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1.
Nat Commun ; 12(1): 5431, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521849

RESUMO

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.


Assuntos
Heterogeneidade Genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Proteínas de Ligação a Retinoblastoma/genética , Carcinoma de Pequenas Células do Pulmão/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Variações do Número de Cópias de DNA , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exoma , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Proteínas de Ligação a Retinoblastoma/metabolismo , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/cirurgia , Fumar/fisiopatologia , Análise de Sobrevida , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
2.
Acta Psychol (Amst) ; 219: 103391, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34412023

RESUMO

Previous studies have elucidated the neural mechanism of syntactic/semantic processing and pragmatic processing. However, the exact mechanisms by which these two aspects of processing interact during language comprehension remain unknown. In this event-related brain potential study, we examined the interaction between politeness processing and local syntactic/semantic processing of a phrase. We used a full factorial design that crossed politeness consistency with local syntactic/semantic coherence. Politeness violations elicited a P200 effect in the 190-320 ms range, centro-parietally distributed positivity in the 360-866 ms range, and pure local syntactic/semantic violation elicited a broad distributed positivity in the 362-868 ms range. Crucially, we found that event-related potential responses elicited by combined politeness and syntactic/semantic violations resemble those elicited by separate syntactic/semantic violations. These results indicated that local syntactic/semantic processing has a functional primacy over politeness processing. Furthermore, our results support the blocking hypothesis from a politeness processing perspective instead of the independent hypothesis.


Assuntos
Eletroencefalografia , Semântica , Encéfalo , Compreensão , Potenciais Evocados , Humanos
3.
Lung Cancer ; 160: 50-58, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34403912

RESUMO

BACKGROUND: The genomic mutation and immune feature landscape of ERBB2 exon 20 insertion (ERBB2-ex20ins)-driven non-small cell lung cancer and the features associated with the response to chemoimmunotherapy are currently unknown. METHODS: The genomic landscape of ERBB2-ex20ins lung adenocarcinoma (LUAD) patients was characterized by next-generation sequencing (NGS) of 1021 cancer genes. The clinical outcomes of chemoimmunotherapy were evaluated among 13 patients with stage IV ERBB2-ex20ins LUAD, and potential biomarkers of the response to chemoimmunotherapy were explored using NGS and T cell receptor sequencing. RESULTS: Among 8247 LUAD patients, 207 (2.5%) had ERBB2-ex20ins, of whom 181 (87.4%) harbored more than one comutation. The most common comutations were in TP53. Patients with ERBB2-ex20ins had a low tumor mutational burden (TMB; median, 4.2 mutations/Mb), and most (66.7%) were PD-L1 negative. Thirteen of the 207 patients received chemoimmunotherapy, for whom the objective response rate, disease control rate, and median progression-free survival were 31%, 77%, and 8.0 months, respectively. Responders exhibited a higher TMB and a trend toward lower clonality in tumors compared with nonresponders (p = 0.0067 and p = 0.085, respectively). A high TMB combined with mutations in DNA damage repair pathways and SWI/SNF chromatin remodeling complexes was associated with a benefit from chemoimmunotherapy. CONCLUSIONS: The efficacy and outcome of chemoimmunotherapy were encouraging among ERBB2-ex20ins LUAD patients, who were characterized by low TMB and negative PD-L1 expression. The combination of TMB and comutations is a potential biomarker to identify patients who will benefit from chemoimmunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Éxons/genética , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor ErbB-2/genética
4.
Clin Transl Med ; 11(7): e498, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34323415

