miR-145 Regulates the sensitivity of esophageal squamous cell carcinoma cells to 5-FU via targeting REV3L
Introduction
Globally, esophageal cancer (EC) ranks the 8th most common cancer and the 6th most common cause of cancer-related death [1]. Meanwhile, EC was one of the most lethal malignancies in China and other Asian countries with the poor 5-year survival rate after curative surgery [2,3]. Esophageal squamous cell carcinoma (ESCC), which accounts for 90% of EC, [3,4], is a serious health problem in China, leading to 375,000 deaths in 2015 [5]. 5-Fluorouracil (5-FU) is a chemotherapy agent which induces cell death mainly through the inhibition of thymidylate synthase and misincorporation into newly synthesized DNA and RNA during cell cycle progression [6]. 5-FU is a commonly used drug alone or in combination with other chemotherapy agents for the treatment of ESCC [7]. However, intrinsic or acquired chemotherapy resistance frequently occur after the chemotherapy treatment of cytotoxic drugs, led to chemotherapy failure and eventually patient death [8]. It was urgent to further investigate molecular mechanism of drug resistance to improve the prognosis of ESCC patients.
MicroRNAs (miRNAs) are a class of endogenous and conserved non-coding 20–22 nt small RNAs which regulates gene expression at post-transcriptional level by binding to 3’-UTR of target mRNAs, resulting in mRNA degradation or translation inhibition [9]. miRNAs may act as an oncogene or a tumor suppressor, through regulating cell differentiation, cell proliferation and cell apoptosis [10,11]. miR-145 is a well-characterized tumor suppressor in various cancer types [[12], [13], [14]]. For EC, miR-145 is firstly reported to be downregulated in ESCC [15]. Recently, miR-145 is reported to inhibit cancer cell migration, invasion and epithelial-mesenchymal transition as well as cell proliferation in ESCC [16,17]. In human colon cancer cells, miR-145 inhibits 5-FU resistance [18]. The role of miR-145 in the sensitivity of ESCC to 5-FU has not been previously reported.
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Tissues
ESCC tissues and normal esophageal tissues were collected from 25 patients with ESCC between May 2015 and Nov, 2016 in Jingjiang Peoples’ Hospital. Histopathologic sections from patients diagnosed with ESCC. The grades were based on “WHO Classification Tumors of the Digestive System” in 2010. All patients hadn’t received radiotherapy or chemotherapy prior to the present study. All patients had provided informed consent. The current study was approved by Ethical Committee of Jingjiang Peoples’
real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR)
miRNA was isolated by a miRNA Extraction Kit (Qiagen, Hilden, Germany). Reverse transcription was carried out by miRNA cDNA Synthesis Kit (Qiagen) in accordance with the manufacturer’s instructions. Total RNA was isolated TRIzol® (Invitrogen, Thermo Fisher Scientific, Inc.). cDNA was prepared using the PrimeScript RT Reagent kit (Takara Biotechnology Co., Ltd.) according to the manufacturer's protocol. PCR amplification was conducted by SYBR green Premix Ex Taq II (Qiagen). The procedure was
miR-145 expression was downregulated in human ESCC tissues and cells
To investigate the expression of miR-145 in ESCC, RT-PCR was applied to compare the levels of miR-145 in ESCC tissues and matched normal tissues from 25 patients. As showed in Fig. 1A, in comparison with normal tissues, expression of miR-145 was significantly decreased in ESCC tissues. We next analyzed expression of miR-145 in esophageal epithelium cell line HEEC and ESCC cell lines TE-1, TE-8, KYSE150. MiR-145 was remarkably downregulated in ESCC cell lines compared with HEEC (Fig. 1B).
The expression of miR-145
miR-145
Discussion
5-FU based chemotherapy is standard therapeutic approach for ESCC patients. However, development of 5-FU resistance remains a critical limitation to its clinical use [19]. The molecular mechanism of 5-FU resistance is quite complicated which involves altered expression of many genes [20]. Recent years, accumulating evidences suggest that aberrant expression of miRNAs contributes to gene expression alteration and chemotherapy resistance [21]. In current study, we found that miR-145 was elevated
Availability of materials and data
They are available on special requests.
Declaration of interest
None.
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