant correlation between its higher expression levels and larger tumor size, cervical node metastasis, and poor prognosis. WWTR1-AS1 knockdown mediated by antisense oligonucleotide markedly inhibited cell proliferation, migration, invasion, tumorsphere formation as well as apoptosis resistance probably by modulating WWTR1 messenger RNA (mRNA) stability in HNSCC cells. Bioinformatics analysis revealed that WWTR1-AS1 expression positively correlated with WWTR1 expression in TCGA-HNSCC data sets. Together, our data provide evidence that aberrant upregulation of WWTR1-AS1 associates with malignant features and unfavorable prognosis in HNSCC, highlighting that WWTR1-AS1 might be a potential oncogenic lncRNA during HNSCC progression.

10.
Ann Thorac Surg ; 108(5): 1505-1513, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31233722

RESUMO

BACKGROUND: It remains unclear whether postoperative chemotherapy improves survival among patients with esophageal squamous cell carcinoma who have undergone preoperative chemotherapy and radical resection. METHODS: Patients treated between January 2000 and December 2016 were reviewed. Eligible patients were divided into two groups: perioperative chemotherapy (preoperative and postoperative chemotherapy) and neoadjuvant chemotherapy only. The primary endpoint was disease-free survival; the secondary endpoints were overall survival and toxicities attributable to postoperative chemotherapy. To minimize the effect of patient heterogeneity between the two groups, we used propensity score matching. The survival analysis was performed using univariate analysis and a multivariable Cox regression model. RESULTS: In total, 252 patients were included in the study. Most were men (208 of 252; 82.5%); median age was 59 years. The follow-up rate was 93.3%. Age, performance status, minimally invasive surgery, and Clavien-Dindo classification were statistically different between the groups (P <.05). After propensity score matching, each group had 59 patients. Five-year disease-free survival (52.4% vs 43.6%, P = .372) and overall survival (68.6% vs 62.4%, P = .359) were not statistically different between the neoadjuvant chemotherapy group and the perioperative chemotherapy group. Cox regression identified both pathologic nodal stage and tumor regression grade are independent prognostic factors for disease-free survival and overall survival (P < .05); adjuvant chemotherapy did not influence disease-free survival (hazard ratio 1.049, 95% confidence interval, 0.587 to 1.876, P = .872) or overall survival (hazard ratio 1.297; 95% confidence interval, 0.606 to 2.775, P = .504). In the perioperative chemotherapy group, 8.5% of patients (5 of 59) had grade 3 or greater toxicity. CONCLUSIONS: Adjuvant chemotherapy is not indicated for patients with locally advanced esophageal squamous cell carcinoma after neoadjuvant platinum-based chemotherapy and surgery.

11.
Theranostics ; 9(6): 1777-1793, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037138

RESUMO

The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

12.
Abdom Radiol (NY) ; 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31111196

RESUMO

OBJECTIVE: The aim of this study was to evaluate PET/FDG metabolic parameters in locally advanced GEJC and correlate it with molecular pathological profiles. METHODS: We retrospectively analyzed data from 66 patients with a histopathological diagnosis of GEJC who had undergone 18F-FDG PET/CT before surgical resection. Maximum standardized uptake (SUVmax), mean standardized uptake (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor were measured and calculated using the region of interest (ROI) technique. The relationship between metabolic parameters and the Lauren's classification, histologic differentiation, Ki-67 staining and positivity for human epidermal growth factor receptor 2 (HER2), c-Met, and epidermal growth factor receptor (EGFR) were investigated through immunohistochemical (IHC) analyses. RESULTS: Of the total 66 patients, significant differences were observed between intestinal and non-intestinal (mixed and diffuse) adenocarcinomas in SUVmax (8.23 ± 2.83 vs. 6.29 ± 2.41, P = 0.008), SUVmean (4.85 ± 1.47 vs. 3.93 ± 1.22, P = 0.017), MTV (24.96 cm3 vs. 8.90 cm3; P = 0.004), and TLG (97.38 cm3 vs. 37.09 cm3, P = 0.005) values. SUVmax, MTV, and TLG of moderately differentiated adenocarcinomas were significantly higher than those of the poorly differentiated ones. SUVmax was significantly higher in tissues with a higher Ki-67 index or in the c-MET-negative group (P = 0.045, P = 0.036). No significant correlation was found between metabolic parameters and the expression of HER2 or EGFR in GEJC. CONCLUSION: 18F-FDG PET/CT may be useful for predicting the molecular pathological profiles of GEJC and for determining appropriate therapeutic strategy.

