摘要：
AIMS: ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-alpha positive. Due to the function of ZBTB7A in ER-alpha positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-alpha positive cancer and explore the underlying mechanisms. MAIN METHODS: In this study, the correlation between ZBTB7A and ER-alpha was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-alpha's level via targeting ER-alpha's expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. KEY FINDINGS: We further confirmed that ZBTB7A shows a significant positive correlation with ER-alpha in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-alpha ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-alpha. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-alpha via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-alpha's downstream genes, and promote the growth of estrogen receptor alpha (ER-alpha)-positive breast cancer cells. SIGNIFICANCE: Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-alpha level and might provide a new avenue for endocrine therapy in breast cancer.
作者机构：
[Hou, Yangfeng; Yang, Wenling] Univ South China, Clin Med Dept, Hengyang Med Sch, Hengyang City 421001, Hunan, Peoples R China.;[Fan, Wenjing; Qu, Shunlin] Univ South China, Dept Pathophysiol, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Fan, Wenjing] Univ South China, Affiliated Hosp 2, Emergency Dept, Hengyang City 421001, Hunan, Peoples R China.;[Samdani, Abdul Qadir] Univ South China, Affiliated Hosp 1, Spinal Surg Dept, Hengyang City 421001, Hunan, Peoples R China.;[Jackson, Ampadu Okyere] Univ South China, Hengyang Med Sch, Int Coll, Hengyang City 421001, Hunan, Peoples R China.
通讯机构：
[Qu, Shunlin] U;Univ South China, Dept Pathophysiol, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.
关键词：
Blood glucose;Farnesoid X receptor;Glycometabolism
摘要：
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA/DNA special binding protein that participates in regulating the expression of related genes, transcription, RNA alternative splicing, translation, posttranslational modification, cell signal transduction, cell movement, interacts with ncRNAs, and induces angiogenesis. Moreover, several cellular functions forcefully indicated that hnRNP K participates in tumorigenesis. Numerous studies indicated hnRNP K is aberrantly elevated in multiple tumors. In addition, hnRNP K abnormal accumulation in cytoplasmic is also associated with poor prognosis. This suggests that hnRNP K may play a role in the development and progression of tumors. However, related studies demonstrated that hnRNP K acts as a tumor suppressor to suppress tumor formation. Therefore, this paper aims to explore the role of hnRNPK in tumors.
摘要：
Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low-density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL-cholesterol (LDL-c) level. Since a PCSK9 induced increase in plasma LDL-c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL-c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.
期刊：
Cancer Cell International,2019年19(1):1-13 ISSN：1475-2867
通讯作者：
Luo, Dixian
作者机构：
[Li, Jia; Hu, Zheng; Luo, Wenna; He, Rongzhang; Luo, Weihao; Duan, Lili; Luo, Dixian; Wang, Qingmei; Tan, Tan] Univ South China, Peoples Hosp Chenzhou 1, Natl & Local Joint Engn Lab High High Throughput, Translat Med Inst, Chenzhou 423000, Peoples R China.;[Luo, Dixian; Wang, Qingmei; Tan, Tan] Univ South China, Peoples Hosp Chenzhou 1, Ctr Clin Pathol, Chenzhou 423000, Peoples R China.;[He, Rongzhang] Cent S Univ, Xiangya Hosp, Dept Clin Pharmacol, Changsha 410078, Hunan, Peoples R China.
通讯机构：
[Luo, Dixian] U;Univ South China, Peoples Hosp Chenzhou 1, Natl & Local Joint Engn Lab High High Throughput, Translat Med Inst, Chenzhou 423000, Peoples R China.
摘要：
Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3beta (GSK-3beta), to evaluate the role of the Wnt-beta-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke, and then were either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood-brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of beta-catenin and downstream proteins while suppressing the expression of GSK-3beta. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt-beta-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.
作者机构：
[Zhang, Mengxia] Hunan Univ Chinese Med, Dept Histol & Embryol, Changsha 410208, Hunan, Peoples R China.;[Tang, Shengsong] Hunan Univ Med, Hunan Prov Key Lab Antibody Based Drug & Intellig, Huaihua 418000, Hunan, Peoples R China.;[Zhang, Mengxia; Liu, Qi; Mo, Zhongcheng] Univ South China, Clin Anat & Reprod Med Applicat Inst, Dept Histol & Embryol, Hengyang 421001, Hunan, Peoples R China.;[Tang, Shengsong; Lei, Xiaoyong; Tu, Jian; Li, Lijun] Univ South China, Insitute Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.;[Ning, Jing; Tang, Shengsong] Hunan Univ Med, Dept Pharmacol, Huaihua 418000, Hunan, Peoples R China.
通讯机构：
[Tang, Shengsong] H;Hunan Univ Med, Hunan Prov Key Lab Antibody Based Drug & Intellig, Huaihua 418000, Hunan, Peoples R China.