RESUMO

BACKGROUND: Cervical cancer (CC) is the second leading cause of cancer death among women worldwide. Epigenetic regulation of gene expression through DNA methylation and hydroxymethylation plays a pivotal role during tumorigenesis. In this study, to analyze the epigenomic landscape and identify potential biomarkers for CCs, we selected a series of samples from normal to cervical intra-epithelial neoplasia (CINs) to CCs and performed an integrative analysis of whole-genome bisulfite sequencing (WGBS-seq), oxidative WGBS, RNA-seq, and external histone modifications profiling data. RESULTS: In the development and progression of CC, there were genome-wide hypo-methylation and hypo-hydroxymethylation, accompanied by local hyper-methylation and hyper-hydroxymethylation. Hydroxymethylation prefers to distribute in the CpG islands and CpG shores, as displayed a trend of gradual decline from health to CIN2, while a trend of increase from CIN3 to CC. The differentially methylated and hydroxymethylated region-associated genes both enriched in Hippo and other cancer-related signaling pathways that drive cervical carcinogenesis. Furthermore, we identified eight novel differentially methylated/hydroxymethylated-associated genes (DES, MAL, MTIF2, PIP5K1A, RPS6KA6, ANGEL2, MPP, and PAPSS2) significantly correlated with the overall survival of CC. In addition, no any correlation was observed between methylation or hydroxymethylation levels and somatic copy number variations in CINs and CCs. CONCLUSION: Our current study systematically delineates the map of methylome and hydroxymethylome from CINs to CC, and some differentially methylated/hydroxymethylated-associated genes can be used as the potential epigenetic biomarkers in CC prognosis.

5.
Psychophysiology ; 58(8): e13837, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33931867

RESUMO

In an electrophysiological experiment, we investigated the effect of reward expectation on the localized attentional interference effect using a cue-target paradigm, while event-related potentials (ERPs) were recorded. A cue indicating the reward condition of each trial (incentive vs. non-incentive) was followed by the presentation of a search array containing two target items. Participants were asked to decide whether the two shape singletons (two triangles, two rectangles, or one triangle and one rectangle) among a set of circles were the same shape. Moreover, we manipulated the distance between the two targets to be adjacent to each other (Separation 1) or further apart (Separation 3 and Separation 5). Behavioral results revealed a larger reward facilitation effect for the larger target separation conditions. The N2pc component locked to the target display exhibited an interaction between reward expectation and the distance between the two targets. For non-incentive trials, the N2pc amplitude increased as the separation between the two targets increased; however, for incentive trials, the N2pc showed comparable amplitudes in the different target separation conditions. These results indicate that reward expectation regulated attentional focus to better resolve the competition between representation and selection of the two targets for acquiring possible reward outcomes.

6.
Ann Transl Med ; 8(12): 750, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32647675

RESUMO

Background: Tracheal adenoid cystic carcinoma (TACC) is the second most common type of cancer in bronchial tumors with poor prognosis. Studies on the genomic profiles and tumor immune microenvironment (TIME) of TACC are still relatively rare. Methods: Here, we performed whole-exome sequencing (WES), T cell repertoire (TCR) sequencing, and immunohistochemistry (IHC) on the resected tumors and matched peripheral blood leukocytes (PBLs) samples from 25 TACCs collected from April-2010 to Mar-2019. Results: WES results revealed that LPAR3 and ALPI were recurrently mutated genes, with no classical lung cancer drivers in TACCs (n=8). The median tumor mutation burden (TMB) was 3.67, lower than other solid tumors. Unexpectedly, one patient showed high microsatellite instability (MSI). Recurrent copy number variations (CNVs) affected genes commonly involved in p53, cell cycle, and PI3K-Akt signaling pathways. For TCR estimators of 13 PBLs, the median clonality and Shannon index was 0.15 and 7.02, respectively. Shannon index showed marginally negative association with age (Pearson r =-0.53, P=0.062). Clonotype number and Shannon index of 7 TACC tissues were significantly lower than those of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (Mann-Whitney test, both P<0.001, both P<0.001). Furthermore, programmed cell death 1 ligand 1 (PD-L1), a vital player in TIME, was negative (tumor proportion score, TPS <1%) in all samples (n=14). Patients with less clonotypes had longer progression-free survival (PFS) than those with more PFS (15.0 vs. 9.5 months, P<0.001, HR 12.5, 95% CI: 0.2-675.7). In particular, the clinical and molecular characteristics of one TACC patient receiving immunotherapy have been explained in detail. Conclusions: In summary, despite the existence of one patient with MSI-H and chromosome instability, TACC was characterized by a lack of common drivers of lung cancer, negative PD-L1 expression, and low CD3+ and CD8+ T cell infiltration.

