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1.
Cell Oncol (Dordr) ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34797559

RESUMO

PURPOSE: Emerging evidence suggests that cytotoxic therapy may promote drug resistance and metastasis while inhibiting the growth of primary tumors. As yet, however, the underlying mechanisms remain unclear. Here, we aimed to investigate the pro-metastatic effects of adriamycin (ADR) therapy on breast cancer cells and to investigate the mechanisms underlying these effects. METHODS: Differentially expressed genes between MCF-7 and ADR-resistant MCF-7 breast cancer cells were identified using high-throughput RNA-seq and differential gene expression analyses. In vitro transwell and scratch wound-healing assays, and an in vivo spontaneous metastasis model were used to study the metastatic potential of the breast cancer cells. The relationship between SIRT7 and TEK expression was studied using promoter activity, electrophoretic mobility shift (EMSA), CHIP-qPCR and Co-IP assays. RESULTS: Using transcriptome sequencing, we identified two key genes (SIRT7 and TEK) that might contribute to the pro-metastatic effect of ADR on breast cancer cells. SIRT7 acted as a negative regulator for TEK by inducing deacetylation of H3K18 at the TEK promoter. Through transcription factor prediction and double fluorescence experiments, we found that EST-1 could bind to the TEK promoter. Knockdown of EST-1 removed the transcriptional inhibition of TEK that was mediated by up-regulation of SIRT7. Co-IP showed that SIRT7 interacts directly with EST-1 in breast cancer cells, indicating that SIRT7 may induce H3K18 deacetylation at the TEK promoter region by directly binding to EST-1. In vitro and in vivo results showed that overexpression of SIRT7 or inhibition of TIE2 significantly reduced ADR-dependent breast cancer cell invasion/metastasis. CONCLUSION: Our findings suggest that ADR therapy may accelerate breast cancer metastasis in a SIRT7/TEK(TIE2) dependent manner.

2.
Adv Mater ; : e2102562, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643001

RESUMO

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O2 under normoxia but produces cytotoxic •OH and H2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents.

3.
Aging (Albany NY) ; 13(19): 22830-22842, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623971

RESUMO

Pancreatic cancer is the fourth leading cause of cancer-related death with the characteristics of chemoresistance and early metastasis. Panaxadiol, a triterpenoid saponin extracted from the roots of American ginseng, has been proved to display anti-tumor activity in colon cancer. In this study, we found panaxadiol significantly inhibited proliferation, and induced apoptosis in human pancreatic cancer cell lines PANC-1 and Patu8988 in a dose-dependent manner. Furthermore, the expression of apoptosis-related proteins (Bax, Bcl2, Cleaved-caspase3) was detected via western blot and immunofluorescence staining. In addition, panaxadiol was also found to inhibit the migration of pancreatic cancer cells by wound healing and transwell assays. In vivo, the growth of xenograft pancreatic cancer models was also notably suppressed by panaxadiol compared to the control group. Moreover, the down-regulation of JAK2-STAT3 signaling pathway was responsible for the underlying pro-apoptosis mechanism of panaxadiol, and this result was in good agreement with molecular docking analysis between panaxadiol and STAT3. In conclusion, our work comprehensively explored the anti-tumor ability in PANC-1 and Patu8988 cells of panaxadiol and provided a potential choice for the clinical treatment of pancreatic cancer patients.

4.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 305-312, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402253

RESUMO

To investigate the effect of dietary fiber on blood glucose and pregnancy outcomes in patients with gestational diabetes mellitus (GDM). One hundred and twelve patients with GDM in the second trimester of pregnancy were recruited from Women's Hospital, Zhejiang University School of Medicine. Patients were randomized into two groups with 56 in each group: the control group received basic nutrition support; while the dietary fiber group were given additional dietary fiber ( total dietary fiber per day) before meals in addition to basic nutrition support. Intervention for all cases lasted for 8 weeks. Fasting blood glucose and postprandial blood glucose (2 h BG) were measured every week, and oral glucose tolerance test (OGTT) was performed at 42 d postpartum to evaluate the glycemic outcomes. Perinatal outcomes were recorded. The dietary fiber intervention markedly improved 2 h BG in patients with GDM and significantly elevated the glucose compliance rate from the 3rd to 8th week compared to the control group ( <0.05 or <0.01). OGTT 2 h glucose and the incidence of impaired glucose tolerance in the dietary fiber group were significantly lower than those in the control group, while the glucose compliance rate was significantly higher than that in the control group (all <0.01). Moreover, the rates of adverse perinatal outcomes, such as premature rupture of membranes and neonatal hyperbilirubinemia were declined in the dietary fiber group (<0.05 or <0.01). Dietary fiber intervention can ameliorate hyperglycemia in GDM patients, improve perinatal outcomes and reduce the incidence of postpartum impaired glucose tolerance.


