Long noncoding RNA XIST is a prognostic factor in colorectal cancer and inhibits 5-fluorouracil-induced cell cytotoxicity through promoting thymidylate synthase expression.

Yang Xiao,Smorzhevskyi Valentyn Yosypovych,Usenko Alexander Yurievich

doi:10.18632/oncotarget.20487

Yang Xiao, Smorzhevskyi Valentyn Yosypovych + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.20487

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Journal: Oncotarget	Publication Date: Aug 24, 2017
Citations: 46	License type: cc-by

Affiliation: Shupyk National Healthcare University of Ukraine

Abstract

A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to 5-fluorouracil (5FU)-based treatment. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical regulators in chemoresistance. By using the next generation HiSeq sequencing assay, we identified lncRNAs showing differential expression levels in 5FU resistant and non-resistant CRC patients. RT-qPCR was then performed for validation in tissues and serum samples, and lncRNA XIST was verified to be up-regulated in non-responding patients and have considerable diagnostic potential to identify responding patients from non-responding patients. In addition, increased serum XIST level was associated with poor response and lower survival rate in CRC patients receiving 5FU-based treatment. Subsequently, the 5FU resistant (5FU-R) cell lines were established, and lncRNA XIST was significantly up-regulated HT29 5FU-R and HCT116 5FU-R cells. Furthermore, knockdown of XIST reversed 5FU resistance while enhanced XIST could restrained the 5FU-induced cell cytotoxcity in both CRC cell lines. Western blotting and immunofluorescence analysis indicated that XIST promoted the expression of thymidylate synthase, a critical 5FU-targetd enzyme. In conclusion, our integrated approach demonstrates that increased expression of lncRNA XIST3 in CRC confers a potent poor therapeutic efficacy, and that lncRNA XIST participated in 5FU resistance through promoting the expression of thymidylate synthase. Thus, specific silence oflncRNA XIST could be a future direction to develop a novel therapeutic strategy to overcome 5FU resistance of CRC patients.

Highlights

Colorectal cancer (CRC) is among the leading causes of mortality and morbidity throughout the world, representing a major public health problem
On the basis of the date obtained from Hiseq sequencing, we identified 677 long non-coding RNAs (lncRNAs) that were differently expressed more than 2-fold chage
After having uncovered the clinical diagnostic and prognostic function of lncRNA XIST in colorectal cancer (CRC) chemotherapy, we investigated the experimental role of XIST of how it can exert the pro-oncogenic role for CRC chemoresistance

Summary

Introduction

Colorectal cancer (CRC) is among the leading causes of mortality and morbidity throughout the world, representing a major public health problem. It is the second- and third-most commonly diagnosed cancer in females and males, respectively [1, 2]. Metastasis is the major cause of death for patients with CRC and increases the risk of tumor recurrence [3]. Fluoropyrimidine-based chemotherapy (e.g., 5-fluorouracil (5FU)) has been the cornerstone of treating advanced CRC for over a half century. Most patients receiving chemotherapy develop drug resistance, and this has been a major obstacle to improving the efficiency of colorectal cancer treatment [5]. Revealing the underlying mechanism and finding new therapeutic approaches are necessary for developing effective therapies for colorectal cancer patients

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