Overexpression of the X-linked ribosomal protein S4 predicts poor prognosis in patients with intrahepatic cholangiocarcinoma.
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ABSTRACT:
SUBMITTER: Kuang J
PROVIDER: S-EPMC5494819 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:FoxM1 is an oncoprotein that is significantly overexpressed in many malignancies including hepatocellular carcinoma, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. This study explores the expression of FoxM1 in human ICC, its relationships with clinical outcomes, and its role in the proliferation, migration, and invasion of ICC in vitro and in vivo. The results show that FoxM1 was markedly elevated in tumor tissues versus the paired peritumoral tissues. Overexpression of FoxM1 was correlated with multiple tumor nodules, tumor size > 5 cm, positive lymph node metastasis and advanced TNM stage. Cox analysis revealed that overexpression of FoxM1 is an independent prognostic indicator for both the overall survival and disease-free survival of ICC patients after hepatectomy. Furthermore, up/downregulation of FoxM1 markedly promoted/inhibited ICC cell proliferation, migration, and invasion in vitro and in vivo. Bioinformatic analysis indicated that overexpression of FoxM1 resulted in the dysregulation of multiple signaling pathways in ICC, and selected components of some key signaling pathways such as c-Myc signaling were confirmed in vitro. In addition, overexpression of FoxM1 enhanced MMP-9 and MMP-2 protein expression in ICC cells. In conclusion, FoxM1 promotes ICC progression and is a reliable predictor of poor prognosis in ICC.
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Project description:Background With the feature of destructive and biliary malignancy, intrahepatic cholangiocarcinoma (ICC), presents unclear molecular mechanisms which contributes to typically poor prognosis for patients. Seizure-related 6 homolog-like 2 (SEZ6L2) is a gene that encodes for a seizure-associated protein localized on the cell surface. Thus far, the function of SEZ6L2 in ICC has not been reported. Methods We used data from The Cancer Genome Atlas and the Gene Expression Omnibus to analyze dynamics behind and levels of expression of SEZ6L2 in ICC. Then we used qRT-PCR and Immunohistochemical staining to detect levels of expression of SEZ6L2 and thereby determined the potential clinical significance of this protein in ICC. Results According to qRT-PCR and immunohistochemical analysis results, SEZ6L2 was overexpressed in ICC. Kaplan-Meier and Cox proportional hazard analyses indicated that patients afflicted by ICC with high levels of relative expression of SEZ6L2 have a poorer prognosis and that SEZ6L2 may be an independent prognostic factor which enables to the accurate prediction of overall survival (OS) and disease-free survivals’ (DFS) expected rates. Subcutaneous xenograft models used to explore the role of SEZ6L2 in tumor formation in vivo. The dynamics of the SEZ6L2 gene being promote angiogenesis in cholangiocarcinoma are related to increasing expressive growth factors which include EGF, VEGF, PDGF and the activation of the P38-MAPK pathway. Conclusions Our findings suggest that SEZ6L2 can serve as an advanced biomarker that can be used to accurately predict a patient prognosis and be used as a target for ICC treatment.
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Project description:Background: Despite recent improvements in the diagnosis and therapy of intrahepatic cholangiocarcinoma (ICC), the prognosis for ICC patients remains poor. Therefore, it is needed to identify new biological indicators for ICC progression. Methods: Immunohistochemistry was engaged to inspect the ecto-5'-nucleotidase (CD73) and CD8 expressions in tissue microarrays including tissues from 140 ICC patients. Then, the association between the level of CD73/CD8 and clinicopathologic characteristics of ICC was analysed. Finally, the prognostic value of CD73 and CD8 levels in ICC patients was assessed by Kaplan-Meier and multivariate and univariate analyses. Results: The CD73 expression was evidently upregulated in ICC tissues compared to the corresponding peritumoral tissues. The elevated CD73 expression was positively related to the lymphatic metastasis (p=0.049). While the level of tumour-infiltrating CD8 T+ cells in tumour tissues was negatively associated with serum AFP (p=0.019), tumor size (p=0.028), and lymphatic metastasis (p=0.039). Additionally, patients with elevated CD73 expression or low tumour-infiltrating CD8+ T cells exhibited shorter overall survival (OS) and higher disease-free survival (DFS) rates than patients with low CD73 expression and/or high tumour-infiltrating CD8+ T cells. Notably, the overexpression of CD73 or low tumour-infiltrating CD8+ T cells was an independent indicator for predicting the OS and DFS of ICC patients. Conclusions: We revealed that CD73 expression and low tumour-infiltrating CD8+T cells are valuable predictors of survival and recurrence in patients with ICC.
