Tumor suppressor miR-29c regulates radioresistance in lung cancer cells

Abstract

Radiotherapy is an important treatment option for non-small cell lung carcinoma patients. Despite the appropriate use of radiotherapy, radioresistance is a biological behavior of cancer cells that limits the efficacy of this treatment. Deregulation of microRNAs contributes to the molecular mechanism underlying resistance to radiotherapy in cancer cells. Although the functional roles of microRNAs have been well described in lung cancer, their functional roles in radioresistance are largely unclear. In this study, we established a non-small cell lung carcinoma Calu-1 radioresistant cell line by continuous exposure to therapeutic doses of ionizing radiation as a model to investigate radioresistance-associated microRNAs. Our data show that 50 microRNAs were differentially expressed in Calu-1 radioresistant cells (16 upregulated and 34 downregulated); furthermore, well-known and novel microRNAs associated with resistance to radiotherapy were identified. Gene ontology and enrichment analysis indicated that modulated microRNAs might regulate signal transduction, cell survival, and apoptosis. Accordingly, Calu-1 radioresistant cells were refractory to radiation by increasing cell survival and reducing the apoptotic response. Among deregulated microRNAs, miR-29c was significantly suppressed. Reestablishment of miR-29c expression in Calu-1 radioresistant cells overcomes the radioresistance through the activation of apoptosis and downregulation of Bcl-2 and Mcl-1 target genes. Analysis of The Cancer Genome Atlas revealed that miR-29c is also suppressed in tumor samples of non-small cell lung carcinoma patients. Notably, we found that low miR-29c levels correlated with shorter relapse-free survival of non-small cell lung carcinoma patients treated with radiotherapy. Together, these results indicate a new role of miR-29c in radioresistance, highlighting their potential as a novel biomarker for outcomes of radiotherapy in lung cancer.

MiR-29c-3p, a target miRNA of LINC01296, accelerates tumor malignancy: therapeutic potential of a LINC01296/miR-29c-3p axis in ovarian cancer

“…MiR-29c pertains to the miR-29 family and has been identified as markedly down-regulated microRNAs in cancer [14,15]. It plays a tumor suppressive role in multiple cancers, such as colorectal cancer [25], lung cancer [26], breast cancer [27], gastric cancer [28], and pancreatic cancer [29]. Our experimental data further confirms this conclusion.…”

Understanding the mechanism underlying the acquisition of radioresistance in human prostate cancer cells

“…One of the causes of tumor recurrence and metastasis is that cancer cells acquire radioresistance (RR) during fractionated irradiation (7). It has been reported that RR is acquired in various cancer types, including head and neck cancer, non-small cell lung cancer, breast cancer and PCa (8)(9)(10)(11). RR cells demonstrate resistance to the induction of apoptosis, decreased production of reactive oxygen species (ROS) (12), increased activation of DNA repair (13), and exhibit high migratory and invasive abilities (14).…”

“…Cancer cells acquire RR by fractionated irradiation, and certain features of RR cells have been described (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, to the best of our knowledge, the mechanism underlying RR acquisition during fractionated irradiation is unclear.…”

New insights into radioresistance in breast cancer identify a dual function of miR‐122 as a tumor suppressor and oncomiR

“…To overcome this problem, it is necessary to detemrine the mechanisms of resistance to radiotherapy. Several studies have demonstrated that tumor recurrence and progression as a consequence of radioresistance can be regulated by microRNAs (miRNAs) (Arechaga‐Ocampo et al ., ; Metheetrairut and Slack, ). miRNAs are master regulators of gene expression; moreover, they have a role in the regulation of carcinogenesis and the control of response to chemo‐ and radiotherapy in breast cancer (Zhang et al ., ).…”