Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival.
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ABSTRACT:
SUBMITTER: Herath NI
PROVIDER: S-EPMC2670002 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Homeodomain-only protein X (HOPX)-? promoter methylation was recently shown to be frequent in human cancers and was suggested as tumor suppressor gene in esophageal and gastric cancer. The aim of this study was to investigate the mechanistic roles of HOPX-? promoter methylation and its clinical relevance in colorectal cancer (CRC). HOPX-? promoter methylation was assessed in human CRC cell lines and 294 CRC tissues. HOPX mRNA and protein levels were measured in relation to HOPX-? promoter methylation. The effects of forced HOPX expression on tumorigenesis were studied using in vitro and in vivo assays. The association between HOPX-? promoter methylation and clinical relevance of CRC patients was determined. HOPX-? promoter methylation is cancer-specific and frequently found in CRC cell lines and tissues, resulting in the down-regulation of HOPX mRNA and protein levels. In CRC cell lines, forced expression of HOPX suppressed proliferation, invasion, and anchorage-independent growth. DNA microarray analyses suggested critical downstream genes that are associated with cancer cell proliferation, invasion or angiogenesis. In a mouse xenograft model, HOPX inhibited tumorigenesis and angiogenesis. Finally, HOPX-? promoter methylation was associated with worse prognosis of stage III CRC patients (hazard ratio= 1.40, P = .035) and also with poor differentiation (P = .014). In conclusion, HOPX-? promoter methylation is a frequent and cancer-specific event in CRC progression. This epigenetic alteration may have clinical ramifications in the diagnosis and treatment of CRC patients.
| S-EPMC3421953 | biostudies-literature
Project description:BackgroundThis study examined Sal-like protein (SALL)3 methylation profiles of head and neck cancer (HNSCC) patients at diagnosis and follow-up and evaluated their prognostic significance and value as a biomarker. SALL3 expression was examined in a panel of cell lines by quantitative reverse transcription polymerase chain reaction (RT-PCR). The methylation status of the SALL3 promoter was examined by quantitative methylation-specific PCR.ResultsSALL3 promoter methylation was associated with transcriptional inhibition and was correlated with disease recurrence in 64.8% of cases, with an odds ratio of 1.914 (95% confidence interval: 1.157-3.164; P?=?0.011) by multivariate Cox proportional hazard regression analysis. SALL3 promoter hypermethylation showed highly discriminatory receiver operator characteristic curve profiles that clearly distinguished HNSCC from adjacent normal mucosal tissue, and was correlated with reduced disease-free survival (DFS) (log-rank test, P?=?0.01). Hypermethylation of tumor-related genes was higher among patients with SALL3 methylation than among those without methylation (P?<?0.001). Furthermore, SALL3 hypermethylation was associated with expression of TET1, TET2, and DNMT3A genes.ConclusionsThis study suggests that CpG hypermethylation is a likely mechanism of SALL3 gene inactivation, supporting the hypothesis that the SALL3 gene may play a role in the tumorigenesis of HNSCC and may serve as an important biomarker.
| S-EPMC5469057 | biostudies-literature
Project description:BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1) encodes an enzyme that oxidizes aldehydes to their corresponding carboxylic acids. In colorectal cancer ALDH1A1 marks cancer stem cells and plays putative roles in tumor progression and drug resistance. However, the potential value of ALDH1A1 as a diagnostic marker or target for therapy remains unclear. Here, we have analyzed ALDH1A1 mRNA and protein levels in relation to clinical, histopathological and molecular tumor features in large series of human colorectal cancer.MethodsALDH1A1 protein levels were determined by immunohistochemistry in a series of primary colorectal tumors and their corresponding liver metastases (n = 158). ALDH1A1 mRNA levels were analyzed in several large patient cohorts of colorectal cancer. ALDH1A1 mRNA and protein levels were then related to overall survival and to clinical, histopathological and molecular tumor features.ResultsHigh levels of ALDH1A1 were associated with a poorly differentiated histology and a right-sided tumor location, but not to a mesenchymal-like molecular subtype. Liver metastases contained significantly higher levels of ALDH1A1 compared to the corresponding primary tumors. Radio- and/or chemotherapy prior to tumor resection was associated with increased ALDH1A1 levels regardless of the molecular subtype. Finally, ALDH1A1 protein expression in primary tumors and metastases correlated with shorter overall survival.ConclusionsALDH1A1 expression is associated with features of poor prognosis, including a poorly differentiated histology and 'right-sidedness' of the primary tumor, and with shorter overall survival. ALDH1A1 is also highly expressed in therapy-surviving tumors and in liver metastases. These results warrant further research into the potential value of targeting ALDH1A1 in order to improve the efficacy of standard treatment and thereby preventing tumor recurrence.
