Huang Jiacheng, Chen Zhitao, Ding Chenchen, Lin Shengzhang, Wan Dalong, Ren Kuiwu
Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.
School of Medicine, Zhejiang University, Hangzhou, China.
Front Oncol. 2021 Aug 23;11:711402. doi: 10.3389/fonc.2021.711402. eCollection 2021.
Pancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified.
Bioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer.
Except for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times.
These findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.
胰腺癌是全球肿瘤相关死亡的主要原因之一。CXC趋化因子是功能性趋化肽的一个亚家族，在几种人类恶性肿瘤中影响肿瘤细胞的起始和临床结局。然而，CXC趋化因子在胰腺癌中的具体生物学功能和临床意义尚未阐明。
利用生物信息学分析工具和数据库，包括ONCOMINE、GEPIA2、人类蛋白质图谱、DAVID、GeneMANIA、cBioPortal、STRING、DGidb、MethSurv、TRRUST、SurvExpress、SurvivalMeth和TIMER，以阐明CXC趋化因子在胰腺癌中的临床意义和生物学功能。
除CXCL11/12外，PAAD组织中其他CXC趋化因子的转录水平显著升高，其中CXCL16的表达水平最高。我们的研究结果还表明，所有CXC趋化因子都与涉及免疫细胞浸润丰度的肿瘤免疫功能障碍有关，Cox比例风险模型证实树突状细胞和CXCL3/5/7/8/11/17与PAAD患者的临床结局显著相关。此外，CXCL5/9/10/11/17表达增加与不良总生存期（OS）相关，仅CXCL17是PAAD患者无病生存期（DFS）的预后因素。CXC趋化因子的表达模式和预后能力在独立的GSE62452数据集中得到进一步验证。对于PAAD患者中CXC趋化因子DNA甲基化单个CpG的预后价值，我们鉴定出CXCL1的3个CpG、CXCL2的2个CpG、CXCL3的2个CpG、CXCL4的3个CpG、CXCL5的10个CpG、CXCL6的1个CpG、CXCL7的1个CpG、CXCL12的3个CpG、CXCL14的3个CpG和CXCL17的5个CpG与PAAD患者的预后显著相关。此外，在两个独立队列中探索并测试了PAAD中CXC趋化因子特征的预后价值，结果表明低风险组患者的OS优于高风险组。CXC趋化因子特征DNA甲基化的生存分析表明，高风险组的PAAD患者生存期更长。
这些发现揭示了CXC趋化因子在胰腺癌中的表达及其生物学功能的新见解，这可能成为胰腺癌患者准确的预后生物标志物和合适的免疫治疗靶点。
