Background: Fascin, an actin-binding protein, is usually expressed at a low level in normal epithelium, but is markedly up regulated in several types of carcinomas. Reports on fascin expression in oesophageal squamous cell carcinoma (ESCC) and precancerous lesions remain rare. Aim: To show the roles of fascin in the progression from normal epithelium to invasive ESCC. Methods: Fascin expression in 102 sections embedded in paraffin wax, including samples of normal mucosa (n = 20), dysplasia (n = 10), ESCC (n = 62) and special sections (n = 10) of a full-length mucosa layer from the distant margin to the cancer focus of the excised oesophagus, and 49 fresh specimens of ESCC was analysed by immunohistochemistry, western blot and real-time reverse transcriptionpolymerase chain reaction. Fascin expression in ESCC cell lines was also investigated. Results: In the immunohistochemical study, the positive rate of fascin was significantly higher in the tumour tissue than in the normal epithelium (p = 0.020), but no significant difference was shown between ESCC and dysplasia (p = 1.000). Immunostaining for fascin was only apparent in the basal layer of the normal epithelium. However, in the dysplasia, positive staining was observed in most of the heterogeneous cells from the basal layer to the granular layer of the epithelium. Fascin expression was seen to increase progressively from the normal epithelium to invasive ESCC. Up regulation of fascin was observed in 87.76% (43/49) and 77.55% (38/49) of the specimens, respectively, using western blot and real-time reverse transcription-polymerase chain reaction assays; 80% (4/5) of ESCC cell lines also expressed fascin at a high level. Furthermore, overexpression of fascin was markedly correlated with cell proliferation and lymph node metastasis. Conclusions: These findings suggested that fascin was associated with the transformation and development of ESCC and implicated the potential of fascin as a novel biomarker that would allow the tumour to be identified at an early stage in high-risk individuals.
Background: CD59 is the sole membrane complement regulatory protein in restricting membrane attack complex assembly. Results: CD59 gene produces eight transcripts that share three transcriptional initiation sites but the same open reading frame. Conclusion: NF-B and CREB (as an enhancer-binding protein) bridged by CBP/p300 are responsible for the inducible expression of CD59. Significance: CD59 regulation mechanism suggests potential drug targets for controlling various complement-related human diseases.
By activating protective pathways, tumour cells are not only capable of survival in stress, but often associated with increased aggressiveness and metastasis. Activating transcription factor 4 (ATF4) is a major coordinator of tumour cell survival in stress and is commonly overexpressed in tumours. Numerous studies suggested that the ATF4 is a potential therapeutic target for cancer. In this report, we describe that a small ribosomal peptide, RPL41, induced rapid ATF4 degradation. By immunofluorescence staining, RPL41 induced ATF4 relocation from nuclei to cytoplasm, where ATF4 co-stained with a proteasome marker; the RPL41-induced ATF4 relocation and degradation were blocked by the proteasome inhibitor MG132. An in vivo phosphorylation study showed that RPL41 induced ATF4 phosphorylation and serine 219 of ATF4 was essential for RPL41-induced ATF4 degradation. Cells with RPL41 knockdown had significantly increased ATF4, suggesting that RPL41 could play a physiological role in regulating the cellular ATF4 level. RPL41 was capable of inducing tumour cell death and cell cycle arrest; at low dose, RPL41 sensitized tumour cells A549 to the DNA damage agent cisplatin. These studies suggest that RPL41, a small peptide that is chemically synthesizable and capable of self-cell penetration, may have potential as an anti-ATF4 agent for cancer therapy.
The planar cell polarity (PCP) pathway is critical for proper embryonic development of the neural tube and heart. Mutations in these genes have previously been implicated in the pathogenesis of neural tube defects (NTDs), but not in congenital heart defects (CHDs) in humans. We systematically identified the mutation patterns of CELSR1-3 , one family of the core PCP genes, in human cohorts composed of 352 NTD cases, 412 CHD cases, and matched controls. A total of 72 disease-specific rare novel coding mutations were identified, of which 37 were identified in CHD cases, and 36 were identified in NTD patients. Most of these mutations differed between the two cohorts, as only one novel missense mutation in CELSR1 (c.2609G>A p.P870L) was identified in both NTD and CHD patients. Both in vivo and in vitro assays revealed that CELSR1 P870L is a gain-of-function mutation. It up-regulates not only the PCP pathway, but also canonical WNT signaling in cells, and also induced both NTDs and CHDs in Zebrafish embryos. As almost equal numbers of mutations were identified in each cohort, our results provided the first evidence that mutations in CELSR genes are as likely to be associated with CHDs as with NTDs, although the specific mutations differ between the two cohorts. Such differences in mutation panels suggested that CELSRs might be regulated differently during the development of these two organ systems.
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