Thymoquinone (TQ, 2‐methyl‐5‐isopropyl‐1,4‐benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti‐tumor efficiency in various cancers. Autophagy is a self‐digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786‐O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ‐treated RCC cells, and then found that autophagy was induced by TQ in 786‐O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy‐dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ‐induced autophagy in RCC treatment.
The chemokine (C-C motif) ligand 2 (CCL2) with its cognate receptor chemokine (C-C motif) receptor 2 (CCR2) plays important roles in tumor invasion and metastasis. However, the mechanisms and mediators for autocrine CCL2 and CCL2-CCR2 axis remain elusive in breast cancer. Here we examined the levels of CCL2 in 4 breast cancer cell lines along with 57 human breast cancer specimens and found them significantly increased with presence of 17β-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cells, while anti-estrogen treatment weakened this enhancement. CCL2 expression positively correlated with Twist staining and aggressiveness of breast cancer. Estrogen exposure facilitated the proliferation, invasion and metastasis of hormone-dependent breast cancer and promoted angiogenesis via the increased secretion of CCL2 in vitro and in vivo, which could be suppressed by disruption of CCL2-CCR2 axis with CCR2 antagonist RS102895. Knockdown of Twist in MCF-7 cells significantly inhibited E2-induced CCL2 production, indicating an essential role of Twist in CCL2 regulation under estrogenic condition. Our data show the hormonal regulation on CCL2-CCR2 axis is associated with enhanced Twist expression via activation of ERα and PI3K/AKT/NF-κB signaling. Thus, CCL2-CCR2 axis may represent as a novel therapeutic target eagerly needed for hormone-dependent breast cancer.
The ocular surface, which is among the most accessible and vulnerable tissues in mammals, is protected by a complex tear film composed of lipid, aqueous and mucin layers. In spite of its importance, the molecular nature of the mucin contribution remains uncertain. Since membrane mucins have been implicated in the protection of other epithelia, we have analysed rat corneal and conjunctival tissues for sialomucin complex (SMC), a membrane mucin found at the apical epithelial cell surfaces in the airway and uterus. Using Northern and Western blot analyses, SMC expression was found in both ocular tissues, being particularly abundant in the cornea. In contrast with the other known membrane mucin, MUC1, SMC was localized more heavily towards the apical surface of the epithelial cells. SMC in ocular surface epithelia was produced in both soluble and membrane forms, the latter being found predominantly in the most superficial cells and at apical surfaces. The soluble form was found loosely adsorbed to apical cell surfaces, particularly of the cornea, as indicated by a mild rinsing protocol. Finally, the tear fluid contained substantial amounts of SMC. From these results, we propose a new model for tear mucin components in which SMC is expressed at the apical ocular surface in both membrane-bound and adsorbed soluble forms to provide a direct protective barrier. SMC secreted into the tear fluid may also participate in maintaining the stability of the preocular tear film by acting with other secreted mucins to determine the physical properties and protective behaviour of the tear film.
Objective-FLRF (Rnf41) gene was identified through screening of subtracted cDNA libraries form murine hematopoietic stem cells and progenitors. Subsequent work has revealed that FLRF acts as E3 ubiquitin ligase, and that it regulates steady-state levels of neuregulin receptor ErbB3, and participates in degradation of IAP protein BRUCE and parkin. The objective of this study was to start exploring the role of FLRF during hematopoiesis.Methods-FLRF was over-expressed in a murine multipotent hematopoietic progenitor cell line EML, which can differentiate into almost all blood cell lineages, and in pro-B progenitor cell line BaF3. The impact of FLRF over-expression on EML cell differentiation into myelo-erythroid lineages was studied using hematopoietic colony-forming assays. The interaction of FLRF with cytokine receptors and receptor levels in control cells and EML and BaF3 cells over-expressing FLRF were examined with Western and immunoprecipitation.Results-Remarkably, over-expression of FLRF significantly attenuated erythroid and myeloid differentiation of EML cells in response to cytokines Epo and IL-3, and retinoic acid (RA), and resulted in significant and constitutive decrease of steady-state levels of IL-3, Epo and RA receptor RARα in EML and BaF3 cells. Immunoprecipitation has revealed that FLRF interacts with IL-3, Epo and RARα receptors in EML and BaF3 cells, and that FLRF-mediated down-regulation of these receptors is ligand binding-independent.Conclusions-The results of this study have revealed new FLRF-mediated pathway for ligandindependent receptor level regulation, and support the notion that through maintaining basal levels of cytokine receptors, FLRF is involved in the control of hematopoietic progenitor cell differentiation into myelo-erythroid lineages.
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