Apple (Malus × domestica) trees are vulnerable to freezing temperatures. However, there has been only limited success in developing cold-hardy cultivars. This lack of progress is due at least partly ...to lack of understanding of the molecular mechanisms of freezing tolerance in apple.
In this study, we evaluated the potential roles for two R2R3 MYB transcription factors (TFs), MYB88 and the paralogous FLP (MYB124), in cold stress in apple and Arabidopsis. We found that MYB88 and MYB124 positively regulate freezing tolerance and cold-responsive gene expression in both apple and Arabidopsis.
Chromatin-Immunoprecipitation-qPCR and electrophoretic mobility shift assays showed that MdMYB88/MdMYB124 act as direct regulators of the COLD SHOCK DOMAIN PROTEIN 3 (MdCSP3) and CIRCADIAN CLOCK ASSOCIATED 1 (MdCCA1) genes. Dual luciferase reporter assay indicated that MdCCA1 but not MdCSP3 activated the expression of MdCBF3 under cold stress. Moreover, MdMYB88 and MdMYB124 promoted anthocyanin accumulation and H2O2 detoxification in response to cold.
Taken together, our results suggest that MdMYB88 and MdMYB124 positively regulate cold hardiness and cold-responsive gene expression under cold stress by C-REPEAT BINDING FACTOR (CBF)-dependent and CBF-independent pathways.
PRDX4 and Its Roles in Various Cancers Jia, Wenqiao; Chen, Pengxiang; Cheng, Yufeng
Technology in Cancer Research & Treatment,
01/2019, Letnik:
18
Book Review, Journal Article
Recenzirano
Odprti dostop
Reactive oxygen species play a vital role in cell survival by regulating physiological metabolism and signal transduction of cells. The imbalance of oxidant and antioxidant states induces oxidative ...stress within a cell. Redox regulation and oxidative stress are closely related to survival and proliferation of stem cells, cancer cells, and cancer stem cells. Peroxiredoxin 4, a typical endoplasmic reticulum-resident 2-Cys antioxidant of peroxiredoxins, can fine-tune hydrogen peroxide catabolism which affects cell survival by affecting redox balance, oxidative protein folding, and regulation of hydrogen peroxide signaling. Recent studies revealed the overexpression of peroxiredoxin 4 in several kinds of cancers, such as breast cancer, prostate cancer, ovarian cancer, colorectal cancer, and lung cancer. And it has been demonstrated that peroxiredoxin 4 causally contributes to tumorigenesis, therapeutic resistance, metastasis, and recurrence of tumors. In this article, the characteristics of peroxiredoxin 4 in physiological functions and the cancer-related research progress of mammalian peroxiredoxin 4 is reviewed. We believe that peroxiredoxin 4 has the potential of serving as a novel target for multiple cancers.
Radiation resistance is a major cause of esophageal cancer relapse or metastasis. Transcriptional coactivator with PDZ binding domain (TAZ) is a final effector of the Hippo signaling pathway and ...plays critical roles in several types of cancer, but how it participates in the progression and radiation resistance of esophageal cancer remains unclear. Here, we revealed that TAZ was the strongest prognostic factor among Hippo pathway members. Overexpression of TAZ predicted poor outcome and adverse pathological features. In cell and animal models, TAZ facilitated cell proliferation, motility, and radiation resistance. Additionally, TAZ promoted expression of nonhomologous end joining (NHEJ)‐related genes, which are the main contributors to repair irradiation‐induced DNA breaks and result in radiation resistance. Amplification of the TAZ gene occurred in 2.5%‐3.2% of esophageal cancers. In addition, the CpG islands of the TAZ gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation. Knockdown of TDG inhibited cell growth, motility, and radiation resistance, which were overridden by TAZ overexpression. Collectively, these findings suggest that the TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radiation resistance, as well as a potential target for radiotherapy.
Transcriptional coactivator with PDZ binding domain (TAZ) was oncogenic in esophageal cancer. Thymine DNA glycosylase (TDG) acted as a regulator of the aberrant TAZ expression by demethylating its CpG islands, and further participated in radiation resistance by regulating expression of a broad range of nonhomologous end joining (NHEJ)‐related genes. The TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radioresistance, and is a potential treatment target for esophageal cancer.
