Liu Qi, Jiang Jianwu, Zhang Xiefu, Zhang Meixiang, Fu Yang
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Oncol. 2021 Oct 21;11:723131. doi: 10.3389/fonc.2021.723131. eCollection 2021.
Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. Insulin-like growth-factor-binding proteins (IGFBPs) were initially identified as passive inhibitors that combined with insulin-like growth factors (IGFs) in serum. However, more recent data have shown that they have different expression patterns and a variety of functions in the development and occurrence of cancers. Thus, their various roles in cancer still need to be elucidated. This study aimed to explore the IGFBPs and their prognostic value as markers in gastric cancer.
Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, cBioPortal, GeneMANIA, and TIMER were used to analyze the differential expression, prognostic value, genetic alteration, and association with immune cell infiltration of IGFPBs in gastric cancer.
Expression levels of IGFBP3, IGFBP4, and IGFBP7 were significantly elevated in gastric cancer tissues, whereas those of IGFBP1 were reduced in normal tissues. IGFBP1/5/7 expression was significantly associated with overall survival whereas IGFBP6/7 expression was significantly correlated with disease-free survival in gastric cancer patients. IGFBP3/5/6/7 were associated with clinical cancer stage. Gene ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that IGFBP3/5/7 were mainly enriched in focal adhesion, extracellular matrix structural constituent, cell-substratist junction, extracellular structure, and matrix organization. Stomach adenocarcinoma (STAD) and gastric cancer had more IGFBP1-7 mutations than other tumor types. Hub gene analysis showed that TP53 and IGF2 expression was significantly elevated in STAD patients; PLG, PAPPA, AFP, and CYR61 were associated with overall survival rate; and IGFALS, PLG, IGF1, AHSG, and FN1 were associated with disease-free survival. Finally, IGFBP3-7 were all associated with cancer-associated fibroblast infiltration in STAD, colon adenocarcinoma, and rectal adenocarcinoma.
Our study provides a comprehensive analysis and selection of IGFBPs as prognostic biomarkers in STAD. This was the first bioinformatic analysis study to describe the involvement of IGFBPs, especially IGFBP7, in gastric cancer development through the extracellular matrix.
胃癌是全球第五大常见癌症，也是癌症相关死亡的第三大主要原因。胰岛素样生长因子结合蛋白（IGFBPs）最初被鉴定为血清中与胰岛素样生长因子（IGFs）结合的被动抑制剂。然而，最近的数据表明它们在癌症的发生发展中具有不同的表达模式和多种功能。因此，它们在癌症中的各种作用仍有待阐明。本研究旨在探讨IGFBPs及其作为胃癌标志物的预后价值。
利用Oncomine、基因表达谱交互式分析（GEPIA）、Kaplan-Meier Plotter、cBioPortal、GeneMANIA和TIMER分析IGFPBs在胃癌中的差异表达、预后价值、基因改变以及与免疫细胞浸润的相关性。
IGFBP3、IGFBP4和IGFBP7在胃癌组织中的表达水平显著升高，而IGFBP1在正常组织中的表达降低。IGFBP1/5/7的表达与总生存期显著相关，而IGFBP6/7的表达与胃癌患者的无病生存期显著相关。IGFBP3/5/6/7与临床癌症分期相关。基因本体论和京都基因与基因组百科全书分析表明IGFBP3/5/7主要富集于粘着斑、细胞外基质结构成分、细胞-基质连接、细胞外结构和基质组织。胃腺癌（STAD）和胃癌比其他肿瘤类型有更多的IGFBP1-7突变。枢纽基因分析表明，STAD患者中TP53和IGF2的表达显著升高；PLG、PAPPA、AFP和CYR61与总生存率相关；IGFALS、PLG、IGF1、AHSG和FN1与无病生存期相关。最后，IGFBP3-7均与STAD、结肠腺癌和直肠腺癌中的癌症相关成纤维细胞浸润有关。
我们的研究对IGFBPs作为STAD预后生物标志物进行了全面分析和筛选。这是第一项通过生物信息学分析研究描述IGFBPs，尤其是IGFBP7通过细胞外基质参与胃癌发生发展的研究。
