Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

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: Cancer; ER stress; Interplay; UPR; ncRNAs.

Fig. 1

Role of the unfolded protein response (UPR) in cancer. Cancer cells frequently encounter intrinsic and extrinsic stresses that disturb protein folding in the endoplasmic reticulum (ER), including oncogene activation, hypoxia, nutrient deprivation, drug-induced toxicity, and low pH, which trigger ER stress to reestablish intracellular homeostasis. Upon detecting an accumulation of ER unfolded and misfolded proteins, the UPR is initiated by three transmembrane ER proteins: inositol-requiring enzyme 1(IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Once ER stress occurs, Bip dissociates from these three ER membrane enzymes, resulting in their activation and initiating the relevant downstream signaling pathway. Activation of the UPR can transcriptionally regulate tumor characteristics

Fig. 2

ER stress regulates miRNAs and lncRNAs expression. a Sustained IRE1α RNase resulted in rapid degradation of miR-17, miR-34a, miR-96, and miR-125b. PERK-induced miR-211 inhibits CHOP, Bmal1, and Clock in tumor cells. PERK promotes translocation of NF-κB into the nucleus to control the expression of miR-30c-2* under ER stress. miR-30c-2* in turn negatively regulates the expression of XBP1s mRNA. b Activated IRE1 and PERK signaling pathways increase the MALAT1 expression. The transcription factor CHOP transcriptionally regulates expression of lnc-MGC and GOLGA2P10

Fig. 3

MiRNAs regulate tumor characteristics including apoptosis, invasion, EMT, and metastasis by regulating the UPR. a MiR-657 mimics can attenuate the CHOP expression to reverse apoptosis. Anticancer compounds downregulate the expression of miR-211 in U937 and U266 cells. The downregulated miR-211 is associated with CHOP and triggers tumor cell apoptosis. MiR-34c overexpression significantly increased the levels of eIF2α and IRE1α by directly targeting the 3ʹUTR of HMGB1 and inhibiting HMGB1 translation, promoting apoptosis. The expression of miR-216b directly targets c-JUN and inhibition of c-JUN sensitizes cells to apoptosis. MiR-451a increases apoptosis by suppressing BAP31 to induce ER stress. MiR-233 downregulates the heat shock protein 70 (Hsp70) protein levels and downstream JNK/JUN signaling pathways, thereby enhancing apoptosis. JUN can bind to the promoter region of miR-223 to promote its transcription, forming a feedback loop. b Some chemotherapy drugs activate the PERK pathway by upregulating the expression levels of SNAI1 and ZEB1. LAMP3 is regulated by activation of the PERK/eIF2a/ATF4 arm of the UPR to promote lymph node metastasis. CHOP induced by PERK- eIF2α can bind to GDF15 and activate its transcription, regulating EMT and metastasis. MiR-410 directly targets ERLIN2 to up-regulate UPR components to inhibit the migration, invasion, and EMT of breast cancer cells. MiR-224/-520c-dependent TUSC3 deletion enhances NSCLC metastasis via increased ATF6α activity

Fig. 4

ER stress is transmitted by extracellular vesicles harboring miRNAs in the tumor microenvironment. Extracellular vesicles derived from tumor cells carry miRNAs and/or proteins that transmit ER stress from tumor cells to recipient cells, thus affecting the function of recipient cells

Fig. 5

LncRNAs regulate the tumor characteristics apoptosis (a), invasion and metastasis (b), and metabolism (c) by regulating the UPR. a FOXD3-AS1 could competitively bind to let-7e-5p to regulate RCN1. Silencing FOXD3-AS1 or upregulating let-7e-5p increased the expression profiles of GRP78, CHOP, and ATF4, consequently promoting ER stress-induced apoptosis. MEG3 increased the expression of ER stress-related proteins, including GRP78, IRE1, PERK, ATF6, and CHOP, consequently inhibiting growth and induce the apoptosis of cancer cells. In addition, MEG3 competitively combines with miR-7-5p or miR-103a-3p to promote ER stress-mediated apoptosis. Ectopic expression of lincRNA-p21 activates ER stress by inducing the expression of IRE1, CHOP, and GRP78 and upregulating the PERK phosphorylation level. Sorafenib also could increase the expression of lincRNA-p21 to induce ER stress-mediated apoptosis. Overexpression of CASC2 increases the stability of PERK mRNA, which triggers the PERK/eIF2α/CHOP pathway and promotes radiation-induced apoptosis. b NORAD may act as a sponge for miR‐205 and reduce the transcriptional repression of the miR-205 target gene EGLN2. NORAD silencing can inhibit UPR-related gene expression including that of GRP78, CHOP, and eIF2α. Downregulation of NORAD also restrained malignant melanoma cell migration and invasion. Overexpression of NEAT1 promote expression of the UPR-related proteins IRE1, XBP-1, and CHOP. Resveratrol attenuates the effects of NEAT1 on inducing ER stress. LUCRC can regulate Bip expression and induce the splicing of XBP1 from XBP1u (unspliced) to XBP1s (spliced), resulting in activation of UPR to promote tumor progression. c OR3A4 functions as a sponge for miR-1207-5p, modulating the target gene glucose-6-phosphate dehydrogenase (G6PD). Knockdown of OR3A4 inhibits the expression of G6PD, blocks the pentose phosphate pathway, and significantly reduces the level of nicotinamide adenine dinucleotide phosphate (NADPH). This abnormal metabolic pathway upregulates the redox state content, which increases the expression of PERK and IRE1 in osteosarcoma cells

Fig. 6

CircRNAs mediate tumor survival and apoptosis by UPR. Circ_002117 induced ER stress by upregulating GRP78, IRE1, eIF2α, and CHOP, subsequently resulting in the apoptosis of gastric cancer cells. CircCDR1as induces ER stress by upregulating eIF2α under hypoxia conditions, increasing OSCC cell survival. Moreover, circCDR1as promoted hypoxia-induced autophagy in OSCC cells by sponging miR-671-5p. CircRNA_101036 induced the UPR pro-apoptosis pathway by increasing CHOP protein, which induces apoptosis