Radiotherapy is one of the most effective treatments for esophageal squamous cell carcinoma (ESCC); however, radioresistance is a clinical problem that must urgently be solved. Here, we found that ...butyrophilin subfamily 3 member A1 (BTN3A1) is upregulated in ESCC tumor tissues compared with nontumor tissues. We also evaluated BTN3A1 expression in patients with ESCC receiving adjuvant radiotherapy. The results demonstrated that BTN3A1 upregulation predicts a poor prognosis for ESCC patients. BTN3A1 overexpression promotes ESCC cell proliferation in vitro and in vivo. Moreover, BTN3A1 knockdown sensitized ESCC cells to radiation. We further explored the mode of death involved in BTN3A1-mediated radioresistance. Previous studies have shown that apoptosis, autophagy, necrosis, pyroptosis and ferroptosis are important for the survival of ESCC cells. We performed an RT-PCR array and western blotting (WB) to identify the mode of death and revealed for the first time that BTN3A1 promotes cell radioresistance by activating autophagy. In addition, by performing immunoprecipitation and mass spectrometry analyses, we found that BTN3A1 regulated the expression of UNC-51-like autophagy activating kinase 1(ULK1) and promoted its phosphorylation to subsequently initiate autophagy. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay results indicated that BTN3A1 is a novel direct target of hypoxia inducible factor-1α (HIF-1α). HIF-1α, a transcription factor, promotes BTN3A1 transcription upon irradiation. Overall, the present study is the first to show that BTN3A1 plays a key role in radioresistance and that targeting BTN3A1 might be a promising strategy to improve radiotherapy efficacy in patients with ESCC.
Exogenous 5-aminolevulinic acid (ALA) positively regulates plants chlorophyll synthesis and protects them against environmental stresses, although the protection mechanism is not fully clear. Here, ...we explored the effects of ALA on chlorophyll synthesis in tomato plants, which are sensitive to low temperature. We also examined the roles of the glutathione S-transferase (GSTU43) gene, which is involved in ALA-induced tolerance to oxidation stress and regulation of chlorophyll synthesis under low temperature.
Exogenous ALA alleviated low temperature caused chlorophyll synthesis obstacle of uroporphyrinogen III (UROIII) conversion to protoporphyrin IX (Proto IX), and enhanced the production of chlorophyll and its precursors, including endogenous ALA, Proto IX, Mg-protoporphyrin IX (Mg-proto IX), and protochlorophyll (Pchl), under low temperature in tomato leaves. However, ALA did not regulate chlorophyll synthesis at the level of transcription. Notably, ALA up-regulated the GSTU43 gene and protein expression and increased GST activity. Silencing of GSTU43 with virus-induced gene silencing reduced the activities of GST, superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, and increased the membrane lipid peroxidation; while fed with ALA significant increased all these antioxidase activities and antioxidant contents, and alleviated the membrane damage.
ALA triggered GST activity encoded by GSTU43, and increased tomato tolerance to low temperature-induced oxidative stress, perhaps with the assistance of ascorbate- and/or a glutathione-regenerating cycles, and actively regulated the plant redox homeostasis. This latter effect reduced the degree of membrane lipid peroxidation, which was essential for the coordinated synthesis of chlorophyll.
As a potent inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway, Apatinib has been used in antitumor treatment for some time. The study aimed to research the therapeutic ...effects and toxicity of Apatinib in the treatment of advanced non-small cell lung cancer (NSCLC).
We retrospectively analyzed 128 NSCLC patients treated with Apatinib in Qilu Hospital of Shandong University. Response Evaluation Criteria in Solid Tumors (RECIST) criteria was adopted to evaluate the treatment effect, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was conducted to determine the Adverse Events (AEs). Cox proportional hazard model and Kaplan-Meier function were applied to evaluate the progression-free survival (PFS) and overall survival (OS).
Among 128 NSCLC patients, partial response (PR) were observed in 15 patients, stable disease (SD) in 66 patients and progressive disease (PD) in 47 patients. The objective response rate (ORR) and disease control rate (DCR) accounted for 11.7% and 63.3% respectively. The median PFS (mPFS) and median OS (mOS) were 4.4 months and 17.2 months. Common side effects of Apatinib were hypertension (n=48), proteinuria (n=35), and hand-foot syndrome (HFS) (n=30), all of the side effects were controllable. No significant difference was observed in efficacy and AEs between the higher dose group (Apatinib>500mg/d) and the lower dose group (Apatinib=500mg/d).
The study suggested that Apatinib with a lower dose (=500mg/d) has good efficacy and safety in the treatment of advanced NSCLC after first-line chemotherapy.
Background
In this study, we aimed to explore and clarify the function of KIF4A in esophageal squamous cell carcinoma (ESCC).
