The vascular smooth muscle cell (VSMC) phenotypic switch is a key pathophysiological change in various cardiovascular diseases, such as aortic dissection (AD), with a high morbidity. Polycystin-1 (PC1) is significantly downregulated in the VSMCs of AD patients. PC1 is an integral membrane glycoprotein and kinase that regulates different biological processes, including cell proliferation, apoptosis, and cell polarity. However, the role of PC1 in intracellular signaling pathways remains poorly understood. In this study, PC1 downregulation in VSMCs promoted the expression of SM22, ACTA2 and calponin 1 (CNN1) proteins. Furthermore, PC1 downregulation in VSMCs upregulated phospho-MEK, phospho-ERK and myc, but did not change phospho-JNK and phospho-p38. These findings suggest that the MEK/ERK/myc signaling pathway is involved in PC1-mediated human VSMC phenotypic switch. Opposite results were observed when an ERK inhibitor was used in VSMCs downregulated by PC1. When the C-terminal domain of PC1 (PC1 C-tail) was overexpressed in VSMCs, the expression levels of phosphor-ERK, myc, SM22, ACTA2 and CNN1 proteins were downregulated. The group with the overexpressed mutant protein (S4166A) in the PC1 C-tail showed similar results to the group with the downregulated PC1 in VSMCs. These results suggest that the Ser at the 4166 site in PC1 is crucial in the PC1 mediated MEK/ERK/myc signaling pathway, which might be the key pathophysiological cause of AD.
Non-small cell lung cancer (NSCLC) is the most prevalent subtype of lung cancer histologically, and an increasing number of evidences have shown during the past years that long non-coding RNAs (lncRNAs) are involved in tumorigenesis. Here we found a long non-coding RNA, GATA2-AS1, repressing NSCLC cells proliferation via regulating GATA2. GATA2-AS1 gene is located at antisense strand of GATA2 on chromosome while GATA2-AS1 RNA interacts with GATA1 protein at promoter region of GATA2 and then inhibits its transcription. Moreover, GATA2-AS1 is transcriptionally repressed by MYC in NSCLC cells. To conclude, our study discovered the role of lncRNA GATA2-AS1 in human non-small cell lung cancer growth thus providing a potential target for lung cancer drugs.
ABSTRACT. We investigated the roles of autoantibodies to different Ro60 epitopes in lymphopenia in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). We recruited 16 patients with SLE, 14 with pSS, and 10 healthy controls; all were female. Patients had active disease, had not received glucocorticoid or immunosuppressants for at least 3 months, and had positive laboratory tests for autoantibodies against Ro60. Patient peripheral blood lymphocyte (LC) counts were < 1 x 10 9 /L: (0.66 ± 0.12) x 10 9 /L and (0.70 ± 0.16) x 10 9 /L for SLE and pSS groups, respectively (P = 0.511). LCs from each group were cultured in vitro with each of the three immunotoxins (ITs) (AE1-3), which specifically combine with one of the three epitopes (aa482-493, aa310-323, and aa230-241, respectively) on Ro60. The cytotoxicity of each IT to the cultured LCs was measured by the MTT colorimetric method. The relationships between IT cytotoxicity and LC counts were analyzed, and autoantibodies against the three epitopes in patient peripheral blood were detected. All ITs showed cytotoxicity to control LCs; however, AE3 and AE2 showed greater toxicity to LCs from SLE and pSS groups, (2015) respectively, and the enhanced cytotoxicity was significantly associated with the respective LC counts (r = 0.653, P = 0.06; r = 0.594, P = 0.025). No difference was found in the prevalence of the autoantibodies between the SLE and pSS groups. These results suggest that autoantibodies to Ro60 might play a pathogenic role in lymphopenia in both SLE and pSS, but the pathogenic mechanisms might differ.
Osteosarcoma is a highly metastatic malignant bone tumor, necessitating the development of new treatments to target its metastasis. Recent studies have revealed the significance of VAMP8 in regulating various signaling pathways in various types of cancer. However, the specific functional role of VAMP8 in osteosarcoma progression remains unclear. In this study, we observed a significant downregulation of VAMP8 in osteosarcoma cells and tissues. Low levels of VAMP8 in osteosarcoma tissues were associated with patients’ poor prognosis. VAMP8 inhibited the migration and invasion capability of osteosarcoma cells. Mechanically, we identified DDX5 as a novel interacting partner of VAMP8, and the conjunction of VAMP8 and DDX5 promoted the degradation of DDX5 via the ubiquitin-proteasome system. Moreover, reduced levels of DDX5 led to the downregulation of β-catenin, thereby suppressing the epithelial–mesenchymal transition (EMT). Additionally, VAMP8 promoted autophagy flux, which may contribute to the suppression of osteosarcoma metastasis. In conclusion, our study anticipated that VAMP8 inhibits osteosarcoma metastasis by promoting the proteasomal degradation of DDX5, consequently inhibiting WNT/β-catenin signaling and EMT. Dysregulation of autophagy by VAMP8 is also implicated as a potential mechanism. These findings provide new insights into the biological nature driving osteosarcoma metastasis and highlight the modulation of VAMP8 as a potential therapeutic strategy for targeting osteosarcoma metastasis.
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