13.
Sci Total Environ ; 683: 258-266, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132705

RESUMO

Proton-binding study of humic acid (HA) is critical for describing and modeling the binding mechanism of HA with heavy metals. However, little is known about the intrinsic relationship between protonation behavior and HA characteristics, especially in sediments. In this study, HA was extracted from sediments and combination of spectrographic titration with parallel factor analysis, Gaussian fitting model and two-dimensional correlation spectroscopy analysis was developed as a novel in-situ tool. Results indicated that the intensity changes of fluorophores of sediment HA might be dependent on the structure characteristics (fused or non-fused ring) of phenolic species in the protonation process. Compared with phenolic groups (A1, 5.27 ±â€¯0.05 eV; A3, 3.91 ±â€¯0.02 eV), the carboxyl groups (A2, 4.65 ±â€¯0.03 eV) exhibited greater contribution in the response of chromophores to the protonation process of sediment HA. Furthermore, proton binding to sediment HA first occurred in carboxyl groups and then in phenolic groups. The combined technique is a promising approach for the examination of the binding sites, binding capacities, and binding order in proton-HA binding process under environmental concentrations. Importantly, this method is a sensitive, effective and non-destructive technique without any need pre-concentrate.

14.
Nat Commun ; 10(1): 2037, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048690

RESUMO

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.


Assuntos
Oncogenes/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Caderinas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Éxons/genética , Feminino , Duplicação Gênica/genética , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Sequenciamento Completo do Genoma
15.
Int J Cancer ; 145(9): 2440-2449, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30957241

RESUMO

Afatinib is a pan-HER inhibitor approved for specific types of lung cancer. We explored antitumor activity, predictive biomarkers and the potential mechanisms underlying antitumor effect and acquired resistance of afatinib in gastric cancer (GC) in vitro and in vivo. Five human GC cell lines and eight patient-derived xenograft (PDX) models with clear molecular profiling were used to evaluate the antitumor activity and mechanisms of afatinib. The ErbB family and downstream PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways were evaluated before and after afatinib treatment. An afatinib-resistant PDX model was established to explore both the potential mechanisms of drug resistance and reversal strategies. We found that afatinib exerted a strong tumor suppression in EGFR/HER2 highly amplified (copy number >6) or overexpressed (IHC 3+) PDX models and a moderate tumor suppression in EGFR/HER2 moderately expressed (IHC 2+) PDX models. Afatinib selectively inhibited the proliferation of HER2 highly amplified GC cells in a dose-dependent manner in vitro. Afatinib also exerted its antitumor effect by inducing cell apoptosis and cell arrest at G1 phase. Diminished activation of the ErbB family and downstream PI3K/AKT/mTOR and MAPK pathways was also observed. Erythropoietin-producing hepatocellular receptor A2 (EPHA2) upregulation and phosphorylation might be involved in afatinib-acquired resistance, and EPHA2 blockade could restore afatinib sensitivity. GC patients with amplification (copy number >6) or overexpression (IHC 3+) of EGFR/HER2 were most likely to benefit from afatinib treatment and EPHA2 blockade reversed acquired resistance to afatinib treatment, which could provide solid evidences for future clinical trials.

16.
Gastric Cancer ; 22(6): 1183-1192, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30989433

RESUMO

OBJECTIVES: Hepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS. METHODS: Forty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan-Meier method. RESULTS: The most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10-20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS (p = 0.007) and tended to be associated with poorer DFS (p = 0.05). CONCLUSION: CNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.

17.
J Cell Mol Med ; 23(6): 4269-4280, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30950191

RESUMO

The long noncoding RNAs (lncRNAs) have been increasingly appreciated as key players underlying tumourigenesis and hold great potentials as prognostic biomarkers and therapeutic targets. However, their roles in head neck squamous cell carcinoma (HNSCC) have remained incompletely known. Here, we sought to reveal the oncogenic roles and clinical significance of a tumour-associated lncRNA, zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1), in HNSCC. ZEB2-AS1 was aberrantly overexpressed in a fraction of HNSCC samples. Its overexpression significantly associated with large tumour size, cervical node metastasis and reduced overall and disease-free survival. Antisense oligonucleotides (ASO)-mediated ZEB2-AS1 depletion markedly inhibited cell proliferation, migration and invasion while triggered apoptosis in HNSCC cells in part via modulating ZEB2 mRNA stability. Enforced overexpression of ZEB2 largely attenuated the phenotypic changes resulted from ZEB2-AS1 inhibition except the impaired cell proliferation. In addition, ZEB2-AS1 was required for TGF-ß1-induced epithelial-mesenchymal transition (EMT) in vitro. Significantly reduced tumour growth and lung metastasis were observed in ZEB2-AS1-depleted cells in HNSCC xenograft animal models. Taken together, our findings reveal that overexpression of ZEB2-AS1 associates with tumour aggressiveness and unfavourable prognosis by serving as a putative oncogenic lncRNA and a novel prognostic biomarker in HNSCC.

