scholarly journals Systematic identification of Celastrol-binding proteins reveals that Shoc2 is inhibited by Celastrol

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Huang Xiao-pei ◽  
Chen Ji-kuai ◽  
Wei Xue ◽  
Yi-Fan Dong ◽  
Lang Yan ◽  
...  
Keyword(s):  
Protein Microarray ◽  
Microarray Experiment ◽  
Protein Microarrays ◽  
Down Regulation ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Systematic Identification ◽  
First Time

Colorectal cancer (CRC) is the third most commonly diagnosed cancer. Celastrol exhibits anti-tumor activities in a variety of cancers. However, the effect of Celastrol on human CRC and the underlying mechanisms still need to be elucidated. The present study aimed to use in vitro and in vivo methods to clarify the anti-tumor effect of Celastrol and use protein microarrays to explore its mechanisms. We demonstrated that Celastrol effectively inhibited SW480 CRC cell proliferation. Two weeks of Celastrol gavage significantly inhibited the growth of xenografts in nude mice. A total of 69 candidate proteins were identified in the protein microarray experiment, including the most highly enriched protein Shoc2, which is a scaffold protein that modulates cell motility and metastasis through the ERK pathway. Celastrol significantly inhibited ERK1/2 phosphorylation in cell lines and xenograft tumors. Down-regulation of Shoc2 expression using Shoc2 siRNA also inhibited ERK1/2 phosphorylation. Furthermore, down-regulation of Shoc2 expression also significantly inhibited proliferation, colony formation, and migration functions of tumor cells. In addition, the LD0 of Celastrol by gavage is equal or more than 80 mg/kg in C57 male mice. In summary, we unraveled the anti-CRC function of Celastrol and confirmed for the first time that it inhibited the ERK1/2 pathway through binding to Shoc2.

scholarly journals CCL14 serves as a novel prognostic factor and tumor suppressor of HCC by modulating cell cycle and promoting apoptosis

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Mengxuan Zhu ◽  
Weiyue Xu ◽  
Chuanyuan Wei ◽  
Jing Huang ◽  
Jietian Xu ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Tumor Suppressor ◽  
Xenograft Tumor ◽  
Tumor Tissues ◽  
Cc Chemokines ◽  
Underlying Mechanisms ◽  
First Time ◽  
Growth Of Tumor

Abstract CCL14 is a member of CC chemokines and its role in hepatocellular carcinoma (HCC) is still unknown. In this study, CCL14 expression were analyzed by tissue microarray (TMA) including 171 paired tumor and peritumor tissues of patients from Zhongshan Hospital of Fudan University. We found for the first time that CCL14 was downregulated in HCC tumor tissues compared with peritumor tissues (P = 0.01). Meanwhile, CCL14 low expression in HCC tumor tissues is associated with a poor prognosis (P = 0.035). CCL14 also displayed its predictive value in high differentiation (P = 0.026), liver cirrhosis (P = 0.003), and no tumor capsule (P = 0.024) subgroups. The underlying mechanisms were further investigated in HCC cell lines by CCL14 overexpression and knock-down in vitro. We found overexpression of CCL14 suppressed proliferation and promoted apoptosis of HCC cells. Finally, the effect was confirmed by animal xenograft tumor models in vivo. The results shown overexpression of CCL14 lead to inhibiting the growth of tumor in nude mice. Interestingly, our data also implied that CCL14 played these effects by inhibiting the activation of Wnt/β-catenin pathway. These findings suggest CCL14 is a novel prognostic factor of HCC and serve as a tumor suppressor.

scholarly journals Chondroitin polymerizing factor (CHPF) promotes development of malignant melanoma through regulation of CDK1

