Curcumin is potentially therapeutic for malignant diseases. The mechanisms of this effect might involve a combination of antioxidant, immunomodulatory, proapoptotic, and antiangiogenic activities. ...However, the exact mechanisms are not fully understood. In the present study, we provided evidences that curcumin suppressed the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells both transcriptionally and post-transcriptionally. Curcumin inhibited the expression of EZH2 through microRNA (miR)-let 7c and miR-101. Curcumin decreased the expression of NOTCH1 through the inhibition of EZH2. There was a reciprocal regulation between EZH2 and NOTCH1 in lung cancer cells. These observations suggest that curcumin inhibits lung cancer growth and metastasis at least partly through the inhibition of EZH2 and NOTCH1.
Background and AimsThe authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (EIF5A2) from 3q26. In this study, EIF5A2 was characterised for its role in colorectal ...carcinoma (CRC) aggressiveness and underlying molecular mechanisms.MethodsThe expression dynamics of EIF5A2 were examined by immunohistochemistry in a cohort of carcinomatous and non-neoplastic colorectal tissues and cells. A series of in-vivo and in-vitro assays was performed to elucidate the function of EIF5A2 in CRC and its underlying mechanisms.ResultsThe overexpression of EIF5A2 was examined by immunohistochemistry in 102/229 (44.5%) CRC patients, and it was significantly correlated with tumour metastasis and determined to be an independent predictor of shortened survival (p<0.05). Ectopic overexpression of EIF5A2 in CRC cells enhanced cell motility and invasion in vitro and tumour metastasis in vivo, and induced epithelial–mesenchymal transition (EMT). The depletion of EIF5A2 expression prevented CRC cell invasiveness and inhibited EMT. Importantly, the metastasis-associated protein 1 (MTA1) gene was identified as a potential downstream target of EIF5A2 in CRC cells, and knockdown of MTA1 eliminated the augmentation of carcinoma cell migration, invasion and EMT by ectopic EIF5A2. The overexpression of EIF5A2 in CRC cells substantially enhanced the enrichment of c-myc on the promoter of MTA1, and MTA1 upregulation by EIF5A2 was partly dependent on c-myc.ConclusionThe data suggest that EIF5A2 plays an important oncogenic role in CRC aggressiveness by the upregulation of MTA1 to induce EMT, and EIF5A2 could be employed as a novel prognostic marker and/or effective therapeutic target for CRC.
The successful gene delivery into the brain is a major challenge due to the presence of the blood-brain barrier (BBB). In order to transport plasmid DNA across the BBB and target the brain glioma, ...the PEGylated liposomes (PLs) modified with OX26 and chlorotoxin (CTX) were developed as a dual-targeting gene delivery system, and the therapeutic efficacy of OX26/CTX-PL/pC27 against glioma was evaluated using in vitro and in vivo experimental models.
The PEGylated liposome complexes were prepared by the reverse phase evaporation method, and their physicochemical properties were examined. The transfection efficiency, intracellular distribution, in vitro effects of OX26/CTX-PL/pC27 were determined on C6, F98 and HEK293T cell lines. The dual-targeting therapeutic efficacy of OX26/CTX-PL/pC27 against glioma were assessed using the BMVECs/C6 cells co-culture model and the rat orthotopic glioma model.
The OX26/CTX-PL/pDNA complexes exhibited a subglobose shape, and possessed notably low toxicities to HEK293T and C6 cells post 4 h incubation. In the in vitro transfection experiment, gene expressions of hTERTC27 from C6 and F98 cells were significantly improved by OX26 and CTX modification. Our in vitro results also showed that OX26 endowed the PLs with the transport ability across the BBB. Using the BMVECs/C6 cells co-culture model, the viability of C6 cells was decreased to 46.0% after OX26/CTX-PL/pC27 transfection. The OX26/CTX-PL/pC27 complexes exhibited enhanced therapeutic effects on C6 cells. Moreover, the dual-targeting therapeutic effects were further conformed with diminished tumor volumes (18.81 ± 6.15 mm³) and extended median survival time (46 days) in C6 glioma-bearing rats. Immunohistochemical analysis revealed the therapeutic effects derived from enhanced hTERTC27 expression in the tumor site.
