MicroRNA‐375‐3p enhances chemosensitivity to 5‐fluorouracil by targeting thymidylate synthase in colorectal cancer

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractResistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA-373-3p (miR-375-3p) in CRC remains unclear. The current study aimed to explore the potential function of miR-375-3p in 5-fluorouracil (5-FU) resistance. MicroRNA-375-3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5-FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR-375-3p, and TYMS knockdown exerted similar effects as miR-375-3p overexpression on the CRC cellular response to 5-FU. Lipidcoated calcium carbonate nanoparticles (NPs) were designed to cotransport 5-FU and miR-375-3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR-375 + 5-FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR-375-3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5-FU. K E Y W O R D S5-fluorouracil, chemosensitivity, colorectal cancer, miR-375-3p, nanoparticles | INTRODUC TI ONAlthough considerable progress has been made in the treatment of CRC in recent years, CRC accounts for approximately 13% of all tumors and is the second leading cause of tumor-related death in developed countries. 1-3 Fluorouracil-based chemotherapy has served as the first-line standard of care and most common regimen for CRC over the past 50 years. 4,5 However, patient resistance to 5-FU is a major obstacle to effective therapy. Therefore, efforts to clarify the molecular mechanism underlying 5-FU resistance and to identify new

Analysis of mRNAs and ncRNAs and Prediction Competing Endogenous RNA Networks in Colorectal Cancer Chemo-Resistance by Whole-Transcriptome Sequencing

“…At present, a large number of studies have shown that, in addition to mRNAs, non-coding RNAs also related to drug resistance of cancers, including gastric cancer [33], bladder cancer [34], lung adenocarcinoma [35]. Moreover, in CRC drug resistance studies, it was reported that LINC00957 could increase 5uorouracil resistance and result in poor survival of patients [36], hsa_circ_0079662 was related to oxaliplatin resistance via TNF-α pathway [25], microRNA-375-3p was involved in 5-uorouracil resistance by targeting thymidylate synthase [37].…”

MicroRNAs in Rectal Cancer: Functional Significance and Promising Therapeutic Value

“…5-FU is a uracil analog that inhibits thymidylate synthase, which is the core enzyme in pyrimidine nucleotide synthesis, blocking the synthesis of DNA and disrupting RNA processing [66]. Resistance to 5-FU is a major obstacle to successful treatment and identifying its underlying molecular mechanisms is one of the major challenges for creating new opportunities for LARC treatment.…”

“…The restoration of miR-375-3p levels enhanced 5-FU sensitivity and induced cell apoptosis and cell cycle arrest, inhibiting cell growth, migration, and invasion in vitro. Therefore, targeting miR-375-3p seems to be an effective method for modulating and enhancing 5-FU antitumor effects [66].…”

<p>MiR-145 Regulates the Chemoresistance of Hepatic Carcinoma Cells Against 5-Fluorouracil by Targeting Toll-Like Receptor 4</p>

“…Subsequently, the cells were cultured with 5 μg/mL 5-FU for 48 hrs, and then their apoptosis was determined via an Annexin V-FITC Kit (Huijia Biotechnology Co., Ltd., Xiamen, China) under the kit instructions. The treated cells were prepared into 1×10 6 cells/mL cell suspension, followed by incubation with Annexin V-FITC and propidium iodide in the dark. Finally, the cells were determined using a CyFlow Cube6 flow cytometer (Jiyuan Biotechnology Co., Ltd., Guangzhou, China).…”

“…5 They play a key regulatory role in the development and progression of tumor cells, and also take a crucial part in the tumor biosynthesis, growth, and drug resistance. 6 Recent studies have found that miRNA expression can enhance the antitumor effect of 5-FU on tumor cells. 7 According to reports, miR-145 acts as a tumor suppressor in various tumors.…”