Biochemical and Biophysical Research Communications
Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance
Introduction
Radiotherapy is an important treatment modality for locally advanced cervical cancer. However, cancer recurrence or metastasis still occurs in approximately 30% of radiotherapy-treated patients with locally advanced cervical cancer [1,2]. A reason for radiotherapy failure may be tumor radioresistance. The mechanisms underlying tumor radioresistance are complex. Currently known factors contributing to resistance include aberrant DNA damage and repair, hypoxia or formation of hypoxia-inducing factors, the presence of cancer stem cells, and production of relevant microRNAs. Understanding the underlying mechanisms and molecular networks involved in tumor radioresistance is important to improve radiotherapy treatment efficacy.
MicroRNAs (miRNAs) are endogenous small noncoding RNAs found in eukaryotes that play a major role in gene silencing. Studies have shown that abnormal miRNA expression is closely related to chemoresistance, recurrence and metastases, and poor prognoses in patients with lung adenocarcinoma, breast cancer, and pancreatic cancer [[3], [4], [5]]. Lui et al. [6] compared differences in miRNA expression of 166 samples from normal and cancerous cervical tissues, as well as miR-143 and miR-21 expression in 29 matched samples of cancerous/normal cervical tissues by northern blot. They found that miR-21 was expressed in all cancerous tissues, but rarely expressed in normal tissues. Conversely, miR-143 was mostly expressed in normal tissue; however, its expression was low or absent in cancerous tissues. These results suggest that miR-143 exerts an inhibitory effect against cervical cancer, whereas miR-21 promotes cervical cancer growth. Wang et al. [7] applied deep sequencing technology to study the miRNA expression profile of Caski cervical cancer cells. Of 46 miRNAs, the expression levels of miR-21, miR-24, miR-27a, and miR-205 were found to be comparatively high. Furthermore, the growth-inhibitory effects of miR-143 and miR-145 and the growth-promoting effects of miR-146a against HeLa cervical cancer cells were validated miR-143, miR-145, and miR-146a expression in HeLa cells. Other studies using miRNA chip analyses or deep sequencing of cervical cancer tissue or cells lines have shown reduced expression of miR-203, miR-23a/b, and miR-34a, and increased expression of miR-15 and miR-16-1, in cervical cancer [[8], [9], [10]]. However, few reports discuss the relationships between aberrant miRNA expression and the radiosensitivity or radioresistance of cervical cancer.
This study screened for differentially expressed miRNAs before and after cervical cancer tissue irradiation. A radioresistant cervical cancer cell line was also successfully established. The functions and mechanisms of miRNAs were evaluated in the parent and radioresistant cervical cancer cell lines. Our study provides a new direction and basis for predicting cervical cancer prognosis following radiotherapy, reversing cervical cancer radioresistance, and increasing the cure rate of cervical cancer in clinical settings.
Section snippets
Patient selection and human tissues
Eight tissue samples were acquired from patients with cervical cancer before radical radiotherapy in the Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University (FMMU). All patients consented to a 3-years follow-up investigation. Three patients had good local control and no evidence of recurrence or metastasis; their tissue samples were grouped into control (radiation-sensitive). The remaining five tissue samples were allocated to the experimental group
Decreased miR-4778-3p expression in tumor tissue of recurrent or metastatic patients and in radioresistant cell lines
miRNA chip results showed that 32 miRNA molecules had differential expression (fold-change > 2). Compared with expression in radiosensitive tissue from control patients, 10 miRNA molecules were upregulated and 9 were downregulated in tissue from patients with recurrence. Further, 9 miRNA molecules were upregulated and 4 were downregulated in tissue from patients with metastasis. Specifically, miR-4778-3p expression was significantly downregulated in both recurrent and metastatic patients.
Discussion
One of the most prevalent treatment modalities for locally advanced cervical cancer is radiotherapy combined with concurrent chemotherapy, which has greatly improved tumor control and cure rate [[11], [12], [13]]. However, many patients still experience recurrence or metastasis. Radioresistance may be a key reason underlying treatment failure. Therefore, we aimed to improve cervical cancer radiosensitivity, thereby increasing the clinical efficacy of radiotherapy [14]. Present data on miRNAs
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
None.
