The FENDRR/FOXC2 Axis Contributes to Multidrug Resistance in Gastric Cancer and Correlates With Poor Prognosis.

Yongzhan Nie,Xiaodi Zhao,Xiangyuan Zhang,Zhe Zhang,Wanning Liu,Yanhong Liu,Ahui Fan,Daiming Fan,Yuanyuan Lu,Haiming Liu,Yanan Han,Hao Liu,Rugang Zhang

doi:10.3389/fonc.2021.634579

Abstract

The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. In vitro and in vivo experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.

Highlights

Gastric cancer (GC), which is the fourth most common cancer worldwide, remains an enormous threat to human health despite the decreases in incidence and mortality observed in recent years [1]
We observed that FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) expression was significantly increased in gastric cancer (GC) tissues compared with their matched adjacent nontumor tissues (Figure 1C)
Further correlation analyses revealed that higher FENDRR expression in tumors was significantly associated with more aggressive tumor phenotypes in GC patients (Table 1)

Summary

Introduction

Gastric cancer (GC), which is the fourth most common cancer worldwide, remains an enormous threat to human health despite the decreases in incidence and mortality observed in recent years [1]. Recent studies have demonstrated that dysregulated FOX members are closely associated with cancer drug resistance [6]. As a member of the C family of FOX proteins, FOXC2 has been reported to play crucial roles in cancer progression, including in chemoresistance. FOXC2 can promote epithelial to mesenchymal transition (EMT) in basallike breast cancer and non-small cell lung cancer, which is an important mechanism in the induction of metastasis and drug resistance [10, 11]. FOXC2 was shown to confer resistance to CDDP and fluorouracil (5-FU) in ovarian cancer and colorectal cancer, respectively [12, 13]. FOXC2 has been observed to be upregulated in GC [14], suggesting its oncogenic roles in gastric carcinogenesis, its functions in GC MDR have yet to be investigated

Methods

Results

Conclusion