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Autophagy is a cellular survival pathway that is necessary for the degradation of cellular constituents such as long-lived proteins and damaged organelles. Conditions resulting in cellular stress such as starvation or hypoxia might activate autophagy. Being at the crossroads of various cellular response pathways, dysregulation of autophagy might result in pathological states including cancer and neurodegenerative diseases. Autophagy has also been shown to participate in stemness. MicroRNAs were introduced as novel regulators of autophagy, and accumulating results underlined the fact that they constituted an important layer of biological control mechanism on the autophagic activity.MicroRNAs are protein noncoding small RNAs that control cellular levels of transcripts and proteins through posttrancriptional mechanisms. Novel miRNAs in human and mouse genomes are yet to be identified. Considering the emerging role of autophagy in health and disease, identification of novel autophagy-regulating miRNAs and determination of relations between miRNA expression and physiological and pathological conditions might contribute to a better understanding of mechanisms governing health and disease. High-throughput techniques were developed for miRNA profiling, yet for a thorough characterization and miRNA target determination, miRNA cloning remains as an important step. Here, we describe a modified miRNA cloning method for the characterization of novel autophagy-regulating miRNAs.

Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers’s disease, Parkinson’s disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.

To cope with stress factors including nutrient deprivation, toxins, abnormal protein accumulation, cells developed mechanisms to repair damage caused by stress or, in cases where the damage is irrepairable, cell death responses. Autophagy and apoptosis are among the most important stress and death response mechanisms. Autophagy is defined by sequestration and transport of cytoplasm pieces and organelles by double- or multi-membrane vesicles and, degradation of the cargo following fusion with lysosomes. Consequently, autophagy plays an important role in elimination of long-lived proteins, damaged organelles, mutant proteins and even intracellular bacteria and viruses, helping to survive stressfull conditions. Paradoxically, depending stress and cell type, autophagy may kill cells by a non-apoptotic programmed cell death mechanism called “autophagic cell death”. Recent studies including our publications suggest that miRNAs add a novel layer of regulation to autophagy pathways. Molecular details of autophagy regulation by miRNAs started to emerge in the last 2 years. In this chapter we will summarize acccumulating data on this novel mechanism of autophagy regulation.