Regulation of cell fate by microRNAs during unfolded protein response and its role in cancer

Abstract

The endoplasmic reticulum (EnR) stress is a common phenomenon in various cancers such as breast, colorectal, skin and hepatocellular carcinoma. Several pathophysiological events (e.g., radiation, aneuploidy, oncogenic transformation and tumour microenvironment) and pharmacological inducers (e.g., thapsigargin, tunicamycin and brefeldin A) can induce EnR stress and initiate the unfolded protein response (UPR) signalling pathway. Tumour microenvironmental factors such as low pH, hypoxia, nutrient starvation, and elevated levels of free radicals cause UPR activation in cancer cells. The UPR signalling pathway has three major sensors which are localised at the EnR membrane, including IRE1, ATF6 and PERK. These three molecules sense any changes in protein folding capacity (accumulation of misfolded proteins) and activate a variety of transcription factors such as ATF6, ATF4, CHOP and XBP1. These downstream effectors of the UPR induce the expression of a wide array of target genes including EnR chaperones and genes involved in ERAD (endoplasmic reticulum associated degradation) to enhance the protein folding capacity of the cell and to decrease the unfolded protein load of the EnR. However, if the primary stimulus causing protein misfolding in the EnR is prolonged or excessive, apoptosis ensues. The exact mechanism involved in transition of the UPR from a cell survival to cell death response is not clearly understood. xiv MicroRNAs are a class of endogenous, short (19-22 nucleotides in length) non-coding RNAs that play a pivotal role in gene expression regulation by translational repression or degradation of target transcripts. MicroRNAs usually interact with the 3’ untranslated region (UTR) of their target mRNA to downregulate its expression. Computational analysis predicts that more than 30% of animal genes may be subject to regulation by miRNAs, suggesting a role for miRNA-mediated gene regulation during UPR. Several studies have shown that miRNA expression is globally repressed in tumour tissues as compared with the tumour adjacent normal tissue. Three potential mechanisms responsible for miRNA dysregulation in cancer are: (i) the miRNAs loci are frequently localized in fragile chromosomic sites and are often altered (methylation, deletion, amplification and translocation) in human cancers (ii) the change in activities of transcription factors (e.g., MYC and P53) that control miRNA expression and (iii) miRNA biogenesis could be affected by the altered expression of DICER, DROSHA and XPO5. MicroRNAs have been shown to act as tumour suppressor and/or oncogene in human cancers. Gain or loss of miRNA functions has been reported in different cancers, with pathological roles in tumour cell proliferation, progression of tumours and metastatic process. Hence, we hypothesize that UPR-regulated microRNAs can influence the cellular response during EnR stress and may contribute to cancer progression. The role of miRNAs in the regulation of the UPR is an emerging area and further research is required to gain an understanding of the pathways involved, which will provide additional therapeutic opportunities. In this study, we identified two UPR regulated miRNAs and determined their effect on cell growth, proliferation, migration and cell fate during conditions of EnR stress.