Rationale: Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. Methods: The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin ( CTNNB1 ) transcription in vitro . Nude mice and conditional transgenic mice were used to investigate the findings in vivo . Results: We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo . Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit CTNNB1 transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. Conclusion: This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.
MicroRNAs (miRNAs) play important roles in regulating tumour development and progression. Here we show that miR-647 is repressed in gastric cancer (GC), and associated with GC metastasis. Moreover, we identify that miR-647 can suppress GC cell migration and invasion in vitro. Mechanistically, we confirm miR-647 directly binds to the 3' untranslated regions of SRF mRNA, and SRF binds to the CArG box located at the MYH9 promoter. CCG-1423, an inhibitor of RhoA/SRF-mediated gene transcription, inhibits the expression of MYH9, especially in SRF downregulated cells. Overexpression of miR-647 inhibits MGC 80-3 cells' metastasis in orthotropic GC models, but increasing SRF expression in these cells reverses this change. Importantly, we found the synergistic inhibition effect of CCG-1423 and agomir-647, an engineered miRNA mimic, on cancer metastasis in orthotropic GC models. Our study demonstrates that miR-647 functions as a tumor metastasis suppressor in GC by targeting SRF/MYH9 axis.
BackgroundConventional measurements are not always helpful in the diagnosis of malignant mesothelioma (MM). Increasing studies indicate that loss of BRCA1–associated protein 1 (BAP1) detected by immunohistochemistry (IHC) is a useful diagnostic marker for MM. In this meta-analysis, we investigated the diagnostic accuracy of BAP1 in MM.ResultsIn total, 12 eligible studies with a total of 1824 patients were selected. Results indicated that loss of BAP1 sustained a pooled sensitivity of 0.56 (95% CI, 0.50–0.62), specificity of 1.00 (95% CI, 0.95–1.00), PLR of 548.82 (95% CI, 11.31–2.7 × 104), NLR of 0.44 (95% CI, 0.39–0.50), DOR of 1247.78 (95% CI, 25.08 −6.2 × 104) in discriminating MM from non-MM. The AUC of 0.72, reflecting the SROC, indicated moderate diagnostic accuracy. Subgroup analysis showed that BAP1 detection in histological specimens owned the higher diagnostic performance than cytological ones. In addition, BAP1 showed superior diagnostic accuracy in epithelioid MM than biphasic or sarcomatoid MM.Materials and MethodsPubMed, Embase and the Cochrane Library and reference lists of related articles were searched, and studies that evaluated the utility of BAP1 in MM were included. Data from eligible studies were pooled to estimate sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR). Summary receiver operating curves (SROC) was applied to estimate overall diagnostic accuracy.ConclusionsCurrent meta-analysis indicates that detection of BAP1 by IHC is a useful diagnostic marker for MM. Loss of BAP1 almost provides confirming diagnosis for MM, while positive staining for BAP1 is not enough to exclude non-MM.
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