Methods
The microarray data were extracted from the Gene Expression ...Omnibus (GEO) database. We then used the database for Annotation, Visualization, and Integrated Discovery (DAVID) to perform the gene ontology function (GO) and KEGG Orthology‐Based Annotation System (KOBAS) to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs). The six core candidate genes were identified using protein–protein interaction (PPI) network analysis and Cytoscape software. Among them, the expression of KIF4A were validated by UALCAN database from the Cancer Genome Atlas (TCGA) (P < 0.05). Western blotting, qRT‐PCR and IHC were used to detect the expression of KIF4A in tissues. Cell experiments (transwell migration assays, wound healing assay, CCK8 assay, and clone formation experiment) were utilized to verify the roles of KIF4A on the ESCC cells. Western blotting was used to explore the mechanism of KIF4A in ESCC.
Results
The expression level of KIF4A was upregulated in ESCC samples compared to those in paracancerous tissues. Transwell migration and wound healing assay showed overexpression of KIF4A significantly promoted the migration of ESCC cells. CCK8 assay and clone formation experiment analysis showed that overexpression of KIF4A promoted proliferation of ESCC cells. Western blot detection found that KIF4A could affect the phosphorylation level of Hippo signaling pathway related proteins.
Conclusions
In summary, KIF4A promotes ESCC cell proliferation and migration by regulating the biological function of ESCC cells through the Hippo signaling pathway.
Key points
Significant findings of the study
We found that high KIF4A expression was associated with poor overall survival in esophageal squamous cell carcinoma. KIF4A expression also promoted the proliferation and migration of ESCC cells in vitro.
What this study adds
Our experimental results explain the role of KIF4A in ESCC, and provide a new biomolecular target for the treatment of ESCC.
We found that high KIF4A expression was associated with poor overall survival in esophageal squamous cell carcinoma. KIF4A expression also promoted the proliferation and migration of ESCC cells in vitro.
CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been ...identified, the deubiquitination pathway for CDC6 has not been investigated.
The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6.
OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer.
We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.
Aiming at the cracking failure of the modified epoxy resin encapsulated module as a result of interface failure under high low temperature cycles, numerical simulation and experimental studies were ...carried out. Firstly, the residual stress field in the encapsulated module was reconstructed after measuring the curing residual stresses in epoxy resin using the hole-drilling method. Temperature-dependent material models were developed after testing the mechanical and thermal characteristic parameters of encapsulated module components, such as modified epoxy resin, in high and low temperature conditions. Then, a finite element model of a high-reduction encapsulated module with multiple components, multiple interfaces, and complicated contacts was established considering residual stress and temperature effects. To simulate the failure behaviour of the resin-embedded part interfaces, the cohesive zone model was utilized. Finally, the stress and strain of the encapsulated module under high and low temperature cycles were simulated, and their distribution features and cracking failure mechanism were analyzed. The results indicate that regardless of the heating/cooling process, significant due to a mismatch in thermal expansion coefficients between the resin and the embedded parts. As the temperature approaches the glass transition temperature
T
g
, the difference grows dramatically. The resulting thermal stress, together with the residual stress, led to the interface failure in encapsulated module. The numerical results were in good agreement with the high and low temperature cycle test results of the encapsulated module, which verified the effectiveness of the analysis method and the established finite element model. The investigation provides an important reference for the high-reliability design of the encapsulation module.
针对改性环氧树脂灌封模块在高低温循环下因界面失效而导致的开裂破坏问题, 开展了数值模拟与试验研究。采用钻孔法测试环氧树脂灌封固化的残余应力, 重构灌封模块内的残余应力场; 试验测试高低温环境下改性环氧树脂等灌封模块组件材料的力热特性参数, 建立与温度相关的材料模型; 建立考虑残余应力和温度效应的含多组件、多界面、复杂接触的高还原度灌封模块有限元模型, 采用内聚力模型来模拟树脂-预埋件界面的失效行为; 对高低温循环下灌封模块的应力应变进行仿真, 并分析其分布特征和开裂破坏机理。结果表明: 无论升温/降温过程, 由于灌封树脂与预埋件热膨胀系数不匹配, 二者间热应变差值均较大; 当温度接近玻璃化转变温度
T
g
时差值急剧扩大, 由此产生的热应力叠加残余应力共同引发了灌封模块的界面失效; 仿真分析结果与灌封模块高低温循环试验结果吻合良好, 验证了分析方法和有限元模型的有效性。研究结果对于灌封模块高可靠性设计具有一定的参考价值。
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