Assuntos
Diabetes Gestacional , Glicemia , Fibras na Dieta , Feminino , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 329-334, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402261

RESUMO

To investigate the impact of family history of diabetes (FHD) on blood glucose, lipid levels and perinatal outcomes in pregnant women with gestational diabetes mellitus (GDM). A total of 1265 GDM women who gave childbirth in Women's Hospital, Zhejiang University School of Medicine during January to December 2019 were enrolled in the study, including 253 women with FHD and 1012 women without FHD. The -test or test were used to compare the blood lipid, blood glucose levels and perinatal outcomes including large for gestational age infant, small for gestational age infant, macrosomia, cesarean delivery, preeclampsia, preterm labor, postpartum hemorrhage, fetal distress. The correlation between FHD and perinatal outcomes were estimated by Logistic regression analysis. The high density lipoprotein level at third-trimester was significantly lower in GDM women with FHD (<0.05); and the women with FHD also had higher fasting blood glucose oral glucose tolerance test (OGTT)1 h, OGTT 2 h and glycosylated hemoglobin level (all <0.01). In GDM women, FHD was an independent risk factor for preeclampsia (=3.27, 95%: 1.39-7.68). GDM women with FHD have lower high density lipoprotein and higher glucose levels. FHD is an independent risk factor for preeclampsia in GDM women.


Assuntos
Diabetes Gestacional , Glicemia , Feminino , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Lipídeos , Gravidez , Gestantes , Fatores de Risco
6.
Nano Today ; 40: 101243, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34249143

RESUMO

The outbreak of SARS-coronavirus 2 (SARS-CoV2) has become a global health emergency. Although enormous efforts have been made, there is still no effective treatment against the new virus. Herein, a TiO2 supported single-atom nanozyme containing atomically dispersed Ag atoms (Ag-TiO2 SAN) is designed to serve as a highly efficient antiviral nanomaterial. Compared with traditional nano-TiO2 and Ag, Ag-TiO2 SAN exhibits higher adsorption (99.65%) of SARS-CoV2 pseudovirus. This adsorption ability is due to the interaction between SAN and receptor binding domain (RBD) of spike 1 protein of SARS-CoV2. Theoretical calculation and experimental evidences indicate that the Ag atoms of SAN strongly bind to cysteine and asparagine, which are the most abundant amino acids on the surface of spike 1 RBD. After binding to the virus, the SAN/virus complex is typically phagocytosed by macrophages and colocalized with lysosomes. Interestingly, Ag-TiO2 SAN possesses high peroxidase-like activity responsible for reactive oxygen species production under acid conditions. The highly acidic microenvironment of lysosomes could favor oxygen reduction reaction process to eliminate the virus. With hACE2 transgenic mice, Ag-TiO2 SAN showed efficient anti-SARS-CoV2 pseudovirus activity. In conclusion, Ag-TiO2 SAN is a promising nanomaterial to achieve effective antiviral effects for SARS-CoV2.

7.
Signal Transduct Target Ther ; 6(1): 250, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34219129

RESUMO

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.

8.
Chem Soc Rev ; 50(16): 9152-9201, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34223847

RESUMO

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.


Assuntos
Nanocompostos/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Animais , Humanos , Fármacos Fotossensibilizantes/uso terapêutico
9.
Front Genet ; 12: 640078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149795

RESUMO

Accumulating evidences indicate that transforming acidic coiled-coil 3 (TACC3) is a tumor-related gene, was highly expressed in a variety of human cancers, which is involved in cancer development. However, the potential role of TACC3 in breast cancer remains largely unknown. In the present study, we found that TACC3 was highly-expressed in breast cancer tissues, and its level was positively correlated with the clinical features of breast cancer patients. Specifically, TACC3 expression was significantly associated with the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, nodal status, the scarff-bloom-richardson (SBR) grade, nottingham prognostic index (NPI), age, subtypes, and triple-negative and basal-like status, suggesting that TACC3 may be a potential diagnostic indicator of breast cancer. Furthermore, functional studies have shown that inhibition of TACC3 can significantly promote the cell proliferation and viability of breast cancer cells. Moreover, TACC3 knockdown suppressed the expression of E-cadherin, but increased the expression of N-cadherin, Snail, ZEB1, and TWIST, which indicate that TACC3 may impact the migration of breast cancer cells in vitro. Taken together, these findings indicate that TACC3 may serve as a prognostic and therapeutic indicator of breast cancer.