关键词：
macrophage colony-stimulating factor;breast cancer;apoptosis;HIF-1 and BINP3
摘要：
Macrophage colony-stimulating factor (M-CSF), a tumour marker, is related to tumour cell anti-apoptosis and drug resistance. However, the role of M-CSF in MCF-7 cells is unknown. In the present study, the effect and mechanism of M-CSF on hypoxia-inducible factor-1 (HIF-1)/BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)/Apoptosis Regulator BAX signalling in human breast cancer MCF-7 cells were investigated. Western blotting revealed that the expression of HIF-1, BNIP3, Bax, caspase-3 and caspase-9 was lower in MCF-7-M cells compared to MCF-7 and MCF-7-C cells treated with adriamycin (ADM). Immunoprecipitation combined with western blotting was used to detect the interaction between Bcl-2 and BNIP3 or Bax protein. MCF-7-M cells had a higher amount of Bax binding to Bcl-2 compared to MCF-7 cells or MCF-7-C cells, while the amount of BNIP3 binding to Bcl-2 was decreased in MCF-7-M cells. Hoechst 33342 staining and flow cytometry were utilized to evaluate the effect of M-CSF on apoptosis in MCF-7 cells treated with ADM. Compared to ADM-treated MCF-7 cells, the apoptotic rate of MCF-7-M cells was significantly decreased. These effects were dependent on the concentration of ADM. In conclusion, cytoplasmic M-CSF suppressed apoptosis by inhibiting the HIF-1/BNIP3/Bax signalling pathway, which potentiated the dissociation of Bcl-2 from Bcl-2-BNIP3 compounds and the formation of Bcl-2-Bax compounds.
摘要：
The early stage of oncogenesis is linked to the disorder of the cell cycle. Abnormal gene expression often leads to cell cycle disorders, resulting in malignant transformation of human cells. Epstein–Barr virus (EBV) is associated with a diverse range of human neoplasms, such as malignant lymphoma, nasopharyngeal carcinoma and gastric cancer. EBV mainly infects human lymphocytes and oropharyngeal epithelial cells. EBV is latent in lymphocytes for a long period of time, is detached from the cytoplasm by circular DNA, and can integrate into the chromosome of cells. EBV expresses a variety of latent genes during latent infection. The interaction between EBV latent genes and oncogenes leads to host cell cycle disturbances, including the promotion of G1/S phase transition and inhibition of cell apoptosis, thereby promoting the development of EBV-associated neoplasms. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis involve diverse genes and signal pathways. Here, we review the molecular mechanisms of EBV-driven cell cycle progression and promoting oncogenesis.
作者机构：
[Xiao, Xiangsheng; Tang, Hailin; Xie, Xinhua; Xiao, XS; Xie, XM; Xie, Xiaoming; Liu, Peng; Zhang, Lijuan; Huang, Xiaojia] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr,Dept Breast Oncol, Guangzhou, Guangdong, Peoples R China.;[Chen, Bo] Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Canc Ctr, Dept Breast Canc, Guangzhou, Guangdong, Peoples R China.;[He, Rongfang] Univ South China, Affiliated Hosp 1, Dept Pathol, Hengyang, Hunan, Peoples R China.
通讯机构：
[Xiao, XS; Xie, XM] S;Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr,Dept Breast Oncol, Guangzhou, Guangdong, Peoples R China.
关键词：
SOX8;ZEB1;cancer stem cells;triple-negative breast cancer
摘要：
The molecular mechanisms underlying triple-negative breast cancer (TNBC) pathology are not fully understood. Here, we reviewed the SOX8 transcript level in 24 types of cancer and normal tissues and the SOX8 expression pattern in breast cancer from the TCGA and METABRIC data sets and found that SOX8 was highly expressed in TNBC. We investigated the effect of SOX8 on tumorigenicity, migration and apoptosis in TNBC cell lines and xenografts models. We identified SOX8 as a functional oncogene that involved in the maintenance of stem-like capacities in TNBC cells. Through a promoter truncation experiment and ChIP experiment, we verified zinc finger E-box binding homeobox 1 (ZEB1) as a transcriptional activator of SOX8 that enhanced SOX8 expression by binding to its promoter. We evaluated the ZEB1 and the SOX8 levels in 240 TNBC patients and high expression of ZEB1 and SOX8 were significantly associated with poor prognosis. We demonstrated the significance of the ZEB1-SOX8 axis in regulating TNBC cancer stem-like cells (CSCs) and its connection with poor prognosis. Due to its vital role in TNBC CSCs, the ZEB1-SOX8 regulatory axis could be a promising therapeutic target for TNBC.
作者机构：
[Liu, Jie; Liu, Zhigang; Wang, Huailing; Sun, Xizhuo] ShenZhen Univ, Affiliated Hosp 3, Shenzhen 518020, Peoples R China.;[Liu, Xiaoyu; Luo, Qiang; Liu, Zhigang; Bao, Hui] Shenzhen Univ, Sch Med, Shenzhen 518060, Peoples R China.;[Zuo, Jianhong] Univ South China, Med Sch, Hengyang 421001, Peoples R China.;[Qiu, Shuqi] Longgang ENT Hosp, Shenzhen ENT Inst, Shenzhen 518172, Peoples R China.
