Dataset Information

LAD1 expression is associated with the metastatic potential of colorectal cancer cells.

ABSTRACT: Background: Anchoring filament protein ladinin-1 (LAD1) was related to the aggressive progression of breast, lung, laryngeal and thyroid cancers. However, the association of LAD1 with colorectal cancer remained unknown. Here, to determine the relationship of LAD1 with colorectal cancer progression, we explored the effect of LAD1 loss on the malignant features of colorectal cancer cells.

Methods: We constructed LAD1-depleted cell lines and examined the effect of LAD1 deficiency on the phenotypic and molecular features of colorectal cancer cells in vitro. The function of LAD1 in metastasis in vivo was examined by establishing a spleen-to-liver metastasis mouse model. LAD1 protein expression in colorectal cancer patient specimens was assessed by immunohistochemistry of tumor microarrays.

Results: We found that LAD1 was abundant in most colorectal cancer cells. In addition, high expression of LAD1 significantly correlated with poor patient outcome. LAD1 depletion inhibited the migration and invasion of two different colorectal cancer cell lines, SW620 and Caco-2, without affecting their proliferation. In addition, LAD1 loss led to defects in liver metastasis of SW620 cells in the mouse model. Immunohistochemistry of colorectal cancer tissues revealed LAD1 enrichment in metastatic tissues compared to that in primary tumor and normal tissues.

Conclusion: These results suggest that LAD1 expression is associated with the metastatic progression of colorectal cancer by promoting the migration and invasion of cancer cells.

SUBMITTER: Moon B

PROVIDER: S-EPMC7709356 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LAD1 expression is associated with the metastatic potential of colorectal cancer cells.

Moon Byul B Yang Suk-Jin SJ Park Seong Min SM Lee Sang-Hyun SH Song Kyu Sang KS Jeong Eun-Jeong EJ Park Mijin M Kim Jang-Seong JS Yeom Young Il YI Kim Jung-Ae JA

BMC cancer 20201202 1

<h4>Background</h4>Anchoring filament protein ladinin-1 (LAD1) was related to the aggressive progression of breast, lung, laryngeal and thyroid cancers. However, the association of LAD1 with colorectal cancer remained unknown. Here, to determine the relationship of LAD1 with colorectal cancer progression, we explored the effect of LAD1 loss on the malignant features of colorectal cancer cells.<h4>Methods</h4>We constructed LAD1-depleted cell lines and examined the effect of LAD1 deficiency on th ...[more]

PMID: 33267790

Similar Datasets

Project description:BackgroundMicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis.ResultsThe expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context.ConclusionMiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in CRC provide a basis for understanding the functional role of miRNAs in cancer.

