CHP2 (calcineurin B homologous protein 2) was initially identified as a tumor-associated antigen highly expressed in hepatocellular carcinoma. Its biological function remains largely unknown except for a potential role in transmembrane Na ؉ /H ؉ exchange. In the present study, we observed that ectopic expression of CHP2 promoted the proliferation of HEK293 cells, whereas knockdown of endogenous CHP2 expression in HepG2 inhibited cell proliferation. When inoculated into nude mice, CHP2 transfected HEK293 cells displayed markedly increased oncogenic potential. In analysis of the underlying molecular mechanisms, we found that like calcineurin B, CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A. In accord with this, CHP2-transfected cells showed increased nuclear presence of NFATc3 (nuclear factor of activated T cells) and enhanced NFAT activity. Finally, both accelerated cell proliferation and NFAT activation following CHP2 transfection could be suppressed by the calcineurin inhibitor cyclosporine A, suggesting an intrinsic connection between these events. Taken together, our results highlighted a potential role of CHP2 in tumorigenesis and revealed a novel function of CHP2 as an activator of the calcineurin/NFAT signaling pathway.

BackgroundChronic inflammation plays a crucial role in the progression of vascular calcification (VC). This study was designed to investigate whether the low-density lipoprotein receptor (LDLr) pathway is involved in the progression of VC in patients with end-stage renal disease (ESRD) during inflammation.Methods and ResultsTwenty-eight ESRD patients were divided into control and inflamed groups according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in the experiments. The expression of tumour necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) of the radial artery were increased in the inflamed group. Hematoxylin-eosin and alizarin red S staining revealed parallel increases in foam cell formation and calcium deposit formation in continuous cross-sections of radial arteries in the inflamed group compared to the control, which were closely correlated with increased LDLr, sterol regulatory element binding protein-2 (SREBP-2), bone morphogenetic proteins-2 (BMP-2), and collagen I protein expression, as shown by immunohistochemical and immunofluorescent staining. Confocal microscopy confirmed that inflammation enhanced the translocation of the SREBP cleavage-activating protein (SCAP)/SREBP-2 complex from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Inflammation increased alkaline phosphatase protein expression and reduced α-smooth muscle actin protein expression, contributing to the conversion of the vascular smooth muscle cells in calcified vessels from the fibroblastic to the osteogenic phenotype; osteogenic cells are the main cellular components involved in VC. Further analysis showed that the inflammation-induced disruption of the LDLr pathway was significantly associated with enhanced BMP-2 and collagen I expression.ConclusionsInflammation accelerated the progression of VC in ESRD patients by disrupting the LDLr pathway, which may represent a novel mechanism involved in the progression of both VC and atherosclerosis.

Inflammation contributed to foam cell formation in the radial arteries of ESRD patients via the dysregulation of the LDLr pathway, which could be modulated by the activation of the mTOR pathway.

Background: miR-4429 acts as an inhibitor in many malignant tumors and participates in the biological processes of them, but the clinical value and potential molecular mechanism of miR-4429 in cervical cancer (CC) are still under investigation. Objective: To analyze the clinical value and molecular mechanism of miR-4429 in CC. Materials and Methods: A qRT-PCR assay was employed to determine the levels of miR-4429 and forkhead-box M1 (FOXM1) in CC tissues, CC cell lines (SiHa, CaSki, ME-180, and C33A) and human normal immortalized epithelial cell lines (HaCaT). The proliferation, migration, invasion, and apoptosis abilities of ME-180 and C33A cells were detected, and the epithelial-to-mesenchymal transition (EMT)-related proteins in the cells were also determined. Results: MiR-4429 acted as a tumor suppressor gene in CC tissues and cells and was linked to lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) staging. The survival analysis revealed that lymph node metastasis, high FIGO staging, and low miR-4429 expression were all related to the unfavorable prognosis of the patients, and the dual-luciferase reporter assay revealed that FOXM1 was the target of miR-4429. Both overexpression of miR-4429 and knock-down of FOXM1 inhibited the proliferation, migration, invasion, and EMT of CCCs, and accelerated the apoptosis of them. Conversely, both knockdown of miR-4429 and overexpression of FOXM1 promoted those biological behaviors of the cells. Moreover, the rescue experiment revealed that the overexpression of FOXM1 reversed the influences of miR-4429 overexpression on the proliferation, migration, invasion, and EMT of CCCs. Conclusion: miR-4429 acts as a tumor suppressor in CC and can directly target FOXM1 to regulate the proliferation, migration, invasion, apoptosis and EMT of CCCs, so miR-4429 is expected to be a new therapeutic target for CC.