| S-EPMC6181398 | biostudies-literature
Project description:To explore epigenetic regulation and the impact of chemokine CXCL14 on colorectal cancer, 7 colorectal cancer cell lines, 107 cases of primary colorectal cancer, and 10 cases of normal colorectal mucosa were evaluated in this study. Methylation specific PCR (MSP), semi-quantitative reverse-transcription PCR (RT-PCR), cell proliferation assay, colony formation, and transwell assay were performed for the evaluation. Complete methylation and loss of CXCL14 expression were found in 5 colorectal cancer cell lines. Partial methylation and weak expression were found in two cell lines. CXCL14 was methylated in 79.4% (85/107) of primary human colorectal cancer. No methylation was found in 10 cases of normal colorectal mucosa. Restoration of CXCL14 expression was induced by the 5-aza-2'-deoxycytidine (DAC) treatment. The cell viability was reduced and colony formation was inhibited by restoration of CXCL14 expression in HCT116 cells, a colorectal cancer cell line. The number of invasive and migration cells was reduced by CXCL14. The expression of MMP-2, Vimentin, and NF-κB was suppressed, and the expression of E-cadherin and IκB-α was induced by CXCL14. In conclusion, CXCL14 is frequently methylated in human colorectal cancer and promoter region hypermethylation silenced CXCL14 expression in colorectal cancer cells. Restoration of CXCL14 expression suppressed colorectal cancer proliferation. CXCL14 inhibits colorectal cancer migration, invasion, and epithelial-to-mesenchymal transition (EMT) by suppressing NF-κB signaling.
| S-EPMC4061567 | biostudies-literature
Project description:Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1? might have the potential to serve as prognostic marker.CK1? RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1? expression levels with patients' survival rate generating Kaplan-Meier survival plots.It could be shown that CK1? is overexpressed in colorectal tumor tissue compared to normal tissue and CK1? overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1? is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side.In summary, this study provides evidence for the first time that CK1? RNA levels might serve as prognostic marker for CRC.
| S-EPMC5801892 | biostudies-other
Project description:BackgroundNeuroligin1 (NLGN1) is a main component of excitatory glutamatergic synapses complex and is important for synapse assembly and function. The clinical value of NLGN1 in colorectal cancer (CRC) is not clear.MethodsWe obtained the expression data of 1143 CRC patients from 3 independent Gene Expression Omnibus (GEO) datasets (GSE32323, GSE24551, GSE39582) and The Cancer Genome Atlas (TCGA) to make the comparison of the NLGN1 expression level between CRC tissues and matched noncancerous tissues, and to evaluate its value in predicting survival of CRC patients. At the protein level, these results were further confirmed by immunohistochemical staining of 52 CRC samples in our own centre. Finally, the function of NLGN1 was explored by gene set enrichment analysis (GSEA).ResultsIncreased mRNA and protein levels of NLGN1 expression were associated with worse overall survival or recurrence-free survival in CRC patients from 2 GEO datasets, the TCGA database, and our cohort. In addition, multivariate regression analysis showed that NLGN1 was an independent poor prognostic factor of survival in patients with CRC in TCGA database (OR = 2.524, P = 0.010). Functional analysis revealed that NLGN1 was correlated with function involving the Hedgehog signaling pathway, mismatch repair process, and some material metabolism processes.ConclusionsThis study is the first to implicate and verify NLGN1 as a new poor prognostic marker for CRC.
| S-EPMC8327451 | biostudies-literature
Project description:The S100 calcium-binding protein A4 (S100A4) induces epithelial mesenchymal transition, migration, invasion, angiogenesis and metastasis. Its induced expression in several cancer types correlates with poor prognosis. Apart from the functional and transcriptional regulatory aspects of S100A4, its post-transcriptional regulation is not yet clearly elucidated. In this study, we show that microRNAs (miR) miR-505-5p and miR-520c-3p target the 3'-UTR of S100A4 and inhibits its expression and its mediated migration and invasion. 5-Aza treatment significantly increased miR-520c-3p expression and reduced the S100A4 protein amounts. The upstream promoter region of miR-520c is hypermethylated irrespective of the metastasis status of colorectal cancer (CRC) patient tissues and in all analyzed CRC cell lines. Moreover, in a cohort of CRC patient specimen (n = 59), miR-520c-3p was significantly downregulated. miR-520c-3p stably expressing HCT116 cells showed a reduced metastasis formation in livers after implanting in mice spleen. Taken together, our findings demonstrate that S100A4 is post-transcriptionally regulated by tumor suppressor miRs, miR-505c-5p and miR-520c-3p, and particularly miR-520c-3p expression is epigenetically silenced in CRC.