7.
Cell Death Dis ; 11(5): 346, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393783

RESUMO

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I-III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991-61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916-21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Gástricas/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Intervalo Livre de Doença , Detecção Precoce de Câncer , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasia Residual , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Fatores de Tempo
8.
J Med Genet ; 56(3): 186-194, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567904

RESUMO

BACKGROUND: To better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC. METHODS: We performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis. RESULTS: Mutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs. CONCLUSION: Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Neoplasia Intraepitelial Cervical/genética , Perfilação da Expressão Gênica , Variação Genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Biomarcadores Tumorais , Neoplasia Intraepitelial Cervical/virologia , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Estadiamento de Neoplasias , Neoplasias do Colo do Útero/virologia , Sequenciamento Completo do Genoma
9.
Front Pharmacol ; 9: 1356, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532707

RESUMO

The tumor suppressor protein p53 plays an important role in the development and progression of colon cancer, and the subcellular organelle localization directly affects its function. Wogonin (5,7-dihydroxy-8-methoxyflavone), a mono-flavonoid extracted from root of Scutellaria baicalensis Georgi, possesses acceptable toxicity and has been used in colorectal cancer (CRC) chemoprevention in pre-clinical trials by oncologist. However, the underlying anti-colon cancer mechanisms of wogonin are not yet fully understood. In the present study, the effect of wogonin on the initiation and development of colitis-associated cancer through p53 nuclear translocation was explored. AOM-DSS CRC animal model and human CRC HCT-116 cell model were used to evaluate the in vivo and in vitro anti-colon cancer action of wogonin. We observed that wogonin showed a dramaticlly preventive effect on colon cancer. Our results showed that wogonin caused apoptotic cell death in human CRC HCT-116 cell through increased endoplasmic reticulum (ER) stress. Meanwhile, excessive ER stress facilitated the cytoplasmic localization of p53 through increasing phosphor-p53 at S315 and S376 sites, induced caspase-dependent apoptosis and inhibited autophagy. Furthermore, we verified the chemoprevention effect and toxicity of wogonin in vivo by utilizing an AOM-DSS colon cancer animal model. We found that wogonin not only reduced tumor multiplicity, preserved colon length to normal (6.79 ± 0.34 to 7.41 ± 0.56, P < 0.05) but also didn't induce side effects on various organs. In conclusion, these results explain the anti-tumor effect of wogonin in CRC and suggest wogonin as a potential therapeutic candidate for the therapeutic strategy in CRC treatment.

10.
J Cancer ; 9(18): 3225-3235, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271481

RESUMO

Infection by chronic hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and primary hepatocellular carcinoma (HCC). Viral DNA integration into the host cell genome is a key mechanism of hepatocarcinogenesis. However, the molecular characterization and the potential clinical implications of HBV DNA integration into patients suffering from different hepatitis and HCC remain unclear. In this study, we analyzed HBV integrations in patients with hepatitis B and HCC using HBV probe-based capturing and next-generation sequencing. The results revealed that the sizes of the HBV integrations ranged from 28 bp to 3215 bp, including the full-length HBV DNA sequence. The integration breakpoints were preferentially distributed in the viral enhancer, X protein, and core protein regions of the HBV genome. The number of HBV integrations followed an increasing trend from hepatitis to HCC, which was positively correlated with the HBV virus load in patients with hepatitis. The number of HBV integrations in the HBeAg positive chronic hepatitis B group was significantly greater than that in the other hepatitis B groups (P < 0.05). However, the relative abundance of HBV integrations was significantly higher in HCC tissues than in the adjacent liver tissues. Interestingly, 61.6% (8/13) of HBV-human DNA integration fragments could be detected at the RNA level. Our results also showed that HBV integration-targeted genes (ITGs) were significantly enriched in many cancer-related pathways, such as MAPK, extracellular matrix (ECM)-receptor interaction, and the hedgehog signaling pathway. Individuals with HBV integrations exhibited shorter disease-free survival (DFS) and overall survival (OS) than those without HBV integrations in some ITGs including LINC00293 (long intergenic non-protein coding RNA 293; DFS P = 0.008, OS P = 0.009), FSHB (follicle stimulating hormone beta subunit; DFS P = 0.05, OS P = 0.186), and LPHN3 (latrophilin-3; DFS P = 0.493, OS P = 0.033). This study determined the underlying mechanism of HBV DNA integration in liver diseases and laid the foundation for future studies on the pathogenesis of liver cancer.