The PEGylated liposomes modified with OX26 and CTX are able to significantly promote cell transfection, increase the transport of plasmid DNA across the BBB and afterwards target the brain glioma cells in vitro and in vivo, exhibit the most significant therapeutic efficacy. The ligand OX26 plays a critical role in transporting the lipoplexes across the BBB, and CTX acts as a major role in targeting brain glioma cells. The results would encourage further developments for non-invasive targeting therapy of brain gliomas by intravenous injection.
Trimethylation of lysine 27 on histone H3 (H3K27ME3) is a transcription-suppressive histone mark mediated by enhancer of zeste homolog 2 (EZH2). We have previously suggested that EZH2-mediated ...H3K27ME3 plays a critical oncogenic role in human hepatocellular carcinoma (HCC) aggressiveness. However, the direct downstream targets of EZH2-H3K27ME3 and the molecular mechanisms by which regulates HCC pathogenesis remain unclear. In this study, we used chromatin immunoprecipitation together with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis to assess genome-wide chromatin occupancy of H3K27ME3 in HCC cells. We identified that claudin14 (CLDN14) is a potentially direct target for EZH2-mediated H3K27ME3 in HCC. In a large cohort of clinical HCC tissues, we found that low expression of CLDN14 was significantly associated with advanced tumor stage and determined to be an independent predictor of shortened survival of HCC patients. Next, functional experiment demonstrated that depletion of CLDN14 substantially restored EZH2-silenced HCC cells motility and invasive capacities and supported cell epithelial-mesenchymal transition (EMT). Furthermore, downregulation of CLDN14 dramatically re-enhanced the wnt/β-catenin signaling activity in EZH2-silenced HCC cells by increasing the levels of active β-catenin and promoting the nuclear localization of β-catenin. These results, collectively, uncover that CLDN14 is a novel direct target of EZH2-mediated H3K27ME3, and provide an explanation for the aggressive nature of HCC with downregulation of CLDN14 and the underling mechanism that links the tumor suppressor CLDN14 to the wnt/β-catenin signaling pathway.
The enhancer of zeste homolog 2 (EZH2), a known repressor of gene transcription, has been reported to be associated with biological malignancy in several cancers. The potential oncogenic role of EZH2 ...and its clinical/prognostic significance, however, in esophageal squamous cell carcinoma (ESCC) are unclear. In this study, the methods of immunohistochemistry and fluorescence in‐situ hybridization were used to examine protein expression and amplification of EZH2 in 98 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (CRT). High expression of EZH2 and amplification of EZH2 was found in 54.1% and 12.0% of ESCCs, respectively. High EZH2 expression was significantly correlated with increased cell proliferation (p = 0.009), high histopathological grade (p = 0.002), regional (p = 0.025) and distant lymph node metastasis (p < 0.001) and lack of clinical complete response to CRT (p = 0.028). Univariate analysis revealed that high expression of EZH2 was associated with poor metastasis‐free survival (MFS) (p = 0.003), poor progression‐free survival (PFS) (p = 0.001) and poor disease‐specific survival (DSS) (p < 0.001). In multivariate analysis, high expression of EZH2, together with lack of clinical complete response, were evaluated as significant independent prognostic factors of MFS, PFS and DSS for patients with ESCC. These findings suggest that high expression of EZH2 correlates with tumor aggressiveness and adverse patient outcome in ESCC treated with definitive CRT. Evaluation of EZH2 expressions might be useful for predicting tumor response to CRT and prognosis for patients with ESCC.
The secretory small GTPase Rab27b was recently identified as an oncogene in breast cancer (BC) in vivo and in vitro studies. This research was designed to further explore the clinical and prognostic ...significance of Rab27B in BC patients.
