CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis.
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ABSTRACT:
SUBMITTER: Wang W
PROVIDER: S-EPMC6990922 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Group A streptococcus (GAS) is an important human pathogen that causes a wide variety of cutaneous and systemic infections. Although originally thought to be an extracellular bacterium, numerous studies have demonstrated that GAS can trigger internalization into nonimmune cells to escape from immune surveillance or antibiotic-mediated killing. Epithelial cells possess a defense mechanism involving autophagy-mediated targeting and killing of GAS within lysosome-fused autophagosomes. In endothelial cells, in contrast, we previously showed that autophagy is not sufficient for GAS killing. In the present study, we showed higher galectin-3 (Gal-3) expression and lower Gal-8 expression in endothelial cells than in epithelial cells. The recruitment of Gal-3 to GAS is higher and the recruitment of Gal-8 to GAS is lower in endothelial cells than in epithelial cells. We further showed that Gal-3 promotes GAS replication and diminishes the recruitment of Gal-8 and ubiquitin, the latter of which is a critical protein for autophagy sequestration. After knockdown of Gal-3 in endothelial cells, the colocalization of Gal-8, parkin, and ubiquitin-decorated GAS is significantly increased, as is the interaction of Gal-8 and parkin, an E3 ligase. Furthermore, inhibition of Gal-8 in epithelial cells attenuates recruitment of parkin; both Gal-8 and parkin contribute to ubiquitin recruitment and GAS elimination. Animal studies confirmed that Gal-3-knockout mice develop less-severe skin damage and that GAS replication can be detected only in the air pouch and not in organs and endothelial cells. These results demonstrate that Gal-3 inhibits ubiquitin recruitment by blocking Gal-8 and parkin recruitment, resulting in GAS replication in endothelial cells.IMPORTANCE In epithelial cells, GAS can be efficiently killed within the lysosome-fused autophaosome compartment. However, we previously showed that, in spite of LC-3 recruitment, the autophagic machinery is not sufficient for GAS killing in endothelial cells. In this report, we provide the first evidence that Gal-3, highly expressed in endothelial cells, blocks the tagging of ubiquitin to GAS by inhibiting recruitment of Gal-8 and parkin, leading to an enhancement of GAS replication. We also provide the first demonstration that Gal-8 can interact with parkin, the critical E3 ligase, for resistance to intracellular bacteria by facilitating the decoration of bacteria with ubiquitin chains. Our findings reveal that differential levels of Gal-3 and Gal-8 expression and recruitment to GAS between epithelial cells and endothelial cells may contribute to the different outcomes of GAS elimination or survival and growth of GAS in these two types of cells.
| S-EPMC5527311 | biostudies-other
Project description:The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity. Here, we examined the functional correlation of HSP72, CHIP, and BAG2, employing human primary fibroblasts. We showed that HSP72 is a substrate of CHIP and that BAG2 efficiently prevented the ubiquitination of HSP72 in young cells as well as aged cells. Aging is associated with a decline in proteostasis and we observed increased protein levels of CHIP as well as BAG2 in senescent cells. Interestingly, the ubiquitination of HSP72 was strongly reduced during aging, which revealed that BAG2 functionally counteracted the increased levels of CHIP. Interestingly, HSPBP1 protein levels were down-regulated during aging. The data presented here demonstrates that the co-chaperone BAG2 influences HSP72 protein levels and is an important modulator of the ubiquitination activity of CHIP in young as well as aged cells.
| S-EPMC5297704 | biostudies-literature
Project description:IntroductionColorectal cancer (CRC) is one of the world's three most common cancers and its incidence is rising. To identify patients who benefit from adjuvant therapy requires novel biomarkers. The regenerating islet-derived gene (REG) 4 belongs to a group of small secretory proteins involved in cell proliferation and regeneration. Its up-regulated expression occurs in inflammatory bowel diseases also in gastrointestinal cancers. Reports on the association of REG4 expression with CRC prognosis have been mixed. Our aim was to investigate tumor REG4 expression in CRC patients and its coexpression with other intestinal markers.MethodsTumor expression of REG4 was evaluated by immunohistochemistry in 840 consecutive surgically treated CRC patients at Helsinki University Central Hospital. Expression of MUC1, MUC2, MUC5AC, synapthophysin, and chromogranin was evaluated in a subgroup of 220 consecutively operated CRC patients. REG4 expression with clinicopathological parameters, other intestinal markers, and the impact of REG4 expression on survival were assessed.ResultsREG4 expression associated with favorable clinicopathological parameters and with higher overall survival from non-mucinous CRC (p = 0.019). For such patients under 65, its expression was an independent marker of lower risk of death within 5 years that cancer; univariable hazard ratio (HR) = 0.57; 95% confidence interval (CI) (0.34-0.94); multivariable HR = 0.55; 95% CI (0.33-0.92). In non-mucinous CRC, REG4 associated with positive MUC2, MUC4, and MUC5AC expression.ConclusionWe show, to our knowledge for the first time, that REG4 IHC expression to be an independent marker of favorable prognosis in non-mucinous CRC. Our results contradict those from studies based on quantification of REG4 mRNA levels, a discrepancy warranting further studies.
