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Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2020; 12(9): 942-956
Published online Sep 15, 2020. doi: 10.4251/wjgo.v12.i9.942
Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids
Amirsaeed Sabeti Aghabozorgi, Mostafa Moradi Sarabi, Reza Jafarzadeh-Esfehani, Shabnaz Koochakkhani, Marziyeh Hassanzadeh, Soudabeh Kavousipour, Ebrahim Eftekhar
Amirsaeed Sabeti Aghabozorgi, Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran
Mostafa Moradi Sarabi, Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
Reza Jafarzadeh-Esfehani, Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran
Shabnaz Koochakkhani, Marziyeh Hassanzadeh, Soudabeh Kavousipour, Ebrahim Eftekhar, Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
Author contribution: Eftekhar E and Moradi Sarabi M conceived the idea for the work; Sabeti Aghabozorgi A, Jafarzadeh Esfehani R, Koochakkhani S, Hassanzadeh M and Kavousipour S performed the literature search and collect the data; Eftekhar E and Sabeti Aghabozorgi A wrote the primary draft of the article; all authors contributed to critical revision, editing and final approval of the manuscript.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ebrahim Eftekhar, PhD, Associate Professor, Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Jomhori Street, Bandar Abbas 7919915519, Iran. eftekhar19@gmail.com
Received: March 21, 2020
Peer-review started: March 21, 2020
First decision: April 26, 2020
Revised: May 11, 2020
Accepted: July 19, 2020
Article in press: July 19, 2020
Published online: September 15, 2020
Abstract

5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.

Keywords: 5-flurouracil, Colorectal cancer, Chemotherapy resistance, Thymidylate synthase, Microsatellite instability, Micro-ribonucleic acid, TP53

Core Tip: Resistance to the main chemotherapy drug, 5-flurouracil (5-FU), is an important cause of failure in clinical colorectal cancer therapy. Microsatellite instability, increased activity and expression level of thymidylate synthase and dihydropyridine dehydrogenase, mutation of TP53 as well as micro-ribonucleic acids alterations are among the main molecular determinants of response to 5-FU-based chemotherapy in colorectal cancer. The identification of potential molecular determinants of response to 5-FU could be an important clinical tool for developing treatment strategies and selecting colorectal cancer patients who are most likely to benefit from 5-FU chemotherapy.