| S-EPMC5400567 | biostudies-literature
Project description:Colorectal cancer (CRC) has a high mortality rate among cancers worldwide. To reduce this mortality rate, chemotherapy (5-fluorouracil, oxaliplatin, and irinotecan) or targeted therapy (bevacizumab, cetuximab, and panitumumab) has been used to treat CRC. However, due to various side effects and poor responses to CRC treatment, novel therapeutic targets for drug development are needed. In this study, we identified the overexpression of EHMT1 in CRC using RNA sequencing (RNA-seq) data derived from TCGA, and we observed that knocking down EHMT1 expression suppressed cell growth by inducing cell apoptosis in CRC cell lines. In Gene Ontology (GO) term analysis using RNA-seq data, apoptosis-related terms were enriched after EHMT1 knockdown. Moreover, we identified the CHOP gene as a direct target of EHMT1 using a ChIP (chromatin immunoprecipitation) assay with an anti-histone 3 lysine 9 dimethylation (H3K9me2) antibody. Finally, after cotransfection with siEHMT1 and siCHOP, we again confirmed that CHOP-mediated cell apoptosis was induced by EHMT1 knockdown. Our findings reveal that EHMT1 plays a key role in regulating CRC cell apoptosis, suggesting that EHMT1 may be a therapeutic target for the development of cancer inhibitors.
| S-EPMC9448644 | biostudies-literature
Project description:IntroductionSyntenin is a scaffolding-PDZ domain-containing protein. Although it is reported that syntenin is associated with melanoma growth and metastasis, the possible role of syntenin in breast cancer has not been well elucidated. The present study investigated the expression and function of syntenin in breast cancer.MethodsReal-time polymerase chain reaction (PCR) and Western blots were used to determine the mRNA and protein expression of syntenin. With a combination of overexpression and RNA interference, the effect of syntenin on migration, invasion, and ERK1/2 activation was examined in breast cancer cell lines. The effect of syntenin in vivo was assessed with an orthotropic xenograft tumor model in BALB/c nu/nu mice. In addition, the expression level of syntenin in clinical breast cancer tissues was evaluated with immunohistochemistry. The Kaplan-Meier survival curve was used to evaluate patient survival, and the Cox proportional hazards model was used for multivariate analysis.ResultsOur study showed that syntenin expression was upregulated in high-metastasis breast cancer cell lines and breast cancer tissues. Overexpression of syntenin in breast cancer cells promoted cell migration and invasion in vitro. Moreover, overexpression of syntenin promoted breast tumor growth and lung metastasis in vivo. We further showed that activation of integrin ?1 and ERK1/2 was required for syntenin-mediated migration and invasion of breast cancer cells. The correlation between syntenin expression and tumor size (P = 0.011), lymph node status (P = 0.001), and recurrence (P = 0.002) was statistically significant. More important, syntenin expression in primary tumors was significantly related to patients' overall survival (OS; P = 0.023) and disease-free survival (DFS; P = 0.001). Its status was an independent prognostic factor of OS (P = 0.049) and DFS (P = 0.002) in our cohort of patients.ConclusionsThese results suggest that syntenin plays a significant role in breast cancer progression, and it warrants further investigation as a candidate molecular marker of breast cancer metastasis and a potential therapeutic target.
| S-EPMC4053163 | biostudies-literature
Project description:BACKGROUND: There is a need for markers in colorectal cancer which will allow subclassification of stage groups into subgroups with high versus low risk of recurrent disease. AIMS: To develop monoclonal antibodies that recognise antigens or immature crypt base cells, on the assumption that in a neoplasm undifferentiated but not the terminally differentiated cells will be responsible for tumour progression. METHODS: Colon crypt cells which were isolated from human colonic mucosa by EDTA/EGTA incubation were studied. By stepwise harvesting, crypt base cell enriched fractions were obtained, and after incubation with antibodies against dominant antigens, used as immunogens. RESULTS: Of one crypt base cell specific antibody (5E9), the reactive epitope appeared to be a non-terminal carbohydrate in the mucin O-glycans of the colon. The epitope did not seem to be colon specific, but was expressed in a variety of other tissues. In colorectal carcinomas, 5E9 immunoreactivity identified a subgroup of patients with a tendency for worse prognosis. CONCLUSION: A mucin associated maturation epitope was identified in colonic crypt base cells, the expression of which in Dukes' stage B3 colorectal carcinoma may be associated with poor prognosis.
| S-EPMC1726940 | biostudies-other