The mRNA/protein expression level of Rab27B was examined by performing Real-time PCR, western blot, and immunohistochemistry (IHC) assays in 12 paired BC tissues and matched adjacent noncancerous tissues (NAT). Then we carried out IHC assay in a large cohort of 221 invasive BC tissues, 22 normal breast tissues, 40 fibroadenoma (FA), 30 ductual carcinoma in situ (DCIS) and 40 metastatic lymph nodes (LNs). The receiver operating characteristic curve method was applied to obtain the optimal cutoff value for high Rab27B expression. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to Rab27B expression.
We observed that the increased expression of Rab27B was dependent upon the magnitude of cancer progression (P < 0.001). The elevated expression of Rab27B was closely correlated with lymph node metastasis, advanced clinical stage, ascending pathology classification, and positive ER status. Furthermore, patients with high expression of Rab27B had inferior survival outcomes. Multivariate Cox regression analysis proved that Rab27B was a significantly independent risk factor for patients' survival (P < 0.001). Furthermore, a significant positive relationship was observed between Rab27B expression and elevated mesenchymal EMT markers.
Our findings suggest that overexpression of Rab27B in BC coincides with lymph node metastasis and acquisition of a poor prognostic phenotype.
Aim
The homeobox gene Barx2 was recently identified as a regulator of ovarian and breast cancer; however, the expression level of BARX2 and its significance in hepatocellular carcinoma (HCC) remain ...unknown.
Methods
Protein and mRNA expression levels of Barx2 were examined using Western blotting and real‐time PCR respectively, in paired HCC tissue and matched adjacent non‐cancerous tissue from 12 patients. The expression levels of epithelial–mesenchymal transition (EMT) markers were also detected in relation to BARX2 expression. Lastly, immunohistochemistry for BARX2 was also performed on a tissue microarray containing 231 HCC tissue samples.
Results
We observed that BARX2 expression was lower in HCC tissues compared to matching adjacent non‐cancerous tissue. The low expression level of BARX2 was significantly correlated with metrics of tumor size, tumor differentiation, clinical stage, metastasis and relapse. Furthermore, the patients with low BARX2 expression had adverse survival outcomes. Importantly, multivariate Cox regression analysis revealed that low BARX2 expression was an independent marker for lower overall survival (P = 0.007). Moreover, a significant negative relationship was observed between the expression of BARX2 and markers of EMT.
Conclusion
These findings provide evidence that the low expression level of BARX2 in HCC is significantly correlated with tumor metastasis, and that BARX2 may be an independent prognostic biomarker for patients with HCC.
The primary aim of this study was to examine the extent of nutritional awareness concerning dietary requisites within a cohort comprising pediatric recipients of liver and kidney transplants, along ...with their respective caregivers. The overarching goal was to establish a foundation for enhancing the dietary nutrition of this specific population.
This was a qualitative research study, involving in-depth interviews and subsequent qualitative data analysis. Our sample included pediatric patients in a specific age range who had undergone a liver or kidney transplant, as well as their parents. The data analysis technique we used was content analysis.
The survey focused on knowledge of dietary requirements and restrictions, nutritional needs, and adherence to daily dietary requirements among pediatric patients and their respective caregivers. Approximately 30% of the parents lacked relevant nutritional awareness, 30% relied on a single source for acquiring nutritional knowledge, and 40% expressed a considerable need for nutritional guidance. Our findings revealed a deficiency in the understanding of nutritional and dietary requirements for children who have undergone a liver or kidney transplant. Their nutrient intake was unbalanced, and their dietary habits were irregular, highlighting the need for better nutritional guidance and monitoring.
The nutritional awareness and knowledge of dietary requirements among pediatric liver and kidney transplant recipients and their care providers are inadequate. Medical professionals are urged to tackle this concern by imparting comprehensive education to parents regarding the nutritional prerequisites essential for their children post-transplant. This approach empowers parents to implement requisite dietary modifications effectively. Furthermore, healthcare institutions should augment the nutritional proficiency of their medical staff through meticulously structured training initiatives.
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