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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Forkhead Box q1 promotes invasion and metastasis in colorectal cancer by activating the epidermal growth factor receptor pathway
Jin-Jin Zhang, Chang-Xiong Cao, Li-Lan Wan, Wen Zhang, Zhong-Jiang Liu, Jin-Li Wang, Qiang Guo, Hui Tang
Jin-Jin Zhang, Chang-Xiong Cao, Li-Lan Wan, Wen Zhang, Zhong-Jiang Liu, Jin-Li Wang, Qiang Guo, Hui Tang, 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
Jin-Jin Zhang, Chang-Xiong Cao, Li-Lan Wan, Wen Zhang, Zhong-Jiang Liu, Jin-Li Wang, Qiang Guo, Hui Tang, Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
Jin-Jin Zhang, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan Province, China
Author contributions: Zhang JJ and Cao CX contributed equally to this work; Tang H and Guo Q designed the project; Cao CX and Zhang JJ analyzed data and wrote the manuscript; Zhang JJ and Wan LL performed qRT-PCR, Elisa, and Western blotting; Zhang W and Wang JL carried out migration assay; Liu ZJ and Tang H analyzed colorectal tissue microarray and survival data; all authors participated in critical revision of the manuscript and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 81502556; and Yunnan Digestive Endoscopy Clinical Medical Center Foundation for Health Commission of Yunnan Province, No. 2X2019-01-02.
Institutional review board statement: Our research does not involve humans and animals.
Conflict-of-interest statement: The authors declare no competing interests.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Hui Tang, PhD, Professor, 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, No. 157 Jinbi Road, Xishan District, Kunming 650032, Yunnan Province, China. htang1122@aliyun.com
Received: October 18, 2021
Peer-review started: October 18, 2021
First decision: December 12, 2021
Revised: December 31, 2021
Accepted: March 27, 2022
Article in press: March 27, 2022
Published online: May 7, 2022
BACKGROUND
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.
AIM
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.
METHODS
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.
RESULTS
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 AKT, RAF, KRAS 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.
CONCLUSION
Based on these collective data, we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.
Core Tip: Invasion and metastasis play important roles in tumorigenesis, resulting in the death of most colorectal cancer (CRC) patients. Forkhead Box q1 (FOXQ1) is a well-established oncogene in multiple tumors, including CRC. Our previous study suggested that FOXQ1 positively regulates the expression of heparin-binding epidermal growth factor (HB-EGF) and triggers the activation of the epidermal growth factor receptor (EGFR) pathway in CRC. However, the role and mechanism of how FOXQ1 promotes tumorigenesis in CRC by activating the HB-EGF/EGFR pathway remain unexplored. In the present study, our findings demonstrated that the essential role of FOXQ1-induced invasion and metastasis in CRC was related to activation of the HB-EGF/EGFR pathway.