18.
J Exp Clin Cancer Res ; 38(1): 140, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925913

RESUMO

BACKGROUND: Autophagy, a process for degrading intracellular substances to maintain basal metabolic turnover, is known to be perturbed in gastric cancer. Programmed cell death-1 (PD-1) with its ligand (PD-L1) are important immune checkpoint proteins and their regulation by autophagy has been reported in mouse melanoma and human ovarian cancer. Here, we explored the interplay between autophagy and the PD1/PD-L1 axis in gastric cancer. METHODS: The expression of PD-L1 in gastric cancer cells was detected by Western blot and flow cytometry analysis. The effect of autophagy inhibition on PD-L1 expression was examined in vitro and in vivo. The molecular mechanisms of the regulation of PD-L1 by autophagy were evaluated in gastric cancer cell lines. The clinical relevance of autophagy-related markers p62/SQSTM1 and LC3 with PD-L1 was evaluated in 137 patients with gastric cancer. RESULTS: We found that inhibition of autophagy by pharmacological inhibitors or small interfering RNAs increased the levels of PD-L1 in cultured gastric cancer cells and in xenografts. Interferon (IFN)-γ also promoted PD-L1 gene transcription, whose action was enhanced by autophagy inhibition. Mechanistically, autophagy inhibition led to the accumulation of p62/SQSTM1 and activation of nuclear factor (NF)-κB, in which NF-κB inhibition or p62/SQSTM1 knockdown attenuated PD-L1 induction by autophagy inhibition. Immunohistochemical staining of primary tumor tissues of 137 patients with gastric cancer showed that LC3 and p62/SQSTM1 protein levels were positively correlated with PD-L1 (LC3, p < 0.001; p62/SQSTM1, p < 0.05). The expression of PD-L1 was also positively correlated with tumor lymphocyte infiltration (p < 0.001). CONCLUSIONS: We discovered that autophagy regulates PD-L1 expression in gastric cancer through the p62/SQSTM1-NF-κB pathway. Pharmacological modulation of autophagy may thus influence the therapeutic efficacy of PD-L1 blockade in gastric cancer.


Assuntos
Autofagia , Antígeno B7-H1/metabolismo , Regulação para Baixo , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Estadiamento de Neoplasias , Transplante de Neoplasias , Neoplasias Gástricas/metabolismo
19.
Environ Int ; 126: 690-698, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30875562

RESUMO

Carbon nanomaterials (CNMs) are widely used because of their unique advantages in recent years. At the same time, the influence of CNMs on the environment is becoming increasingly prominent. This review mainly introduces the research progress in the effects of fullerenes, multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs) and graphene on microorganisms and their toxicity mechanisms. On this basis, we have analyzed beneficial and adverse effects of fullerenes, graphene, MWCNTs and SWCNTs to microorganisms, and discussed the similarities of the toxicity mechanisms of different CNMs on microorganisms. This review helps provide ideas on how to protect microorganisms from the impacts of carbon nanomaterials, and it will be conductive to providing a strong theoretical basis for better application of carbon nanomaterials.


Assuntos
Fulerenos/efeitos adversos , Grafite/efeitos adversos , Microbiota/efeitos dos fármacos , Nanotubos de Carbono/efeitos adversos , Microbiota/fisiologia
20.
World J Gastroenterol ; 25(8): 923-940, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30833799

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC patients suffer from a high mortality-to-incidence ratio and low cure rate since we still have no specific and effective treatment. Although tremendous advances have been made in the investigation of HCC, the specific mechanisms of the progression of this disease are still only partially established. Hence, more research is needed to elucidate the underlying potential mechanisms to develop effective strategies for HCC. AIM: To determine the role of developing brain homeobox 2 (Dbx2) gene in promoting the development of HCC. METHODS: Dbx2 expression in clinical specimens and HCC cell lines was detected by Western blot (WB) and immunohistochemistry. Gain and loss of Dbx2 function assays were performed in vitro and in vivo. Cell viability assays were used to investigate cell growth, flow cytometry was employed to assess cell cycle and apoptosis, and trans-well assays were conducted to evaluate cell migration, invasion, and metastasis. The expression of key molecules in the sonic hedgehog (Shh) signaling was determined by WB. RESULTS: Compared to matched adjacent non-tumorous tissues, Dbx2 was overexpressed in 5 HCC cell lines and 76 surgically resected HCC tissues. Dbx2 overexpression was correlated with large tumor size. Both gain and loss of function assays indicated that Dbx2 promoted HCC cell proliferation by facilitating the transition from G1 to S phase, attenuating apoptosis and promoted HCC proliferation, migration, and invasion in vitro and in vivo. Mechanistically, Dbx2 modulated Shh signaling by enhancing FTCH1 and GLi1 expression in HCC cells that overexpressed Dbx2, which was reversed in HCC cells with Dbx2 knockdown. CONCLUSION: Our results indicate that Dbx2 is significantly upregulated in HCC tissues and plays significant roles in proliferation and metastasis of HCC cells by activating the Shh pathway.


Assuntos
Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/patologia , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Transdução de Sinais , Adulto , Idoso , Apoptose , Carcinoma Hepatocelular/cirurgia , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Proteína GLI1 em Dedos de Zinco/metabolismo
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