通讯机构：
[Sun, Xizhuo; Liu, Xiaoyu] S;[Qiu, Shuqi] L;ShenZhen Univ, Affiliated Hosp 3, Shenzhen 518020, Peoples R China.;Shenzhen Univ, Sch Med, Shenzhen 518060, Peoples R China.;Longgang ENT Hosp, Shenzhen ENT Inst, Shenzhen 518172, Peoples R China.
摘要：
Twenty-one xanthone derivatives (XDs) were synthesized by a microwave-assisted technique. Their in vitro inhibition potency against the growth of four cancer cell lines was evaluated. XD-1 similar to [6,9,10-trihydroxy-3,3-dimethyl-5-(2-methylbut-3-en-2-yl)-3H,7H-pyrano[2,3-c]xanthen-7-one] was confirmed as the most active agent against HepG2 cell line growth with IC50 of 18.6 +/- 2.31 mu M. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for XD-1. XD-1 arrested HepG2 cells on the G0/G1 phase, as indicated by the decreased expressions of cyclin D and CDK2 and the increased expressions of p21. Western blot implied that XD-1 regulated p53/MDM2 to a better healthier state. Moreover, XD-1-induced cell apoptosis was mitochondrion-mediated, as evidenced by caspase activation and involved the PI3K/AKT/mTOR signaling pathway. All the evidence supports that XD-1 is a significant anti-cancer agent for HCC.
摘要：
Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (P-max), minimum P-wave duration (P-min), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RTPCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging P-max, P-min, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect. (C) 2019 Elsevier Inc. All rights reserved.
期刊：
Journal of Cellular and Molecular Medicine,2019年23(10):6919-6929 ISSN：1582-1838
通讯作者：
Wang, Jingfeng;Liang, Ying
作者机构：
[Yuan, Woliang; Lin, Yongqing; Zhang, Haifeng; Yang, Ying; Wang, Jingfeng; Xie, Yong] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Cardiol, Guangzhou 510120, Guangdong, Peoples R China.;[Tian, Guoping] Univ South China, Affiliated Hosp 2, Dept Cardiovasc Med, Hengyang, Peoples R China.;[Liang, Ying] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Endocrinol, Guangzhou 510120, Guangdong, Peoples R China.
通讯机构：
[Wang, Jingfeng; Liang, Ying] S;Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Cardiol, Guangzhou 510120, Guangdong, Peoples R China.;Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Endocrinol, Guangzhou 510120, Guangdong, Peoples R China.
摘要：
The present study investigated the role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 16 (SNHG16) in the human aortic smooth muscle cell (HASMC) proliferation and migration and explored the potential link between SNHG16 and atherosclerosis. Our results showed that platelet-derived growth factor (PDGF)-bb treatment promoted cell proliferation and migration with concurrent up-regulation of SNHG16 in HASMCs. Small nucleolar RNA host gene 16 overexpression promoted HASMC proliferation and migration, while SNHG16 knockdown suppressed cell proliferation and migration in PDGF-bb-stimulated HASMCs. The bioinformatic analyses showed that SNHG16 possessed the complementary binding sequence with miR-205, where the interaction was confirmed by luciferase reporter assay and RNA pull-down assay in HASMCs, and SNHG16 inversely regulated miR-205 expression. MiR-205 overexpression attenuated the enhanced effects of PDGF-bb treatment on HASMC proliferation and migration. Moreover, Smad2 was targeted and inversely regulated by miR-205, while being positively regulated by SNHG16 in HASMCs. Smad2 knockdown attenuated PDGF-bb-mediated actions on HASMC proliferation and migration. Both miR-205 overexpression and Smad2 knockdown partially reversed the effects of SNHG16 overexpression on HASMC proliferation and migration. Moreover, SNHG16 and Smad2 mRNA were up-regulated, while miR-205 was down-regulated in the plasma from patients with atherosclerosis. Small nucleolar RNA host gene 16 expression was inversely correlated with miR-205 expression and positively correlated with Smad2 expression in the plasma from atherosclerotic patients. In conclusion, our data showed the up-regulation of SNHG16 in pathogenic-stimulated HASMCs and clinical samples from atherosclerotic patients. Small nucleolar RNA host gene 16 regulated HASMC proliferation and migration possibly via regulating Smad2 expression by acting as a competing endogenous RNA for miR-205.
摘要：
CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding to its promoter region, which was repressed by CXCL12. We found that CXCL12 increased the levels of phosphorylated glycogen synthase kinase 3 beta (GSK3 beta) and the phosphorylation of beta-catenin at the Thr120 position. Inactivation of GSK3 beta or beta-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on TCF21 and ABCA1 expression and the phosphorylation of GSK3 beta and beta-catenin. In vivo, the overexpression of CXCL12 in Apoe(-/-) mice via lentivirus enlarged the atherosclerotic lesion area and increased macrophage infiltration in atherosclerotic plaques. We further found that the overexpression of CXCL12 reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), and suppressed cholesterol efflux from MPMs to apoA-I in Apoe(-/-) mice. Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then activates the GSK-3 beta/beta-catenin(T120)/TCF21 signaling pathway to inhibit ABCA1-dependent cholesterol efflux from macrophages and aggravate atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the prevention and treatment of atherosclerotic cardiovascular diseases.