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Wei Sun ◽  
Fang Zhao ◽  
Yu Xu ◽  
Kai Huang ◽  
Xianling Guo ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Pathway Analysis ◽  
Normal Skin ◽  
Over Expression ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Chondroitin polymerizing factor (CHPF) is an important member of glycosyltransferases involved in the biosynthesis of chondroitin sulfate (CS). However, the relationship between CHPF and malignant melanoma (MM) is still unknown. In this study, it was demonstrated that CHPF was up-regulated in MM tissues compared with the adjacent normal skin tissues and its high expression was correlated with more advanced T stage. Further investigations indicated that the over-expression/knockdown of CHPF could promote/inhibit proliferation, colony formation and migration of MM cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of CHPF could also suppress tumorigenicity of MM cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of CHPF and identified CDK1 as the potential target. Furthermore, our study revealed that knockdown of CDK1 could inhibit development of MM in vitro, and alleviate the CHPF over-expression induced promotion of MM. In conclusion, our study showed, as the first time, CHPF as a tumor promotor for MM, whose function was carried out probably through the regulation of CDK1.

scholarly journals Partial Inhibition of HO-1 Attenuates HMP-Induced Hepatic Regeneration against Liver Injury in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Ning He ◽  
Jun-Jun Jia ◽  
Hai-Yang Xie ◽  
Jian-Hui Li ◽  
Yong He ◽  
...  
Keyword(s):  
Protein Level ◽  
Liver Graft ◽  
Hepatocyte Proliferation ◽  
Hepatic Regeneration ◽  
Significant Elevation ◽  
Hypothermic Machine Perfusion ◽  
Underlying Mechanisms ◽  
First Time

We found better liver graft regeneration with hypothermic machine perfusion (HMP) compared with static cold storage (SCS) for the first time in our pilot study, but the underlying mechanisms are unknown. Upregulated heme oxygenase- (HO-) 1 expression has been reported to play a pivotal role in promoting hepatocyte proliferation. Here, we evaluated the novel role of HO-1 in liver graft protection by HMP. Rats with a heterozygous knockout of HO-1 (HO-1+/−) were generated and subjected to 3 h of SCS or HMP pre-half-size liver transplantation (HSLT) in vivo or 6 h of SCS or HMP in vitro; control rats were subjected to the same conditions (HO-1+/+). We found that HSLT induced significant elevation of the HO-1 protein level in the regenerated liver and that HO-1 haplodeficiency resulted in decreased proliferation post-HSLT. Compared with SCS, HMP induced significant elevation of the HO-1 protein level along with better liver recovery, both of which were reduced by HO-1 haplodeficiency. HO-1 haplodeficiency-induced decreased proliferation was responsible for the attenuated regenerative ability of HMP. Mechanistically, HO-1 haploinsufficiency resulted in suppression of hepatocyte growth factor (HGF)/Akt activity. Our results suggest that inhibition of HO-1 mitigates HMP-induced liver recovery effects related to proliferation, in part, by downregulating the HGF-Akt axis.

Antiseptic effect of vicenin-2 and scolymoside from Cyclopia subternata (honeybush) in response to HMGB1 as a late sepsis mediator in vitro and in vivo

2015 ◽  
Vol 93 (8) ◽  
pp. 709-720 ◽  
Author(s):  
Wonhwa Lee ◽  
Eun-Kyung Yoon ◽  
Kyung-Min Kim ◽  
Dong Ho Park ◽  
Jong-Sup Bae
Keyword(s):  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
High Mobility ◽  
Nuclear Factor Κb ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells ◽  
Factor Α

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. In this study, we investigated the antiseptic effects and underlying mechanisms of vicenin-2 and scolymoside, which are 2 active compounds from C. subternata that act against high mobility group box 1 (HMGB1)-mediated septic responses in human umbilical vein endothelial cells (HUVECs) and mice. The antiseptic activities of vicenin-2 and scolymoside were determined by measuring permeability, neutrophil adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, vicenin-2 and scolymoside effectively inhibited lipopolysaccharide-induced release of HMGB1, and suppressed HMGB1-mediated septic responses such as hyperpermeability, the adhesion and migration of leukocytes, and the expression of cell adhesion molecules. In addition, vicenin-2 and scolymoside suppressed the production of tumor necrosis factor-α and interleukin 6, and activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate that vicenin-2 and scolymoside could be a potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

LncRNA MEG3 inhibits the progression of prostate cancer by facilitating H3K27 trimethylation of EN2 through binding to EZH2

