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CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

ABSTRACT: CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P?=?0.015 for overall survival [OS], P?=?0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P?=?0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P?=?0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR]?=?2.066, 95% confidence interval [CI]?=?1.296-3.292, P?=?0.002) and RFS (HR?=?1.844, 95% CI?=?1.218-2.793, P?=?0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies.

SUBMITTER: Li L

PROVIDER: S-EPMC4193880 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

Li Li L Yan Jing J Xu Jing J Liu Chao-Qun CQ Zhen Zuo-Jun ZJ Chen Huan-Wei HW Ji Yong Y Wu Zhi-Peng ZP Hu Jian-Yuan JY Zheng Limin L Lau Wan Yee WY

PloS one 20141010 10

CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T ...[more]

PMID: 25303284

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Project description:IntroductionHepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Identifying specific molecular markers that can predict HCC prognosis is extremely important. The protein deoxythymidylate kinase (DTYMK) has been reported to contribute to unfavorable prognosis in non-small cell lung cancer patients, but its role in the prediction of HCC patient prognosis has not been clarified.MethodsSamples from the TCGA and GEO databases were consecutively enrolled for gene expression analysis, clinicopathology analysis, immune microenvironment analysis and chemotherapeutic response prediction. The results were validated using 86 samples from the First Affiliated Hospital of Sun Yat-sen University. Cox regression analysis was used to analyze the effect of DTYMK on progression-free survival (PFS) and overall survival (OS). Functional enrichment analysis was used to describe the marker pathways that were significantly related to DTYMK. TIMER (Tumor Immune Estimation Resource), TISIDB (Tumor and Immune System Interaction DataBase) and CIBERSORT (Cell type Identification By Estimating Relative Subsets Of RNA Transcripts) were used to explore the immune microenvironment.ResultsWe found that DTYMK expression upregulation is associated with poor prognosis in HCC patients and tightly related to the pathways regulating the cell cycle and acid metabolism. Our findings revealed that hepatocellular carcinoma cell lines with high DTYMK expression were more sensitive to sorafenib and many other chemotherapeutic drugs. We also found an inhibiting effect of DTYMK on the immune microenvironment in the process of tumorigenesis.DiscussionWe found that DTYMK has potential as a new prognostic and chemotherapeutic response biomarker for HCC patients and correlates with the immune microenvironment in HCC. However, there are some deficiencies in our study. First, this is a retrospective study that may lead to selection bias. Second, the protein expression of DTYMK was investigated via immunohistochemical analysis. Finally, we did not explore the exact underlying molecular mechanisms of DTYMK in tumorigenesis in this study, which is needed to be clarified in future research.

Project description:BackgroundIGF2BP3 expression is associated with poor prognosis in cancers of multiple tissue origins. However, the precise mechanism of its co-carcinogenic action in bladder cancer is unknown.MethodsWe aimed to demonstrate the relationship between IGF2BP3 expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. We next validated IGF2BP3 expression in the Gene Expression Omnibus (GEO) database (GSE3167). Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic values of IGF2BP3. Cox and logistic regression were used to explore the factors affecting the prognosis. Protein-protein interactions (PPIs) network was constructed by STRING. Enrichment analyses were performed to infer involved pathways and functional categories of IGF2BP3 using the cluster Profiler package. We applied single-sample gene set enrichment analysis (ssGSEA) algorithm and TIMER database to evaluate the expression level of immune genes.ResultsPan-cancer analyses reveal that IGF2BP3 was higher in most cancer types, including bladder cancer, and the same results were found in GSE3167. The area under the ROC curve of IGF2BP3 was 0.736, which indicated that IGF2BP3 may be a potential diagnostic biomarker. High IGF2BP3 expression was associated with poorer overall survival (OS) (P = 0.015). For validation, we collected 95 bladder cancer samples and found that IGF2BP3 expression was higher in bladder cancer tissues than that in non-tumor bladder tissues by immunohistochemistry staining. We found a positive correlation between the expression level of IGF2BP3 and the clinical stage of bladder cancer. Immunocyte infiltration analysis showed that high IGF2BP3 expression was correlated with regulating the infiltration level of immune cell, including neutrophil cells and macrophages. IGF2BP3 promotes migration and invasion of bladder cancer cells, while IGF2BP3 inhibition had the opposite effects. Higher IGF2BP3 expression was closely associated with advanced TNM stage.ConclusionIGF2BP3 overexpression was related to disease progression and poor prognosis, as well as infiltration of immune cells in bladder cancer. IGF2BP3 can be a promising independent prognostic biomarker and potential treatment target for bladder cancer.

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Project description:BackgroundGlucosamine 6-phosphate N-acetyltransferase (GNPNAT1) is a key enzyme in the hexosamine biosynthetic pathway (HBP), which functions as promoting proliferation in some tumors, yet its potential biological function and mechanism in lung adenocarcinoma (LUAD) have not been explored.MethodsThe mRNA differential expression of GNPNAT1 in LUAD and normal tissues was analyzed using the Cancer Genome Atlas (TCGA) database and validated by real-time PCR. The clinical value of GNPNAT1 in LUAD was investigated based on the data from the TCGA database. Then, immunohistochemistry (IHC) of GNPNAT1 was applied to verify the expression and clinical significance in LUAD from the protein level. The relationship between GNPNAT1 and epigenetics was explored using the cBioPortal database, and the miRNAs regulating GNPNAT1 were found using the miRNA database. The association between GNPNAT1 expression and tumor-infiltrating immune cells in LUAD was observed through the Tumor IMmune Estimation Resource (TIMER). Finally, Gene set enrichment analysis (GSEA) was used to explore the biological signaling pathways involved in GNPNAT1 in LUAD.ResultsGNPNAT1 was upregulated in LUAD compared with normal tissues, which was verified through qRT-PCR in different cell lines (P < 0.05), and associated with patients' clinical stage, tumor size, and lymphatic metastasis status (all P < 0.01). Kaplan-Meier (KM) analysis suggested that patients with upregulated GNPNAT1 had a relatively poor prognosis (P < 0.0001). Furthermore, multivariate Cox regression analysis indicated that GNPNAT1 was an independent prognostic factor for LUAD (OS, TCGA dataset: HR = 1.028, 95% CI: 1.013-1.044, P < 0.001; OS, validation set: HR = 1.313, 95% CI: 1.130-1.526, P < 0.001). GNPNAT1 overexpression was correlated with DNA copy amplification (P < 0.0001), low DNA methylation (R = -0.52, P < 0.0001), and downregulation of hsa-miR-30d-3p (R = -0.17, P < 0.001). GNPNAT1 expression was linked to B cells (R = -0.304, P < 0.0001), CD4+T cells (R = -0.218, P < 0.0001), and dendritic cells (R = -0.137, P = 0.002). Eventually, GSEA showed that the signaling pathways of the cell cycle, ubiquitin-mediated proteolysis, mismatch repair and p53 were enriched in the GNPNAT1 overexpression group.ConclusionGNPNAT1 may be a potential prognostic biomarker and novel target for intervention in LUAD.

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CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

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CXCL17 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

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