11.
Front Pharmacol ; 9: 519, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875661

RESUMO

Lung adenocarcinoma (LAC), predominant subclassfication of lung cancer, leads high incidence and mortality annually worldwide. During the premalignant transition from lung adenomas to LAC, cellular senescence is regard as a critical physiological barrier against tumor progression. Nevertheless, the role of senescence in tumorigenesis is controversial and few senescence inducers are extensively determined. In this study, we used two classical cell lines A549 and H1299 and two NSCLC xenograft models on Balb/c-nude mice to reveal the pro-senescence effects of shikonin and the corresponding underlying mechanism in LAC. Shikonin, a pure compound isolated from the herbal medicine Lithospermum erythrorhizon, remarkably stimulated cellular senescence including increased SAHF formation, enlarged cellular morphology, and induced SA-ß-Gal positive staining. Further mechanism study revealed that the pro-senescence effect of shikonin was dependent on the increased intercellular ROS generation, which subsequently triggered DNA damage-p53/p21waf axis without activating oncogenes such as Ras and MEK-1. Meanwhile, Kdm2b, an H3K36me2-specific demethylase effectively suppressed ROS generation, was also notably suppressed by shikonin treatment. Moreover, shikonin at 10 mg/kg significantly inhibited tumor weights by 55.84% and 50.98% in A549 and H1299 xenograft model, respectively (P < 0.05) through activating cellular senescence. Our study suggested that shikonin, a ROS-dependent senescence inducer, could serve as a promising agent for further lung cancer treatment.

12.
Pharmacol Res ; 129: 318-328, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29199082

RESUMO

DACT2, a tumor suppressor gene in various tumors, is frequently down-regulated via hypermethylation. We found DACT2 gene expressions were dramatically silenced (P = 0.002, n = 8) in our clinical colorectal cancer (CRC) tissues, and TCGA data revealed DACT2 hypermethylation correlated to CRC poor prognosis (P = 0.0129, HR = 0.2153, n = 248). Thus, by screening twelve nutritional compounds, we aimed to find out an effective DACT2 epigenetic stimulator to determine whether DACT2 epigenetic restoration could reverse CRC tumorigenesis. We found that kaempferol significantly increased DACT2 expressions up to 3.47-fold in three CRC cells (HCT116, HT29, and YB5). Furthermore, kaempferol remarkably decreased DACT2 methylation (range: 19.58%-67.00%, P < 0.01), while increased unmethylated DACT2 by 13.72-fold (P < 0.01) via directly binding to DNA methyltransferases DNMT1. By epigenetic reactivating DACT2 transcription, kaempferol notably inhibited nuclear ß-catenin expression to inactivate Wnt/ß-catenin pathway, which consequently restricted CRC cells proliferation and migration. Moreover, in AOM/DSS-induced CRC tumorigenesis, kaempferol-demethylated DACT2 effectively decreased tumor load (range: 50.00%-73.52%, P < 0.05). By determining the chemopreventive and chemotherapeutic efficacy of a novel DACT2 demethylating stimulator, we demonstrated that DACT2 epigenetic restoration could successfully slow down and reverse CRC tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/prevenção & controle , Epigênese Genética , Humanos , Quempferóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL
13.
Oncogene ; 37(10): 1354-1368, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269867