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Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant neoplasm arising from the intrahepatic bile ducts. As a scaffold protein of lipid rafts, flotillin-2 is upregulated in several types of cancer and promotes tumor progression and metastasis. To the best of our knowledge, the present study was the first to detect the upregulation of flotillin-2 in iCCA tissues compared with matched adjacent non-tumor tissues. In addition, immunohistochemistry was used to investigate the expression of flotillin-2 in a microarray consisting of 92 iCCA tissues. A total of 59 samples (64.1%) exhibited high flotillin-2 expression, which was significantly related to lymph node metastasis (P=0.029) and tumor-node-metastasis stage (P=0.016). Further in vitro study demonstrated that knockdown of flotillin-2 inhibited the invasive capability of iCCA cell lines, further supporting the participation of flotillin-2 in cancer invasion and metastasis. Moreover, Kaplan-Meier analysis showed patients with high flotillin-2 expression had worse overall survival outcomes. The multivariate Cox proportional hazards model further revealed that high flotillin-2 expression was an independent indicator (P=0.005) of poor prognosis for patients with iCCA. Collectively, the present study revealed that as a promoter of invasion and an independent marker of poor prognosis, flotillin-2 may serve as a potential target for the development of novel therapeutic agents for iCCA.
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Project description:WW domain-containing E3 ubiquitin protein ligase1 (WWP1) is reported to be upregulated in many types of human cancers; however, its expression and function in intrahepatic cholangiocarcinoma (ICC) remain unknown. Here, in this study we investigated the expression pattern, clinical prognosis, tumor biological functions, and molecular mechanisms of WWP1 in ICC. The expression of WWP1 in patient tissues was detected by western blotting, immunohistochemistry (IHC), and immunofluorescence. CCK-8, colony formation, EdU, transwell, and xenograft models were used to explore the role of WWP1 in the proliferation and metastasis of ICC. Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, and immunofluorescence were performed to detect the potential mechanisms. Our study revealed that WWP1 was highly expressed in ICC, and high levels of WWP1 were associated with poor prognosis. Functionally, WWP1 overexpression enhanced the proliferation and metastasis of ICC cells and vice versa. Mechanistically, MYC could be enriched in the promoter region of WWP1 to facilitate its expression. Then, WWP1 targets Nedd4 family interacting protein1 (NDFIP1) and reduces NDFIP1 protein levels via ubiquitination. Downregulation of NDFIP1 in ICC cells rescued the effects of silenced WWP1 expression. WWP1 expression was also negatively correlated with the protein level of NDFIP1 in patient tissues. In conclusion, WWP1 upregulated by MYC promotes the progression of ICC via ubiquitination of NDFIP1, which reveals that WWP1 might be a potential therapeutic target for ICC.
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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.
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Project description:Background & aimsIntrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide with an increasing incidence and limited therapeutic options. Therefore, there is an urgent need to open the field to new concepts for identifying clinically relevant therapeutic targets and biomarkers. Here, we explored the role and the clinical relevance of circular RNA (circRNA) circLTBP2 in iCCA.MethodsTransforming growth factor β (TGFβ)-regulated circRNAs were identified by dedicated microarrays in human HuCC-T1 iCCA cell line, and their clinical relevance was evaluated in independent cohorts of patients. Gain and loss of function of circLTBP2 combined with functional tests was performed in vitro and in vivo in mice. RNA pulldown, microRNA sequencing, and RNA immunoprecipitation were performed to explore the sponging activity of circLTBP2.ResultsCircLTBP2 (has_circ_0032603) was identified as a novel TGFβ-induced circRNA in several cholangiocarcinoma cell lines. CircLTBP2 promotes tumour cell proliferation, migration, and resistance to gemcitabine-induced apoptosis in vitro and tumour growth in vivo. Mechanistically, circLTBP2 acts as a competitive RNA regulating notably the activity of the tumour suppressor microRNA miR-338-3p, leading to the overexpression of its pro-metastatic targets. The restoration of miR-338-3p levels in iCCA cells reversed the pro-tumourigenic effects driven by circLTBP2, including the resistance to gemcitabine-induced apoptosis. In addition, circLTBP2 expression predicted a reduced survival, as detected in not only tumour tissues but also serum extracellular vesicles isolated from patients with iCCA.ConclusionsCircLTBP2 is a novel effector of the pro-tumourigenic arm of TGFβ and a clinically relevant biomarker easily detected from liquid biopsies in iCCA.Impact and implicationsIntrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with limited therapeutic options. Opening the field to new concepts is urgently needed to improve the survival of patients. Here, we evaluated the role and the clinical relevance of circular RNA. We report that TGFβ-induced circLTBP2 contributes to CCA carcinogenesis and may constitute a clinically relevant prognostic biomarker detected in liquid biopsies.
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