Song Qingyu, Wang Pengchao, Wu Jingyu, Lu Ming, Xia Qingcheng, Shi Yexin, Wang Zijun, Ma Xiang, Zhao Qinghong
Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Discov Oncol. 2024 Sep 18;15(1):458. doi: 10.1007/s12672-024-01340-2.
Chondroitin polymerizing factor (CHPF) has been found to be involved in the development of numerous cancers and correlated with poor prognosis. However, its role in the tumorigenesis and development of colorectal cancer (CRC) remains unknown.
In our research, we explored CHPF expression and clinicopathological characteristics using The Cancer Genome Atlas Program (TCGA), UALCAN, GSE9348, TIMER2.0 and The Human Protein Atlas (HPA) database, in addition, we validated CHPF expression in CRC cell lines by Real-Time Quantitative PCR (qRT-PCR) and Western blot (WB). KM-Plotter, PrognoScan and TCGA were also utilized to verify its prognosis value in CRC. Small-interfer RNA (Si-RNA) was used to perform Cell Counting Kit-8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridine (EDU), transwell and wound healing assays to testify its function on the tumor progression. Based on TCGA database, we probed potential biological mechanism by which CHPF play its role via clusterProfiler package and GEPIA database and we validated their correlation by WB assay. Moreover, we explored its potential association with the tumor microenvironment (TME), immune infiltrated cells, immune checkpoints, tumor mutation burden (TMB) as well as microsatellite instability (MSI), and investigated immunotherapy sensitivity via Tumor Immune Dysfunction and Exclusion (TIDE) algorithm as well as potentially effective therapeutic drugs via pRRophetic algorithm.
CHPF was identified upregulated in CRC tissues and cells, correlated with poor prognosis, and nodal metastasis status, stage and histological subtype. Down-regulation of CHPF inhibited CRC cell proliferation, migration and its expression correlated with wnt pathway key molecules. In addition, high expression of CHPF was positively correlated with TME scores, Regulatory T cells (Tregs) cell infiltration degree, Programmed death-1 (PD-1), MSI-high (MSI-H), and TIDE scores, however, not with TMB. Targeted drug analysis showed that patients with high CHPF expression were more sensitive to telatinib, recaparib, serdemetan, and trametinib.
CHPF could promote the proliferation and migration of CRC cells and lead to poor prognosis, possibly through wnt pathways as well as changes in TME. Patients with high expression of CHPF had poor efficacy in immunotherapy, which might be related to Tregs cell infiltration. Above all, it might offer more reliable guidance for future immunotherapy.
已发现硫酸软骨素聚合因子（CHPF）参与多种癌症的发生发展，且与预后不良相关。然而，其在结直肠癌（CRC）发生发展中的作用尚不清楚。
在我们的研究中，我们使用癌症基因组图谱计划（TCGA）、UALCAN、GSE9348、TIMER2.0和人类蛋白质图谱（HPA）数据库探索CHPF的表达及临床病理特征，此外，我们通过实时定量聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法（WB）验证CHPF在CRC细胞系中的表达。还利用KM-Plotter、PrognoScan和TCGA验证其在CRC中的预后价值。使用小干扰RNA（Si-RNA）进行细胞计数试剂盒-8（CCK8）、集落形成、5-乙炔基-2'-脱氧尿苷（EDU）、Transwell和伤口愈合实验，以证实其对肿瘤进展的作用。基于TCGA数据库，我们通过clusterProfiler软件包和GEPIA数据库探究CHPF发挥作用的潜在生物学机制，并通过WB实验验证它们的相关性。此外，我们探索了其与肿瘤微环境（TME）、免疫浸润细胞、免疫检查点、肿瘤突变负荷（TMB）以及微卫星不稳定性（MSI）的潜在关联，并通过肿瘤免疫功能障碍和排除（TIDE）算法研究免疫治疗敏感性，通过pRRophetic算法研究潜在有效的治疗药物。
CHPF在CRC组织和细胞中被鉴定为上调，与预后不良、淋巴结转移状态、分期和组织学亚型相关。CHPF的下调抑制了CRC细胞的增殖、迁移，且其表达与Wnt通路关键分子相关。此外，CHPF的高表达与TME评分、调节性T细胞（Tregs）浸润程度、程序性死亡蛋白1（PD-1）、微卫星高度不稳定（MSI-H）和TIDE评分呈正相关，但与TMB无关。靶向药物分析表明，CHPF高表达的患者对替拉替尼、瑞卡帕布、塞尔地米坦和曲美替尼更敏感。
CHPF可能通过Wnt通路以及TME的改变促进CRC细胞的增殖和迁移，并导致预后不良。CHPF高表达的患者免疫治疗效果不佳，这可能与Tregs细胞浸润有关。最重要的是，它可能为未来的免疫治疗提供更可靠的指导。