RESUMO

Abnormalities in epigenetic modifiers are emerging as driving events in prostate cancer (PCa). The histone methyltransferase KMT2D, a frequently aberrant epigenetic modifier in various tumors, has an undefined role in PCa. Moreover, little is known regarding KMT2D's mutation in Chinese patients or its downstream signaling pathways and targets. Here, we profiled the mutational spectrum of 32 significantly PCa-associated genes by using disease-targeted sequencing, and found that KMT2D was highly mutated (63.04%, 29/46) in Chinese patients. Moreover, high KMT2D transcription was also associated with poor prognosis in an independent cohort (n = 51). In KMT2D-knockdown PC-3 and DU145 cells, cell proliferation (P < 0.01), invasion (P < 0.001), and migration (P < 0.01) were consequently suppressed. KMT2D depletion effectively suppressed tumor growth by 92.21% in vivo. Notably, integrative analyses of RNAseq and ChIPseq characterized two crucial genes downregulated by KMT2D, leukemia inhibitory factor receptor (LIFR) and Kruppel-like factor-4 (KLF4), which are regulators in PI3K/Akt and EMT, respectively. Our present study revealed that KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting LIFR and KLF4 and thus serves as a putative epigenetic-based target for treating PCa.


Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição Kruppel-Like/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Proteínas de Ligação a DNA/genética , Epigênese Genética/fisiologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Células PC-3 , Próstata/patologia , Transdução de Sinais/genética , Ativação Transcricional/genética , Células Tumorais Cultivadas
14.
J Ethnopharmacol ; 220: 44-56, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29258855

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Camptosorus sibiricus Rupr (CSR) is a widely used herbal medicine with antivasculitis, antitrauma, and antitumor effects. However, the effect of CSR aqueous extract on B[a]P-initiated tumorigenesis and the underlying mechanism remain unclear. Moreover, the compounds in CSR aqueous extract need to be identified and structurally characterized. AIM OF THE STUDY: We aim to investigate the chemopreventive effect of CSR and the underlying molecular mechanism. MATERIALS AND METHODS: A B[a]P-stimulated normal cell model (BEAS.2B) and lung adenocarcinoma animal model were established on A/J mice. In B[a]P-treated BEAS.2B cells, the protective effects of CSR aqueous extract on B[a]P-induced DNA damage and ROS production were evaluated through flow cytometry, Western blot, real-time quantitative PCR, single-cell gel electrophoresis, and immunofluorescence. Moreover, a model of B[a]P-initiated lung adenocarcinoma was established on A/J mice to determine the chemopreventive effect of CSR in vivo. The underlying mechanism was analyzed via immunohistochemistry and microscopy. Furthermore, the new compounds in CSR aqueous extract were isolated and structurally characterized using IR, HR-ESI-MS, and 1D and 2D NMR spectroscopy. RESULTS: CSR effectively suppressed ROS production by re-activating Nrf2-mediated reductases HO-1 and NQO-1. Simultaneously, CSR attenuated the DNA damage of BEAS.2B cells in the presence of B[a]P. Moreover, CSR at 1.5 and 3 g/kg significantly suppressed tumorigenesis with tumor inhibition ratios of 36.65% and 65.80%, respectively. The tumor volume, tumor size, and multiplicity of B[a]P-induced lung adenocarcinoma were effectively decreased by CSR in vivo. After extracting and identifying the compounds in CSR aqueous extract, three new triterpene saponins were isolated and characterized structurally. CONCLUSIONS: CSR aqueous extract prevents lung tumorigenesis by exerting dual effects against ROS and DNA damage, suggesting that CSR is a novel and effective agent for B[a]P-induced carcinogenesis. Moreover, by isolating and structurally characterizing three new triterpene saponins, our study further standardized the quality of CSR aqueous extract, which could widen CSR clinical applications.


Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/farmacologia , Gleiquênias/química , Neoplasias Pulmonares/prevenção & controle , Extratos Vegetais/farmacologia , Adenocarcinoma de Pulmão , Animais , Anticarcinógenos/isolamento & purificação , Benzo(a)pireno/toxicidade , Western Blotting , Dano ao DNA/efeitos dos fármacos , Citometria de Fluxo , Humanos , Camundongos , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo , Saponinas/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
15.
Molecules ; 22(11)2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-29072615

RESUMO

Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of LSS-11, a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells. LSS-11 enhanced cell death in A549/T cells by inducing apoptosis through increasing the DR5 protein level and PARP1 cleavage. Importantly, LSS-11 dose-dependently reduced STAT3 phosphorylation and downregulated its target genes MDR1 and MRP1, without affecting P-gp transport function. Chromatin coimmunoprecipitation (ChIP) assay further revealed that LSS-11 hindered the binding of STAT3 to the MDR1 and MRP1 promoters. Additionally, pharmacological inhibition of p-STAT3 by sulforaphane downregulated MDR1 and MRP1, resulting in A549/T cell death by triggering apoptosis. Collectively, our data show that LSS-11 is a potent naphthalimide-based chemosensitizer that could enhance cell death in paclitaxel-resistant lung cancer cells through the DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Naftalimidas/farmacologia , Paclitaxel/farmacologia , Triazóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fator de Transcrição STAT3/metabolismo
16.
Int J Cancer ; 141(8): 1690-1703, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28677156

RESUMO

Connexin 43 (Cx43), a vital gap junction protein in tumor microenvironment (TME), is a novel molecular target for melanoma chemotherapeutics due to its tumor suppressive function. Dioscin, an herbal steroidal saponin, exerts anti-tumor effects while the underlying mechanism is unclear. Using WB, FACS, and immunofluorescence methodologies, we found dioscin significantly activated the transcription and translation of Cx43 via the retinoid acid signaling pathway and simultaneously enhanced the transporting function of Cx43. Through stimulating Cx43, dioscin remarkably suppressed the migratory and invasive capacities of B16 cells, and notably decreased pluripotency markers of cancer stem cells and epithelial-to-mesenchymal transition in B16 cells and animal tumor tissues. Conversely, dioscin improved the secretion of pro-inflammatory cytokines (IL-6, TNFα, and IL-1ß), and the phagocytic capacity of tumor-associated macrophages by increasing M2-to-M1 phenotype transition. More strikingly, even in Cx43 functional deficient B16 and RAW264.7 cells, dioscin still dramatically reversed the aggravated tumor malignancy and reduced macrophage phagocytic activity. Two classical metastasis animal models were utilized in vivo and results showed that dioscin showed significant anti-metastatic effects, which is closely related to the expression of Cx43 either in in situ tumor or metastatic lung nodes. In conclusion, dioscin targets Cx43 to suppress the tumor cell malignancy and activate macrophage sensitivity, thereby targeting melanoma microenvironment.


Assuntos
Conexina 43/metabolismo , Melanoma Experimental/tratamento farmacológico , Animais , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Feminino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Células RAW 264.7 , Regulação para Cima/efeitos dos fármacos
17.
Oncotarget ; 8(23): 37394-37408, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28445124