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2021, Journal of Oral Biology and Craniofacial ResearchmiRNA as promising theragnostic biomarkers for predicting radioresistance in cancer: A systematic review and meta‐analysis
2021, Critical Reviews in Oncology/HematologyCitation Excerpt :The included studies in the current systematic review and meta-analysis were published between 2011−2019. The sources of the malignant tumor included breast cancer (BC) (Anastasov et al., 2012; Lai et al., 2018; Gasparini et al., 2014; Pajic et al., 2018; Wolfe et al., 2016; Song et al., 2011), cervical cancer (CC) (Bu et al., 2018; Liu et al., 2015b; Ke et al., 2013; Liu et al., 2017b, a; Lu et al., 2018; Wu et al., 2018a; Wang et al., 2016a; Zhang et al., 2019; Pedroza-Torres et al., 2018; Song et al., 2016; Ye et al., 2015; Song et al., 2015), lung cancer (LC) (Chen et al., 2018a; Tang et al., 2016b; Yang et al., 2014), non-small cell lung cancer (NSCLC) (Chen et al., 2014; Du et al., 2019; He et al., 2015; Lan et al., 2015a; Shen et al., 2015a; Liu et al., 2013; Xiao-chun et al., 2013; Song et al., 2017; Wang et al., 2011a; Wu et al., 2017; Xue et al., 2017a; Wang et al., 2017; Zhai et al., 2016; Song et al., 2018; Jiang et al., 2017), hepatocellular carcinoma (HCC) (Chen and Zhang, 2019; Luo et al., 2019a; Wang et al., 2011b; Shao et al., 2018a; Wang et al., 2019a; Shao et al., 2019), esophageal cancer (EC) (Cui et al., 2017; Fan et al., 2019; Lynam-Lennon et al., 2016; Xia et al., 2014; Yang et al., 2017a; Zhang et al., 2016a), esophageal squamous cell carcinoma (ESCC) (Lin et al., 2016; Luo et al., 2019b; Wang et al., 2013a, b; Pan et al., 2017a), nasopharyngeal carcinoma (NPC) (Feng et al., 2018; Guo et al., 2019; Hu et al., 2019; Li et al., 2013, 2014; Qu et al., 2015a; Huang et al., 2016; Wang et al., 2014, 2016b; Wang et al., 2015; Wu et al., 2018b; Zhang et al., 2017a, 2013; Zhao et al., 2015; Xu et al., 2015a; Qu et al., 2015b; Yang et al., 2015a; Wu et al., 2018c), prostate cancer (PCa) (Tao et al., 2018; Gong et al., 2015; Hoey et al., 2018), glioma (Yang et al., 2017b; Chen et al., 2016; Hou et al., 2017; Lan et al., 2015b; Li et al., 2018; Sun et al., 2018; Xue et al., 2017b; Peruzzi et al., 2013; Yue et al., 2019), colorectal cancer (CRC) (Hu et al., 2018a; Ji et al., 2018; Wang et al., 2019c; Zhang et al., 2014; Yang et al., 2015b), gastric cancer (GC) (Jiang et al., 2019; Wu et al., 2016), osteosarcoma (Li et al., 2019), melanoma (Jiang et al., 2012), NK/T cell lymphoma (Wu et al., 2018d), oral squamous cell carcinoma (OSCC) (Zhang et al., 2017b; Shiiba et al., 2013), laryngeal squamous cell carcinoma (LSCC) (Xu et al., 2015b), head and neck cancer (HNC) (Suh et al., 2015) and, pancreatic cancer (PC) (Wang et al., 2013b; Wei et al., 2013). Out of the 100 studies, 88 were from China, 3 were from the USA, and there was one article from each of Japan, Australia, Germany, Taiwan, Mexico, UK, and Canada.
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2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The exposure to a low dose of ionizing radiation cannot be avoided where the radiation with a low dose comes from many situations such as cosmic rays [3] and nuclear accidents [4,5]. Besides, hospitals use ionizing radiation during diagnostic procedures and therapy process [6–8]. Ionizing radiation can induce peroxidation in the biological system [9,10].
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2020, PancreatologyCitation Excerpt :Chemerin has been recognized as a chemical attractant that mediates the recruitment of immune cells to lymphatic organs and tissue injury sites [38]. miR-4778–3p was recently found to be involved in the radioresistance of cervical cancer, which could reduce the vitality, proliferation, and migration of radioresistant cells [39]. Taken together, we speculated that CMKLR1, as a CD4+ T cell-related gene, may be involved in the tumor microenvironment in pancreatic cancer through ceRNA chr22-38_28785274-29006793.1-miR-4778-3p-CMKLR1.
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Ying Zhang, Pei Li, and Jing Hu are first co-authors.