Zinc Finger Protein CTCF Regulates Extracellular Matrix (ECM)-Related Gene Expression Associated With the Wnt Signaling Pathway in Gastric Cancer.

Chenbin Liu,Jianjun Zhang,Le Ying,Jinglin Zhao,Jinrong Lin,Shu Huang,Dakang Xu,Peipei Jin,Peihua Ni,Peiqing Xu,Linyi Deng,Yiqun Hu

doi:10.3389/fonc.2020.625633

Abstract

Gastric cancer (GC), a leading cause of cancer-related death, is a heterogeneous disease. We aim to describe clinically relevant molecular classifications of GC that incorporate heterogeneity and provide useful clinical information. We combined different gene expression datasets and filtered a 7-gene signature related to the extracellular matrix (ECM), which also exhibited significant prognostic value in GC patients. Interestingly, putative CCCTC-binding factor (CTCF) regulatory elements were identified within the promoters of these ECM-related genes and were confirmed by chromatin immunoprecipitation sequencing (ChIP-Seq). CTCF binding sites also overlapped with histone activation markers, indicating direct regulation. In addition, CTCF was also correlated with the Wnt signaling pathway. A comparison of human GC cell lines with high or low expression of ECM-related genes revealed different levels of tumor aggressiveness, suggesting the cancer development-promoting functions of ECM-related genes. Furthermore, CTCF regulated COL1A1 and COLA31 expression in vitro. Silencing CTCF or COL1A1/COL1A3 markedly inhibited cell growth and migration in the metastatic GC cell line BGC823. Collectively, this ECM-related 7-gene signature provides a novel insight for survival prediction among GC patients. The zinc finger protein CTCF regulates ECM-related genes, thereby promoting GC cell growth and migration.

Highlights

Gastric cancer (GC) is the fourth most common cancer in the world and causes approximately 738,000 deaths each year, making it the third leading cause of cancer-related death worldwide [1,2,3,4]
We aimed to identify the differentially expressed genes (DEGs) between tumor and normal tissues, establish clinically relevant molecular subtypes and identify significant signatures for GC
Further in vitro experiments were applied to validate the role of CCCTC-binding factor (CTCF) in tumorigenesis and regulating these key genes (Figure 1)

Summary

Introduction

Gastric cancer (GC) is the fourth most common cancer in the world and causes approximately 738,000 deaths each year, making it the third leading cause of cancer-related death worldwide [1,2,3,4]. Detection and reliable screening are of vital importance in improving the survival rate. There are more new insights into the molecular basis of GC than ever before, currently available diagnostic and therapeutic methods do not significantly improve the overall survival (OS) of GC patients. The use of disease risk stratification (tumor-node-metastasis (TNM) stage) and histological grade based on tumor size, lymph node or distant metastasis is not sufficient to determine the prognosis of a given GC patient. The discovery and identification of molecular subtypes and novel biomarkers play an important role in clinical decision making for more effective and selective treatment. Molecular biomarkers have potential values as diagnostic and prognostic tools in GC. It is worthwhile to investigate the molecular mechanisms of GC and to identify novel and specific biomarkers and targets

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