RESUMO

DNA and DNA-associated processes have been classes of the most important targets of chemotherapeutic drugs. As classic DNA intercalators and topoisomerase inhibitors, naphthalimides have been extensively investigated as potential anti-cancer drugs. We recently synthesized a novel series of triazolonaphthalimides with excellent anti-cancer activities. In the present study, one of the most potent triazolonaphthalimides, LSS-11, was investigated. LSS-11 bound to DNA in vitro and in cell mainly by minor groove binding and significantly increased the stability of DNA, which could be fundamental for the biological activities of LSS-11. In addition to inhibiting DNA topoisomerase II-catalyzed decatenation of knotted circulated DNA, LSS-11 dramatically inhibited DNA replication mediated by polymerase chain reaction and isothermal helicase-dependent amplification, as well as the expression of luciferase driven by a minimal TA promoter in cell. Furthermore, LSS-11 exhibited strong cytotoxicity in selected human colon cancer cell lines by inducing cell cycle arrest and apoptosis, which was accompanied by DNA damage response. Finally, LSS-11 potently inhibited the growth of S180 murine sarcoma and SW480 human colorectal cancer xenografts in vivo without significant major toxicities. These results suggest that LSS-11 deserves further research and development as a novel anti-cancer agent, and provided new understandings of mechanisms by which LSS-11 inhibited multiple DNA-associated processes and tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , DNA/metabolismo , Naftalimidas/uso terapêutico , Sarcoma/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Apoptose , Ciclo Celular , Proliferação de Células , Replicação do DNA , DNA Topoisomerases Tipo II/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftalimidas/síntese química , Triazóis/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pharmacol Res ; 114: 1-12, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27697644

RESUMO

Epigenetic modifications include DNA methylation, histone modification, and other patterns. These processes are associated with carcinogenesis and cancer progression. Thus, epigenetic modification-related enzymes, such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone demethylases (HDMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), as well as some related proteins, including methyl-CpG binding proteins (MBPs) and DNMT1-associated protein (DMAP 1), are considered as potential targets for cancer prevention and therapy. Numerous natural compounds, mainly derived from Chinese herbs and chemically ranging from polyphenols and flavonoids to mineral salts, inhibit the growth and development of various cancers by targeting multiple genetic and epigenetic alterations. This review summarizes the epigenetic mechanisms by which active compounds from Chinese herbs exert their anti-cancer effect. A subset of these compounds, such as curcumin and resveratrol, affect multiple epigenetic processes, including DNMT inhibition, HDAC inactivation, MBP suppression, HAT activation, and microRNA modulation. Other compounds also regulate epigenetic modification processes, but the underlying mechanisms and clear targets remain unknown. Accordingly, further studies are required.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neoplasias/prevenção & controle
19.
Eur J Med Chem ; 122: 488-496, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27423028

RESUMO

A series of benzenesulfonamide derivatives were synthesized and evaluated for their anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferative and tubulin polymerization. Compound BA-3b proved to be the most potent compound with IC50 value ranging from 0.007 to 0.036 µM against seven cancer cell lines, and three drug-resistant cancer cell lines, which indicated a promising anti-cancer agent. The target tubulin was also verified by dynamic tubulin polymerization assay and tubulin intensity assay.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Multimerização Proteica , Estrutura Quaternária de Proteína , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Água/química
20.
Soc Cogn Affect Neurosci ; 11(2): 191-203, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26245838

RESUMO

We investigated the effect of reward expectation on the processing of emotional words in two experiments using event-related potentials (ERPs). A cue indicating the reward condition of each trial (incentive vs non-incentive) was followed by the presentation of a negative or neutral word, the target. Participants were asked to discriminate the emotional content of the target word in Experiment 1 and to discriminate the color of the target word in Experiment 2, rendering the emotionality of the target word task-relevant in Experiment 1, but task-irrelevant in Experiment 2. The negative bias effect, in terms of the amplitude difference between ERPs for negative and neutral targets, was modulated by the task-set. In Experiment 1, P31 and early posterior negativity revealed a larger negative bias effect in the incentive condition than that in the non-incentive condition. However, in Experiment 2, P31 revealed a diminished negative bias effect in the incentive condition compared with that in the non-incentive condition. These results indicate that reward expectation improves top-down attentional concentration to task-relevant information, with enhanced sensitivity to the emotional content of target words when emotionality is task-relevant, but with reduced differential brain responses to emotional words when their content is task-irrelevant.


Assuntos
Atenção/fisiologia , Encéfalo/fisiologia , Emoções/fisiologia , Potenciais Evocados/fisiologia , Recompensa , Adulto , Mapeamento Encefálico , Eletroencefalografia , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia , Adulto Jovem
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