10.
Cancer Cell Int ; 21(1): 272, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020650

RESUMO

PURPOSE: Von Willebrand Factor C and EGF Domains (VWCE) is an important gene that regulates cell adhesion, migration, and interaction. However, the correlation between VWCE expression and immune infiltrating in breast cancer remain unclear. In this study, we investigated the correlation between VWCE expression and immune infiltration levels in breast cancer. METHODS: The expression of VWCE was analyzed by the tumor immune estimation resource (TIMER) and DriverDB databases. Furthermore, genes co-expressed with VWCE and gene ontology (GO) enrichment analysis were investigated by the STRING and Enrichr web servers. Also, we performed the single nucleotide variation (SNV), copy number variation (CNV), and pathway activity analysis through GSCALite. Subsequently, the relationship between VWCE expression and tumor immunity was analyzed by TIMER and TISIDB databases, and further verified the results using Quantitative Real-Time PCR (RT-PCR), Western blotting, and immunohistochemistry. RESULTS: The results showed that the expression of VWCE mRNA in breast cancer tissue was significantly lower than that in normal tissues. We found that the expression level of VWCE was associated with subtypes, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status of breast cancer patients, but there was no significant difference in the expression of VWCE was found in age and nodal status. Further analyses indicated that VWCE was correlated with the activation or inhibition of multiple oncogenic pathways. Additionally, VWCE expression was negatively correlated with the expression of STAT1 (Th1 marker, r = - 0.12, p = 6e-05), but positively correlated with the expression of MS4A4A (r = 0.28, p = 0). These results suggested that the expression of VWCE was correlated with immune infiltration levels of Th1 and M2 macrophage in breast cancer. CONCLUSIONS: In our study, VWCE expression was associated with a better prognosis and was immune infiltration in breast cancer. These findings demonstrate that VWCE is a potential prognostic biomarker and correlated with tumor immune cell infiltration, and maybe a promising therapeutic target in breast cancer.

11.
Cancer Cell Int ; 21(1): 268, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006286

RESUMO

BACKGROUND: Accumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear. METHODS: The clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein-protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer. RESULTS: We found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20-6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06-3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression. CONCLUSIONS: These findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.

12.
Int J Nanomedicine ; 16: 1961-1976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727809

RESUMO

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Dióxido de Silício/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Invasividade Neoplásica , Metástase Neoplásica , Oxirredução , Porosidade , RNA Interferente Pequeno/farmacologia , Distribuição Tecidual/efeitos dos fármacos
13.
Recent Pat Anticancer Drug Discov ; 16(3): 393-406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33602075

RESUMO

BACKGROUND: ATP-Binding Cassette subfamily G member 2 (ABCG2) is a semi-transport protein that plays a key role in human diseases, including bladder cancer and lung cancer, and maybe resistant to chemotherapy drugs. OBJECTIVE: The present study aimed to determine the role and underlying mechanisms of breast cancer resistance protein (ABCG2) in breast cancer and to study the reversal effect of inhibiting ABCG2 expression on the drug resistance of breast cancer cells and provide new ideas for gene-targeted therapy of breast cancer. METHODS: The structure and genomic alterations of ABCG2 were systematically investigated using GeneCards and cBioPortal to reveal the genetic alterations (including amplification and deep deletions) of ABCG2. We performed the correlation between ABCG2 expression and clinicopathological parameters using the data in bc-GenExMiner 4.4. Then, the protein-protein interaction and functional enrichment analysis of ABCG2 were performed based on the STRING, bc-GenExMiner 4.4, and Enrichr databases. Besides, we analyzed the pathway activity of genes that interact with ABCG2 using GSCALite and PharmGKB. Using magnetic nanoparticles polyMAG as the carrier of ABCG2-siRNA, polyMAG-ABCG2-siRNA was transfected into the Doxorubicin (DOX)-resistant breast cancer cell line MCF-7/ADR and directly into the tumors in nude mice. Patent US20150328485 points out that magnetic nanoparticles can be attached to an anti-cancer drug, such as an antibody-based anti-cancer drug. RESULTS: We found a statistically significant correlation between ABCG2 expression and clinicopathological parameters, such as Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor-2 (HER2), and nodal status in breast cancer patients. ABCG2 is closely related to SLC2A9, KIT, ABCG1, and MRPS7, which suggests that these proteins may be functional partners of breast cancer. The expression of ABCG2 is correlated with the activation or inhibition of multiple oncogenic pathways. Moreover, we found that ABCG2 is involved in the DOX signaling pathway. The small interfering RNA (siRNA) carried by magnetic nanoparticles can reduce the expression of ABCG2, thereby significantly improving the therapeutic effect of DOX on tumors. CONCLUSION: Our findings provide a more in-depth understanding of ABCG2 as a biomarker for predicting DOX-resistance and insights into the development of related therapeutic targets in breast cancer.

14.
Cell Biosci ; 11(1): 34, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557942

RESUMO

BACKGROUND: Targeting ubiquitin-dependent proteolysis is one of the strategies in cancer therapy. CRLCDT2 and CRLDDB2 are two key E3 ubiquitin ligases involved in DNA replication and DNA damage repair. But CDT2 and DDB2 are opposite prognostic factors in kinds of cancers, and the underlining mechanism needs to be elucidated. METHODS: Small interfering RNAs were used to determine the function of target genes. Co-immunoprecipitation (Co-IP) was performed to detect the interaction between DDB2 and CDT2. Immunofluorescence assays and fluorescence activating cell sorting (FACS) were used to measure the change of DNA content. In vivo ubiquitination assay was carried out to clarify the ubiquitination of CDT2 mediated by DDB2. Cell synchronization was performed to arrest cells at G1/S and S phase. The mechanism involved in DDB2-mediated CDT2 degradation was investigated by constructing plasmids with mutant variants and measured by Western blot. Immunohistochemistry was performed to determine the relationship between DDB2 and CDT2. Paired two-side Student's t-test was used to measure the significance of the difference between control group and experimental group. RESULTS: Knockdown of DDB2 stabilized CDT2, while over-expression of DDB2 enhanced ubiquitination of CDT2, and subsequentially degradation of CDT2. Although both DDB2 and CDT2 contain PIP (PCNA-interacting protein) box, PIP box is dispensable for DDB2-mediated CDT2 degradation. Knockdown of PCNA had negligible effects on the stability of CDT2, but promoted accumulation of CDT1, p21 and SET8. Silencing of DDB2 arrested cell cycle in G1 phase, destabilized CDT1 and reduced the chromatin loading of MCMs, thereby blocked the formation of polyploidy induced by ablation of CDT2. In breast cancer and ovarian teratoma tissues, high level of DDB2 was along with lower level of CDT2. CONCLUSIONS: We found that CRL4DDB2 is the novel E3 ubiquitin ligases of CDT2, and DDB2 regulates DNA replication through indirectly regulates CDT1 protein stability by degrading CDT2 and promotes the assembly of pre-replication complex. Our results broaden the horizon for understanding the opposite function of CDT2 and DDB2 in tumorigenesis, and may provide clues for drug discovery in cancer therapy.

15.
Anal Chim Acta ; 1151: 338222, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33608075

RESUMO

Circulating tumor cell (CTC) clusters, which are multicellular groups of CTCs, were recently suggested to had the greater potential of forming distal metastasis than single CTCs. However, our understanding of the forming of CTC clusters is still limited since there are few existing methods to study cancer cells aggregation kinetics, especially for a small number of cells. Herein we report a high-throughput miniaturized microwell-based cell aggregation-chip (AG-chip) to enable better characterize of the tumor cells clustering process. We successfully demonstrated the capability of the AG-chip in determining cell aggregation, and found that: (1) high metastatic breast cancer cells (MDA-MB-231 & MDA-MB-436) have stronger aggregation capacities than those low metastatic breast cancer cells (MCF-7 & SK-BR-3); (2) cells with similar aggregation ability were distinguished through the analysis of aggregation kinetics; (3) the detected aggregation ability can be used to indicate the metastatic potential of the cells; (4) the inhibition of integrins could regulate the cell clustering via blockage of cell adhesion or/and cell migration. This newly developed microdevice may promote further study of CTC clusters and metastasis.


Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Contagem de Células , Linhagem Celular Tumoral , Análise por Conglomerados , Humanos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia
17.
Biometals ; 34(2): 277-289, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33389333

RESUMO

A new schiff base cobalt(III) complex [N,N'-bis(2'-hydroxyphenylacetone)-o-ethanediamine] cobalt(III) (M3) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M3 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 by MTT assays. The IC50 is in the range of 6.27-22.68 µM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M3 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, western blot analysis indicated M3 dramatically decreased the target protein c-Myc and KLF5 expression levels, and activated many signaling pathways including ER stress, apoptosis, cell cycle and DNA damage in HeLa. M3 did not affect proteasomal activity.

18.
J Am Chem Soc ; 143(5): 2433-2440, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33507070

RESUMO

Ammonia electro-oxidation is an extremely significant reaction with regards to the nitrogen cycle, hydrogen economy, and wastewater remediation. The design of efficient electrocatalysts for use in the ammonia electro-oxidation reaction (AOR) requires comprehensive understanding of the mechanism and intermediates involved. In this study, aggregation-induced emission (AIE), a robust fluorescence sensing platform, is employed for the sensitive and qualitative detection of hydrazine (N2H4), one of the important intermediates during the AOR. Here, we successfully identified N2H4 as a main intermediate during the AOR on the model Pt/C electrocatalyst using 4-(1,2,2-triphenylvinyl)benzaldehyde (TPE-CHO), an aggregation-induced emission luminogen (AIEgen). We propose the AOR mechanism for Pt with N2H4 being formed during the dimerization process (NH2 coupling) within the framework of the Gerischer and Mauerer mechanism. The unique chemodosimeter approach demonstrated in this study opens a novel pathway for understanding electrochemical reactions in depth.

19.
Sci China Life Sci ; 64(3): 352-362, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32974854

RESUMO

Ferritin, an iron-storage protein, regulates cellular iron metabolism and oxidative stress. The ferritin structure is characterized as a spherical cage, inside which large amounts of iron are deposited in a safe, compact and bioavailable form. All ferritins readily catalyze Fe(II) oxidation by peroxides at the ferroxidase center to prevent free Fe(II) from participating in oxygen free radical formation via Fenton chemistry. Thus, ferritin is generally recognized as a cytoprotective stratagem against intracellular oxidative damage The expression of cytosolic ferritins is usually regulated by iron status and oxidative stress at both the transcriptional and post-transcriptional levels. The mechanism of ferritin-mediated iron recycling is far from clarified, though nuclear receptor co-activator 4 (NCOA4) was recently identified as a cargo receptor for ferritin-based lysosomal degradation. Cytosolic ferritins are heteropolymers assembled by H- and L-chains in different proportions. The mitochondrial ferritins are homopolymers and distributed in restricted tissues. They play protective roles in mitochondria where heme- and Fe/S-enzymes are synthesized and high levels of ROS are produced. Genetic ferritin disorders are mainly related to the L-chain mutations, which generally cause severe movement diseases. This review is focused on the biochemistry and function of mammalian intracellular ferritin as the major iron-storage and anti-oxidation protein.

20.
BMC Genomics ; 21(Suppl 11): 860, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33372594

RESUMO

BACKGROUND: Abnormal metabolic pathways have been considered as one of the hallmarks of cancer. While numerous metabolic pathways have been studied in various cancers, the direct link between metabolic pathway gene expression and cancer prognosis has not been established. RESULTS: Using two recently developed bioinformatics analysis methods, we evaluated the prognosis potential of metabolic pathway expression and tumor-vs-normal dysregulations for up to 29 metabolic pathways in 33 cancer types. Results show that increased metabolic gene expression within tumors corresponds to poor cancer prognosis. Meta differential co-expression analysis identified four metabolic pathways with significant global co-expression network disturbance between tumor and normal samples. Differential expression analysis of metabolic pathways also demonstrated strong gene expression disturbance between paired tumor and normal samples. CONCLUSION: Taken together, these results strongly suggested that metabolic pathway gene expressions are disturbed after tumorigenesis. Within tumors, many metabolic pathways are upregulated for tumor cells to activate corresponding metabolisms to sustain the required energy for cell division.


Assuntos
Neoplasias , Transformação Celular Neoplásica , Biologia Computacional , Humanos , Redes e Vias Metabólicas/genética , Neoplasias/genética , Prognóstico
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