Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-cateninviaEzh2

Wei Wang,Zhibo Shen,Yamin Qiao,Yi Zhang,Guozhong Jiang,Sanni Li,Pengyuan Zheng,Liping Wang,Xinfeng Chen,Yunan Zhu

doi:10.18632/oncotarget.8257

Abstract

Evidences have shown that lncRNAs involve in the initiation and progression of various cancers including esophageal squamous cell carcinoma (ESCC). The aberrant expression of lncRNA MALAT1 was investigated in 106 paired ESCC tissues and adjacent non-cancerous tissues by qRT-PCR. Down-regulated MALAT1 and Ezh2 over-expression plasmid were constructed respectively to analyze the expression of β-catenin, Lin28 and Ezh2 genes. We found that the MALAT1 expression level was higher in human ESCC tissues (P=0.0011), which was closely correlated with WHO grade (P=0.0395, P=0.0331), lymph node metastasis (P=0.0213) and prognosis (P=0.0294). Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro. Down-regulation of MALAT1 decreased the expression of β-catenin, Lin28 and Ezh2 genes, while over-expressed Ezh2 combined with MALAT1 down-regulation completely reversed the si-MALAT1-mediated repression of β-catenin and Lin28 in esophageal cancer cells. Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival. MALAT1 promotes the initiation and progression of ESCC, suggesting that inhibition of MALAT1 might be a potential target for treatment of ESCC.

Highlights

Esophageal cancer (EC) is one kind of the most frequently invasive malignancies and ranks as the sixth cancer-related mortality in worldwide [1]
The Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression level was closely associated with lymph nodes metastasis (P=0.0213, Figure 1C, Table 2), while no association was found between the expression of MALAT1 and gender, age in esophageal squamous cell carcinoma (ESCC) (Table 2)
Several long noncoding RNAs (lncRNAs) including Prostate Cancer-Associated ncRNA Transcript 1 (PCAT-1) [19], Urothelial Carcinoma Associated 1 (UCA1) [20] and SPRY4-IT1 [21] were significantly increased in ESCC tissues and their high expressions were significantly correlated with the tumor invasion, advanced clinical stage, lymph node metastasis and poor prognosis

Summary

Introduction

Esophageal cancer (EC) is one kind of the most frequently invasive malignancies and ranks as the sixth cancer-related mortality in worldwide [1]. More and more evidences have shown that the long noncoding RNAs (lncRNAs) are multiple biomarkers for predicting cancer in recent years [2]. Exploring the aberrant expression of the lncRNAs contributes to a better understanding of the molecular events and offers insight into potential molecular targets for diagnosis and therapy in ESCC [3]. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a bona fide lncRNA [4]. Increasing evidences have shown that the aberrant expression of MALAT1 plays a crucial role in cancinogenesis [5]. MALAT1 was firstly reported in invasive non-small cell lung carcinoma, overexpression of MALAT1 was investigated in the cancers of liver [6], colon [7], cervical [8], etc. Accumulated evidences have shown that β-catenin is activated in many cancers including ESCC [11, 12]

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