2019 ◽  
Vol 167 (3) ◽  
pp. 295-301 ◽  
Author(s):  
Yaojun Zhou ◽  
Hongqiong Yang ◽  
Wei Xia ◽  
Li Cui ◽  
Renfang Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Colony Formation ◽  
H3k27 Trimethylation ◽  
Invasion And Migration ◽  
Over Expression ◽  
Pc3 Cells ◽  
Underlying Mechanisms ◽  
And Migration

Abstract This study aims to study the effects of intra-nuclear lncRNA MEG3 on the progression of prostate cancer and the underlying mechanisms. Expressions of relative molecules were detected by Quantitative real time PCR (qRT-PCR) and western blot. Chromatin immunoprecipitation and RNA immunoprecipitation (RIP) assays were used to evaluate the interaction between intra-nuclear MEG3, histone methyltransferase EZH2 and Engrailed-2 (EN2). The impacts of MEG3 on the viability, proliferation and invasion of prostate cancer cells (PC3) were evaluated by methyl thiazolyl tetrazolium, colony formation and transwell assays, respectively. PC3 cells were transfected with MEG3 and transplanted into nude mice to analyse the effect of MEG3 on tumourigenesis of PC3 cells in vivo. EN2 expression was inversely proportional to MEG3 in the prostate cancer tissues and PC3 cells. RIP results showed that intra-nuclear MEG3 could bind to EZH2. Knockdown of MEG3 and/or EZH2 up-regulated EN2 expression and reduced the recruitment of EZH2 and H3K27me3 to EN2, while over-expressed MEG3 caused opposite effects. MEG3 over-expression suppressed cell viability, colony formation, cell invasion and migration of PC3 cells in vitro and inhibited tumourigenesis of PC3 cells in vivo, while EN2 over-expression diminished the effects. These findings indicated that MEG3 facilitated H3K27 trimethylation of EN2 via binding to EZH2, thus suppressed the development of prostate cancer.

ZNF280A Promotes Lung Adenocarcinoma Development through Regulating the Expression of EIF3C

2020 ◽  
Author(s):  
Hongsheng Liu ◽  
Yingzhi Qin ◽  
Na Zhou ◽  
Dongjie Ma ◽  
Yingyi Wang
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Small Cell Lung ◽  
Normal Tissues ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Background: Lung cancer is the most commonly diagnosed malignant tumor worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer (NSCLC). The relationship between ZNF280A and LUAD has not been demonstrated and remains unclear. Methods: In this study, it was demonstrated that ZNF280A was upregulated in LUAD tissues compared with the normal tissues. Further investigations indicated that the overexpression/knockdown of ZNF280A could promote/inhibit proliferation, colony formation and migration of LUAD cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of ZNF280A could also suppress tumorigenicity of LUAD cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of ZNF280A and identified EIF3C as the potential target. Results: Furthermore, our study revealed that knockdown of EIF3C could inhibit development of LUAD in vitro, and alleviate the ZNF280A overexpression induced promotion of LUAD. Conclusions: In conclusion, our study showed, as the first time, ZNF280A as a tumor promotor for LUAD, whose function was carried out probably through the regulation of EIF3C.

The XBP1-MARCH5-MFN2 Axis Confers ER Stress Resistance by Coordinating Mitochondrial Fission and Mitophagy in Melanoma

2020 ◽  
Author(s):  
Huina Wang ◽  
Xiuli Yi ◽  
Sen Guo ◽  
Sijia Wang ◽  
Jinyuan Ma ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Resistance ◽  
Mitochondrial Fission ◽  
Melanoma Cells ◽  
Stress Sensitivity ◽  
Mitochondrial Genes ◽  
Down Regulation ◽  
Underlying Mechanisms

