Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China.
World J Gastroenterol. 2022 May 7;28(17):1781-1797. doi: 10.3748/wjg.v28.i17.1781.
Colorectal cancer (CRC) is an extremely malignant tumor with a high mortality rate. Little is known about the mechanism by which forkhead Box q1 (FOXQ1) causes CRC invasion and metastasis through the epidermal growth factor receptor (EGFR) pathway.
To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor (HB-EGF)/EGFR pathway.
We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis (GEPIA) website (http://gepia.cancer-pku.cn/index.html). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues, and we constructed a stable low-expressing FOXQ1 cell line and verified it with the above method. The expression changes of membrane-bound HB-EGF (proHB-EGF) and soluble HB-EGF (sHB-EGF) in the low-expressing FOXQ1 cell line were detected by flow cytometry and ELISA. Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells. Proliferation experiments, transwell migration experiments, and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF, and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.
GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate. PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways. Knockdown of FOXQ1 suppressed the expression of HB-EGF, and led to a decrease in EGFR and its downstream genes , , expression levels. After knockdown of FOXQ1 in CRC cell lines, cell proliferation, migration and invasion were attenuated. Adding HB-EGF restored the migration and invasion ability of CRC, but not the cell proliferation ability. Kaplan-Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.
Based on these collective data, we propose that FOXQ1 promotes the invasion and metastasis of CRC the HB-EGF/EGFR pathway.
结直肠癌（CRC）是一种恶性程度极高的肿瘤，死亡率很高。目前尚不清楚叉头框蛋白 Q1（FOXQ1）如何通过表皮生长因子受体（EGFR）途径导致 CRC 的侵袭和转移。
阐明 FOXQ1 通过激活肝素结合表皮生长因子（HB-EGF）/EGFR 途径促进 CRC 侵袭和转移的机制。
我们使用基因表达谱分析交互分析（GEPIA）网站（http://gepia.cancer-pku.cn/index.html）研究了 FOXQ1 和 HB-EGF 在 CRC 中的差异表达和预后。使用定量实时聚合酶链反应（qRT-PCR）和 Western blot 检测细胞系和组织中 FOXQ1 和 HB-EGF 的表达，并构建了稳定的低表达 FOXQ1 细胞系，并通过上述方法进行了验证。通过流式细胞术和 ELISA 检测低表达 FOXQ1 细胞系中膜结合 HB-EGF（proHB-EGF）和可溶性 HB-EGF（sHB-EGF）的表达变化。当向 FOXQ1 敲低细胞中添加外源性重组人 HB-EGF 时，Western blot 检测 HB-EGF 和 EGFR 信号通路相关下游基因的表达水平变化。进行增殖实验、Transwell 迁移实验和划痕实验，以确定 FOXQ1 通过 HB-EGF 激活 EGFR 信号通路的机制，然后评估 FOXQ1 和 HB-EGF 的临床相关性。
GEPIA 显示 CRC 组织中 FOXQ1 的表达相对较高，与总生存率降低有关。PCR 数组结果表明 FOXQ1 与 HB-EGF 和 EGFR 途径有关。敲低 FOXQ1 抑制 HB-EGF 的表达，并导致 EGFR 及其下游基因,, 表达水平降低。在 CRC 细胞系中敲低 FOXQ1 后，细胞增殖、迁移和侵袭能力减弱。添加 HB-EGF 恢复了 CRC 的迁移和侵袭能力，但不能恢复细胞增殖能力。Kaplan-Meier 生存分析结果表明，FOXQ1 和 HB-EGF 的组合可能有助于预测 CRC 的生存。
基于这些综合数据，我们提出 FOXQ1 通过 HB-EGF/EGFR 途径促进 CRC 的侵袭和转移。