| S-EPMC4190354 | biostudies-literature
Project description:PurposeThe epithelial-mesenchymal transition (EMT) is a key hallmark of cancer which promotes malignant progression, especially during the process of cancer invasion. A better understanding of EMT will help elucidate the molecular mechanism underlying colorectal cancer (CRC) metastasis and may provide new insights into the identification of potential biomarkers and therapeutic targets.MethodsA series of bioinformatic approaches were combined and identify GLI3 as a potential key regulator in EMT. In vitro experiments were performed to knockdown GLI3 expression in two CRC cell lines and to reveal the oncogenic role of GLI3 in CRC. qRT-PCR and western blot were performed to show the influence of GLI3 in EMT and downstream pathways. The Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic value of GLI3 in CRC patients.ResultsGLI3 was identified as a key regulator in coexpression and protein-protein interaction (PPI) networks involved in EMT. Bioinformatic analyses indicated that GLI3 had a high correlation with EMT markers in CRC. In vitro experiments showed that GLI3 knockdown attenuated the migratory and invasive capacities of CRC cells via influencing EMT property, especially by regulating phosphorylation of ERK signaling pathway. In addition, higher expression of GLI3 predicts worse prognosis in CRC patients.ConclusionsIn summary, we presented the first evidence that GLI3 could promote the migratory and invasive capacities of CRC cells by regulating the EMT process. Our study might provide some useful clues to a better understanding of GLI3 in EMT during CRC progression.
| S-EPMC7814942 | biostudies-literature
Project description:Bone morphogenetic proteins (BMPs) both promote and suppress tumorigenesis, and multiple BMP antagonists reportedly contribute to cancer progression. In this study, we demonstrated that the BMP antagonist Chordin-like 2 (CHRDL2) is upregulated in colorectal cancer (CRC) tissues, and that CHRDL2 levels correlate with clinical features of CRC patients, including tumor size, TNM staging, and tumor differentiation. In addition, survival rate and Cox proportional hazards model analyses showed that high CHRDL2 levels correlate with a poor prognosis in CRC. Moreover, CHRDL2 promoted CRC cell proliferation in vitro and in vivo, perhaps through up-regulation of Cyclin D1 and down-regulation of P21. Co-immunoprecipitation assays showed that CHRDL2 bound to BMPs, which inhibited p-Smad1/5, thereby promoting CRC cell proliferation and inhibiting apoptosis. These results suggest CHRDL2 could serve as a biomarker of poor prognosis in CRC, and provide evidence that CHRDL2 acts as an oncogene in human CRC, making it a novel potential therapeutic target.
| S-EPMC5355280 | biostudies-literature
Project description:Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation.MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls.High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.
| S-EPMC4919275 | biostudies-literature
Project description:Purpose:Eyes absent homologue 2 (EYA2), which functions as a transcription activator and phosphatase, plays an important role in several types of cancer. However, the impact of EYA2 in colorectal cancer (CRC) remains elusive. Patients and methods:We evaluated the significance of EYA2 expression in the development and progression of CRC in a large cohort, including 922 CRC cases. EYA2 protein expression was determined via immunohistochemistry in colorectal tissues. The correlation between EYA2 expression and CRC occurrence was investigated in tumor tissue and the adjacent normal tissues. Factors contributing to CRC prognosis were evaluated using Kaplan-Meier and Cox model analyses. Results:EYA2 expression was progressively lower in the adjacent normal tissue, adenomas, primary tumor and the metastatic CRC (all P<0.05). Furthermore, EYA2 expression had significant associations with disease stage, differentiation grade, and number of resected lymph nodes (all P<0.001). Compared with patients with EYA2-high tumors, those with EYA2-low tumors had shorter disease-free survival (hazard ratio [HR], 2.347; 95% CI, 1.665-3.308) and disease-specific survival (HR, 3.560; 95% CI, 2.055-6.167) in multivariate Cox analysis, after adjusting confounding factors such as tumor-node-metastasis stage and grade. In particular, patients with stage II or III EYA2-low CRC might be harmed by postoperative chemotherapy. Conclusion:EYA2 expression was generally reduced in CRC. Higher EYA2 expression can predict a more favorable prognosis for CRC.