Abstract Background: Melanoma cells are relatively resistant to ER stress, which contributes to tumor progression under stressful conditions and renders tolerance to ER stress-inducing therapeutic agents. Mitochondria are tightly interconnected with ER. However, whether mitochondria play a role in regulating ER stress resistance in melanoma remains elusive.Methods: Integrative bioinformatics was employed to figure out the implication of mitochondria in the resistance of melanoma cells to ER stress. A panel of biochemical assays and pre-clinical xenograft mouse model were used to investigate the role of mitochondrial fission and mitophagy in affecting ER stress sensitivity and the underlying mechanisms. Results: Our integrative bioinformatics analysis revealed that the down-regulation of mitochondrial genes was highly correlated with UPR activation in melanoma. Then we proved that mitochondrial fission and mitophagy were prominently induced in melanoma cells upon ER stress. Pharmacological inhibition of either mitochondrial fission or mitophagy effectively restored the sensitivity of melanoma cells to ER stress both in vitro and in vivo. Mechanistically, the down-regulation of MFN2 was essential for rendering the resistance by promoting mitochondrial fission and mitophagy. XBP1-mediated transcriptional up-regulation of E3 ligase MARCH5 contributed to the ubiquitination and degradation of MFN2 in ER stress-resistant cells, whereas the impaired transduction of this axis indicated the fragile to ER stress. Finally, the relationships among UPR pathway molecules, MARCH5 and mitochondrial genes were confirmed in both publicly accessible databases and tumor specimens.Conclusions: Together, our findings demonstrate a novel regulatory axis that links mitochondrial fission and mitophagy to the resistance to ER stress. Targeting mitochondrial quality control machinery can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

scholarly journals Downregulation of B7-H4 suppresses tumor progression of hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lijie Dong ◽  
Lulu Xie ◽  
Minjing Li ◽  
Hanhan Dai ◽  
Xia Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mr Images ◽  
Caspase 7 ◽  
Adc Values ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Related Proteins ◽  
Proliferation And Migration

Abstract B7-H4, as a member of the B7 superfamily, was overexpressed in various types of cancers. However, the effects of B7-H4 on the aggressiveness of HCC and the underlying mechanisms have not yet been fully explored. For this purpose, B7-H4 expression was detected by Flow cytometry and Western blotting, it was highly expressed in several HCC cell lines but not in normal LO2 cell line. Knockdown B7-H4 expression induced HCC cells apoptosis by flow cytometry and colony formation assays and increased several apoptosis-related proteins, including survivin, cleaved caspase-3, cleaved caspase-7, and Bax, while the pro-growth protein survivin was reduced. Then the proliferation and cell cycle were suppressed after treated by siB7-H4. Moreover, the level of B7-H4 was significantly correlated with cell migration. In vivo, intra-tumor injection of siRNA targeting B7-H4 can significantly inhibited the growth of HepG2 cells in nude mice. Finally, regions of interest were manually traced on T1WI, T2WI, DWI and ADC of MR images. ADC values were increased in HCC xenografts after B7-H4 siRNA treatment. These data indicated that downregulation of B7-H4 suppressed the proliferation and migration and promoted apoptosis in vitro and in vivo. Blocking the B7-H4 channel might be a potential therapeutic strategy for HCC.

scholarly journals TNPO1-Mediated Nuclear Import of FUBP1 Contributes to Tumor Immune Evasion by Increasing NRP1 Expression in Cervical Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
BiKang Yang ◽  
Jing Chen ◽  
YinCheng Teng
Keyword(s):  
Cervical Cancer ◽  
Binding Protein ◽  
Tumor Immune Evasion ◽  
Protein Expressions ◽  
Element Binding Protein ◽  
Underlying Mechanisms ◽  
And Migration ◽  
First Time ◽  
Proliferation And Migration

Far upstream element binding protein 1 (FUBP1), a DNA-binding protein, participates in diverse tumor-promoting behaviors by regulating the expression of oncogenes in the nucleus, but the underlying mechanisms remain to be elucidated. In the present study, we found that FUBP1 mRNA and protein expressions were markedly upregulated and closely linked with poor prognosis in cervical cancer. In vitro, functional experiments showed that knockdown of FUBP1 inhibited CC cell proliferation and migration. Therefore, FUBP1 plays a prooncogenic function in CC progression. Further investigations for the first time demonstrated that nuclear localization of FUBP1 regulated the gene expression of immune checkpoint NRP1. Moreover, our work demonstrated that FUBP1 translocated into the nucleus which was mediated by interacting with Transportin-1 (TNPO1). Collectively, this study revealed that FUBP1 might be a potential therapeutic target for the restriction of tumor progression.

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