Project description:To investigate the function of Pea3 in colorectal carcinoma (CRC) invasion and metastatic potential.The expression of Pea3 during clinical progression of human CRC was investigated using Oncomine Research Edition. To assay Pea3 expression in established CRC cell lines, we performed western blotting of cell lysates. We employed shRNA-mediated knockdown of Pea3 in HCT116 (HCT) and LS174T CRC cells which was confirmed by real-time quantitative PCR (qPCR) and western blotting. Transwell invasion assays, MTS proliferation assays, anoikis assays, and fluorometric matrix metalloprotease (MMP) assays were performed to determine the effects of Pea3 knockdown on invasion, proliferation, anoikis and MMP activity in CRC cells in vitro. Alterations in epithelial-mesenchymal transition (EMT) and matrix metalloprotease (MMP) mRNA levels were determined by qPCR. CRC cells were injected into the flanks of nude mice to generate xenografts and tumor growth monitored with serial calliper measurements. To assay metastatic potential, CRC cells were injected into the spleen of nude mice, and histological analysis performed on the livers 21 d later.We demonstrated that reduction of Pea3 expression in CRC cells significantly impaired their invasive capacity (HCT.shPea3, 0.28 ± 0.04 fold, P < 0.01; LS.shPea3, 0.15 ± 0.04 fold; SW.shPea3, 0.23 ± 0.03, P < 0.01), reduced anoikis resistance (HCT.shPea3 75.4% ± 1.9% viable cells vs HCT.shCtrl 88.6% ± 0.6% viable cells, P < 0.01; LS.shPea3 71.7% ± 0.5% viable cells vs LS.Ctrl 89.6% ± 0.3% viable cells, P < 0.005, but had no effect on proliferation (HCT.shCtrl AUC 5098 ± 123 vs HCT.shPea3 5689 ± 151, P < 0.05; LS.shCtrl AUC 5600 ± 324.1 vs LS.shPea3 6423 ± 400, P < 0.05). In vivo, HCT.shPea3 and HCT.shCtrl tumour xenografts grew at a similar rate (HCT.shPea3 2.64 ± 0.82 fold vs HCT.shCtrl 2.88 ± 0.80 fold, P > 0.05). In keeping with a pro-metastatic function for Pea3 in CRC, several EMT markers and MMPs were downregulated in shPea3-expressing cells, suggesting that Pea3 may exert its effects through these processes. A reduction in overall MMP activity was observed in HCT.shPea3 cells compared to their control counterparts (HCT.shPea3 0.61 ± 0.04 fold, P < 0.005). This translated in vivo to the complete absence of metastases in the livers of mice that were grafted with CRC cells lacking Pea3. Conversely, CRC cells expressing Pea3 formed liver metastases in all mice.Our study implicates Pea3 as a mediator of metastases, and provides a biological rationale for the adverse prognosis associated with elevated Pea3 expression in human CRC.

Project description:Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA).Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status.TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016).TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.

Project description:BackgroundFucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-ß-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC.MethodsIn this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided.ResultsWe found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT,P= .003; F50 vs SN38,P= .02, F50 vs F0,P= .04), as well as prolonging survival of mouse xenograft models (log-rank test,P< .001).ConclusionsThus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

Project description:Background and aimsAccumulated evidence indicates that the intestinal microbiota plays crucial roles in the initiation and progression of colorectal cancer (CRC). However, the effects of the tissue-associated microbiota on CRC metastasis are poorly defined. The aim of this study was to explore the differences in bacteria between metastatic and non-metastatic CRC tissues and identify potential bacterial species that associate with CRC metastasis.Methods16S rDNA amplicon high-throughput sequencing was used to test the intestinal tissue-associated microbiota in patients with metastatic CRC (n = 48) and non-metastatic CRC (n = 44). The microbial diversity and differential species were analysed by standard microbiological methods, and then the differential bacteria were confirmed by qPCR. Receiver operating characteristic (ROC) curves were plotted to evaluate the ability of the differential bacteria in predicting the metastasis of CRC. In addition, the microbial compositions of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were analysed.ResultsThe α- or β-diversity of microbial community between the metastatic and non-metastatic CRC groups did not exhibit significant differences. However, some bacterial abundances between two groups showed significant differences. At the phylum level, Bacteroidota and Desulfobacterota were significantly higher in the metastatic group than in the non-metastatic group, while Proteobacteria was significantly decreased in the metastatic group. At the genus level, Bacteroides (mainly composed of Bacteroides fragilis and Bacteroides uniformis) was significantly higher in the metastatic group than in the non-metastatic group, while Streptococcus and Escherichia-Shigella were significantly decreased. The ROC curves of the selected bacteria showed area under the curve (AUC) values ranging from 0.598 to 0.69; when CEA and the selected bacteria were combined, the AUC values increased from 0.678 to 0.705. In addition, the bacterial composition of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were also different, and the differential bacteria were consistent with those between metastatic and non-metastatic CRC tumor tissues.ConclusionThe bacterial composition of tumor and tumor adjacent tissue from the metastatic CRC group was different from that of the non-metastatic CRC group; in particular, Bacteroides was increased, and Streptococcus was decreased. These findings are helpful to further reveal the mechanism of CRC metastasis and provide new ideas for the clinical diagnosis and treatment of CRC metastasis.

Dataset Information

LAD1 expression is associated with the metastatic potential of colorectal cancer cells.

Publications

LAD1 expression is associated with the metastatic potential of colorectal cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets