Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer
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REVIEW
Interplay between endoplasmic reticulum stress and non‑coding RNAs in cancer Tianming Zhao, Juan Du and Hui Zeng*
Abstract To survive, cancer cells are subjected to various internal and external adverse factors, including genetic mutations, hypoxia, nutritional deficiencies, and drug toxicity. All of these factors result in the accumulation of unfolded proteins in the endoplasmic reticulum, which leads to a condition termed endoplasmic reticulum stress (ER stress) and triggers the unfolded protein response (UPR). UPR downstream components strictly control transcription and translation reprogramming to ensure selective gene expression, including that of non-coding RNA (ncRNAs), to adapt to adverse environments. NcRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating target gene expression and protein translation, and their aberrant expression is related to tumor development. Dysregulation of ncRNAs is involved in the regulation of various cellular characteristics of cancer cells, including growth, apoptosis, metastasis, angiogenesis, drug sensitivity, and tumor stem cell properties. Notably, ncRNAs and ER stress can regulate each other and collaborate to determine the fate of tumor cells. Therefore, investigating the interaction between ER stress and ncRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we summarize the ER stress-triggered UPR signaling pathways involved in carcinogenesis followed by the mutual regulation of ER stress and ncRNAs in cancer, which provide further insights into the understanding of tumorigenesis and therapeutic strategies. Keywords: ER stress, UPR, ncRNAs, Cancer, Interplay Introduction The endoplasmic reticulum (ER), a multifunctional organelle, is involved in regulating fundamental cellular processes, including nascent protein folding and modification, calcium storage, liquid biosynthesis, and detoxification. Unfavorable external and internal factors, such as hypoxia, nutrient deprivation, drug-induced toxicity, acidic extracellular pH, and genetic mutation, result in unfolded or misfolded protein accumulation in the ER lumen. Under these conditions, tumor cells trigger endoplasmic reticulum stress (ER stress) to reestablish intracellular homeostasis and promote cell survival. This self-adaptive response process is called the unfolded *Correspondence: [email protected] Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China
protein response (UPR), which aims to restore protein homeostasis [1, 2]. If these unfavorable factors persistently exist and cells fail to achieve self-adaptation, the ER-related apoptotic pathway is initiated [3, 4]. Briefly, there are three transmembrane sensor proteins located on the ER membrane involved in the UPR, including inositol-requiring enzyme 1 (IRE1), protein kinase RNAlike ER kinase (PERK), and activating transcription factor 6 (ATF6). In
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