鉴定肝细胞癌微环境中 CXC 趋化因子的治疗靶点和预后生物标志物。

Identification of therapeutic targets and prognostic biomarkers among CXC chemokines in hepatocellular carcinoma microenvironment.

机构信息

General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.

Obstetrics and Gynecology Department, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

出版信息

Cancer Biomark. 2023;36(3):231-250. doi: 10.3233/CBM-210300.

DOI:10.3233/CBM-210300

PMID:36938723

Abstract

BACKGROUD

Hepatocellular carcinoma (HCC) is characterized by occult onset, rapid progression and poor prognosis. CXC chemokines play an important role in tumor microenvironment and development.

OBJECTIVE

The potential mechanistic values of CXC chemokines as clinical biomarkers and therapeutic targets in HCC have not been fully clarified.

METHODS

ONCOMINE, UALCAN, GEPIA, cBioPortal, SurvExpress, MethSurv, SurvivalMeth, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this study.

RESULTS

The transcriptional levels of CXCL9/16/17 in HCC tissues were significantly elevated while CXCL1/2/5/6/7/12/14 were significantly reduced. Significant correlation was found between the expression of CXC3/5 and the pathological stage of HCC patients. High level of CXCL4 was associated with a longer disease-free survival. For overall survival, lower expressions of CXCL1/3/5/8 and higher expressions of CXCL2 were associated with a better outcome. In addition, the prognostic values of CXC chemokines signature in HCC were explored in four independent cohorts, the high-risk group displayed unfavorable survival outcome compared with the low-risk group. And for the prognostic value of the DNA methylation of CXC chemokines, we identified the CpGs which were significantly associated with prognosis in HCC patients. DNA methylation signature analysis also showed a statistically significant association between the high- and low-risk groups. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in HCC were performed, the transcription factor targets, kinase targets, and miRNA targets of CXC chemokines were also identified in HCC. We also found significant correlations among CXC chemokines expression and the infiltration of immune cells, the tumor infiltration levels among HCC with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR2/6/8/12, B cell, macrophage and dendritic cell were significantly related to the clinical outcome of HCC patients.

CONCLUSION

CXC chemokines might serve as therapeutic targets and prognostic biomarkers in HCC.

摘要

背景

肝细胞癌（HCC）的特点是隐匿性发病、进展迅速和预后不良。CXC 趋化因子在肿瘤微环境和发展中发挥重要作用。

目的

CXC 趋化因子作为 HCC 的临床生物标志物和治疗靶点的潜在机制价值尚未得到充分阐明。

方法

本研究应用了 ONCOMINE、UALCAN、GEPIA、cBioPortal、SurvExpress、MethSurv、SurvivalMeth、String、GeneMANIA、DAVID、Metascape、TRRUST、LinkedOmics 和 Timer。

结果

HCC 组织中 CXCL9/16/17 的转录水平显著升高，而 CXCL1/2/5/6/7/12/14 的表达显著降低。CXC3/5 的表达与 HCC 患者的病理分期之间存在显著相关性。高水平的 CXCL4 与无病生存期延长相关。对于总生存期，CXCL1/3/5/8 的表达较低和 CXCL2 的表达较高与较好的预后相关。此外，在四个独立队列中探讨了 CXC 趋化因子特征在 HCC 中的预后价值，与低危组相比，高危组的生存结局较差。并且对于 CXC 趋化因子 DNA 甲基化的预后价值，我们确定了与 HCC 患者预后显著相关的 CpG。DNA 甲基化特征分析也显示高危组和低危组之间存在统计学显著关联。对于潜在机制，对 HCC 中 CC 趋化因子受体的邻近基因网络、相互作用分析、功能富集分析进行了研究，还鉴定了 CXC 趋化因子的转录因子靶点、激酶靶点和 miRNA 靶点。我们还发现 CXC 趋化因子表达与免疫细胞浸润之间存在显著相关性，评估了这些趋化因子受体在 HCC 中不同体细胞拷贝数改变的肿瘤浸润水平。此外，Cox 比例风险模型显示 CCR2/6/8/12、B 细胞、巨噬细胞和树突状细胞与 HCC 患者的临床结局显著相关。