Esophageal cancer-related gene 4 inhibits gastric cancer growth and metastasis by upregulating Krüppel-like factor 2 expression

Ximei Li; Shengjuan Hu; Meijuan Ma; Pengda Wang; Yao Qi; Yan Zhou; Zishao Zhong; Hengjun Gao; Feihu Bai

doi:10.21037/atm-23-139

Esophageal cancer-related gene 4 inhibits gastric cancer growth and metastasis by upregulating Krüppel-like factor 2 expression

Ann Transl Med. 2023 Feb 28;11(4):176. doi: 10.21037/atm-23-139.

Authors

Ximei Li^{1

2}, Shengjuan Hu², Meijuan Ma², Pengda Wang², Yao Qi^{3

4}, Yan Zhou¹, Zishao Zhong³, Hengjun Gao^{3

4}, Feihu Bai^{5

6}

Affiliations

¹ School of Clinical Medicine, Ningxia Medical University, Yinchuan, China.
² Department of Gastroenterology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China.
³ Department of Gastroenterology, Tongji Hospital, Institute of Digestive Disease, School of Medicine, Tongji University, Shanghai, China.
⁴ National Engineering Center for Biochip at Shanghai, Shanghai, China.
⁵ The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, China.
⁶ Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China.

Abstract

Background: There are a large number of people suffering from gastric cancer (GC) worldwide, so the study of biomarkers for GC is urgently needed. This study aimed to investigate the role of esophageal cancer-related gene 4 (ECRG4) in the growth, metastasis, and prognosis of GC and the possible underlying mechanism.

Methods: The expression of ECRG4 was detected in GC tissues by quantitative polymerase chain reaction (PCR), Western blot, and immunohistochemistry. The relationships between ECRG4 expression and clinicopathological parameters of patients with GC were statistically analyzed, and Kaplan-Meier prognosis and survival curves of the patients were plotted. ECRG4 was overexpressed in the human gastric adenocarcinoma cell line (AGS) and human GC cell line 27 (HGC27), and the in vivo effects of ECRG4 overexpression on the growth, invasion, and metastasis of GC were analyzed and verified in nude mice. To identify the downstream transcription factors potentially regulated by ECRG4, ribonucleic acid (RNA) sequencing and differential gene expression analysis were performed on ECRG4-overexpressing cells. Quantitative PCR, Western blot, and immunohistochemistry were used to detect the expression of the downstream transcription factors targeted by ECRG4 in GC.

Results: The ECRG4 mRNA and protein expression levels were low in GC tissues and were associated with a poor prognosis. Least absolute shrinkage and selection operator (LASSO) Cox regression and Kaplan-Meier survival analyses showed that patients with low ECRG4 expression had worse prognosis and survival. Overexpression of ECRG4 inhibited the proliferation, metastasis, and invasion of GC cells. RNA sequencing analysis showed that overexpression of ECRG4 induced the upregulation of Krüppel-like factor 2.

Conclusions: Our findings show that ECRG4 promotes GC progression via Krüppel-like factor 2 signaling and highlight ECRG4 as a potential GC biomarker and therapeutic target.

Keywords: Esophageal cancer-related gene 4 (ECRG4); Krüppel-like factor 2 (KLF2); clinicopathological parameters; gastric cancer (GC); prognosis.