| S-EPMC6087027 | biostudies-literature
Project description:Colorectal cancer is a heterogeneous disease. Although many risk factors are used to predict colorectal cancer patients' prognosis after surgical resection, new prognostic factors are still needed to be defined to promote predictive efficacy of prognosis and further guide therapies. Herein, we identified the prognostic significance of CXCR2 in colorectal cancer patients. We retrospectively analysed 134 patients with colorectal cancer who underwent minimally invasive surgery between 2010 and 2011. The overall cohort was divided into a training set (n = 78) and a validation set (n = 56). We detected CXCR2 expression using immunohistochemical staining and defined the cut-off value using X-tile program. Next, we analysed the association between CXCR2 expression and clinicopathologic features in training and validation sets. High expression of CXCR2 was associated with Dukes stage (P = 0.018), tumor invasion (P = 0.018) and liver metastasis (P = 0.047). Multivariate COX regression analyses confirmed that high CXCR2 level was an independent prognostic risk factor for both overall survival and disease free survival. Kaplan-Meier survival analysis demonstrated that patients with high expression of CXCR2 had a poor overall survival and disease free survival even in low-risk group (I + II). This indicated that CXCR2 can help to refine individual risk stratification. In addition, we established Nomograms of all significant factors to predict 3- or 5-years overall survival and disease free survival. Moreover, we found the combination of CXCR2 and its ligand CXCL5 had more significant value in predicting the prognosis than single CXCR2 factor.
| S-EPMC5438662 | biostudies-literature
Project description:Transforming growth factor-beta-induced (TGFBI) serves as a linker protein and plays a role in the activation of morphogenesis, cell proliferation, adhesion, migration, differentiation and inflammation. High expression levels of the human TGFBI gene are correlated with numerous human malignancies. In order to explore the roles of TGFBI in the tumor progression of colorectal cancer, colorectal cancer specimens from 115 patients with strict follow-up were selected for the analysis of TGFBI by immunohistochemistry. The correlations between TGFBI expression and the clinicopathological features of colorectal cancers were evaluated. In the colorectal cancer tissues, TGFBI was mainly localized in the cytoplasm and stroma and scarcely in the nucleus. TGFBI expression in the cytoplasm and stroma was not found to be associated with age, gender, tumor histopathological grading, PT category and tumor location (P > 0.05 for each). However, high TGFBI expression in the cytoplasm and stroma correlated with lymph node metastasis, distant metastasis and Dukes stage (P < 0.05 for each). The survival rate was significantly lower in patients with high TGFBI expression than in those with low TGFBI expression. Furthermore, we found that tumor node metastasis (TNM) staging (HR: 2.963; 95% CI: 1.573-1.664; P = 0.000), differentiation (HR: 1.574; 95% CI: 1.001-2.476; P = 0.049) and high TGFBI cytoplasmic expression (HR: 3.332; 95% CI: 1.410-7.873; P = 0.000) proved to be independent prognostic factors for survival in colorectal cancer. In conclusion, TGFBI plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor for colorectal cancer patients.
| S-EPMC4348825 | biostudies-literature
Project description:BackgroundLncRNA MIR4435-2HG is observed in a variety of cancers, while its role in colorectal cancer is unknown. We aimed to demonstrate the relationship between MIR4435-2HG and colorectal cancer based on The Cancer Genome Atlas (TCGA) database.Materials and methodsPatients with colorectal cancer were collected from TCGA. We compared the expression of MIR4435-2HG in colorectal cancer and normal tissues with Wilcoxon rank sum test, and logistic regression was used to evaluate the relationship between MIR4435-2HG and clinicopathological characters. Moreover, Kaplan-Meier and Cox regression was performed to evaluate the correlation between MIR4435-2HG and survival rate. Gene set enrichment analysis (GSEA) was also conducted to annotate biological function of MIR4435-2HG.ResultsMIR4435-2HG level was elevated in colorectal cancer tissues. Increased level of MIR4435-2HG was significantly correlated with TNM stage (OR = 1.66 for T1/T2 vs. T3/T4; OR = 1.68 for N0 vs. N1/N2), stage (OR = 1.66 for stage 1/2 vs. stage 3/4), and carcinoembryonic antigen level before treatment (OR = 1.70 for <5 vs. ≥5) (all P-value <0.05). High MIR4435-2HG expression had a poorer progression-free survival (p = 0.048), and overall survival (OS) (P = 0.028), which were validated in the GSE92921 and GSE29621 datasets. MIR4435-2HG expression (P = 0.040, HR = 1.955 (95% CI [1.031-3.710])) was independently correlated with OS. GSEA demonstrated that the P38/MAPK pathway, the VEGF pathway, the cell adhesion molecules cams, the NOD-like receptor signaling pathway, the cell surface interactions at the vascular wall, and integrin cell surface interactions were differentially enriched in MIR4435-2HG high expression phenotype.ConclusionsIncreased MIR4435-2HG might be a potential biomarker for the diagnosis and prognosis of colorectal cancer. Moreover, MIR4435-2HG might participate in the development of colorectal cancer via the P38/MAPK and VEGF pathway.
| S-EPMC6450379 | biostudies-literature