Introduction
Three UPR signaling pathways are involved in carcinogenesis
IRE1α-XBP1 pathway
PERK-eIF2α pathway
ATF6α pathway
ER stress regulates ncRNAs expression
ER stress influences miRNAs expression
Effectors | Regulators | Targets | Cancer type | Biological process | References |
---|---|---|---|---|---|
miR-214 | NA | XBP-1 | HCC | Regulates HCC cell proliferation and apoptosis | [73] |
miR-199a-3p/5p | NA | NA | HCC | NA | [73] |
miR-1281 | NA | USP93 | Osteosarcoma | Promotes ER stress-mediated apoptosis | [75] |
miR-34a | IRE1α | MYC, cyclin D1, CDK4 | AML | Inhibition of IRE1α increases expression of miR-34a in AML cells | [78] |
miR-216b | PERK | c-Jun | Osteosarcoma | Sensitizes cells to ER stress-dependent apoptosis | [79] |
miR-211 | PERK | CHOP | Osteosarcoma | Inhibits circadian rhythm oscillations and ongoing protein synthesis | [81] |
miR-211 | PERK | CHOP | Mammary tumors | Regulates ER stress-dependent apoptosis | [84] |
miR-663 | NA | ZBTB7A | Osteosarcoma | Regulates ER stress-induced cell apoptosis | [88] |
miR-23a-3p | NA | PTEN AKT | HCC | Upregulates macrophage PD-L1 expression and inhibits T cell function, which promotes tumor cells to escape immune surveillance | [115] |
miR-765 | NA | FOXA2 | Melanoma | Enhances tumor stem cell renewal and apoptosis inhibition | [120] |
miR-663 | NA | TGFB1 | HCC | Regulates ER stress-induced apoptosis | [184] |
miR-221/222 | NA | NA | HCC | Promotes ER stress-mediated apoptosis | [185] |
miR-346 | XBP1 | TAP1 | Cervical cancer | Reduces MHC class I-associated antigen presentation | [186] |
ER stress regulates lncRNAs expression
LncRNAs | Expression level | Tumor type | UPR-related mechanism | Biological process | References |
---|---|---|---|---|---|
GOLGA2P10 | Upregulated | HCC | CHOP can directly bind to the GOLGA2P10 promoter | Induces resistance to cytotoxic effect of ER stress | [26] |
MALAT1 | Upregulated | Colorectal cancer | Activated IRE1 and PERK signaling pathways increase MALAT1expression | Promotes the migration of CRC cells | [87] |
MIAT | Upregulated | Breast cancer | Overexpression of GRP78 upregulates the expression of MIAT by increasing OCT4 in 5-fluorouracil resistant cells | Contributes to 5-FU resistance | [175] |
NcRNAs regulate UPR in cancer progression
MiRNAs regulate UPR in cancer
Regulators | Effectors | Targets | Cancer type | Biological process | Reference |
---|---|---|---|---|---|
miR-233 | HSP70 | HSPA1A | Osteosarcoma | Regulates apoptosis | [25] |
miR-216b | CHOP | c-JUN | Osteosarcoma | Sensitizes cells to apoptosis | [79] |
miR-30c-2* | XBP1 | XBP1 | Cervical cancer | Influences the fate of cells challenged with ER stress | [80] |
miR-657 | CHOP | NA | Hematological cancer | Attenuates the expression of CHOP, p-ATF2, and PARP cleavage to reverse SSD-induced apoptosis | [91] |
miR-211 | CHOP | NA | Lymphoma, multiple myeloma | Attenuates COM-induced apoptosis | [92] |
miR-34c | eIF2α CHOP IRE1α | HMGB1 | NSCLC | Inhibits cell proliferation, promotes apoptosis, and induces ER stress in NSCLC cells | [93] |
miR-451a | GRP78 PERK elF2α ATF4 CHOP | BAP31 | Colorectal cancer | Inhibits proliferation and increases apoptosis | [98] |
miR-410 | CHOP GRP94 GRP78 eIF2α | ERLIN2 | Breast cancer | Inhibits cell migration and invasion and EMT | [108] |
miR-224 miR-520c | ATF6α | TUSC3 | NSCLC | Enhances UPR and ERAD to promote metastatic potential of | [109] |
miR-122 | GRP78 CHOP | CDK4 | HCC | Regulates anticancer drug–mediated apoptosis | [167] |
miR-146a | CHOP | CHOP | Lung cancer | Reduces the sensitivity of lung cancer cells to cisplatin | [171] |
miR-7112-3p | PERK | PERK | Colorectal cancer | Enhances apoptosis in CX-1 cells treated with DVDMS-PDT | [174] |
miR-1202 | GRP78 | Rab1A | Glioma | Inhibits proliferation and induces ER stress and apoptosis | [187] |
miR-15b-5p | GRP78 | Rab1A | HCC | Induces apoptosis | [188] |
miR-1291 | IRE1α | IRE1α | HCC | Regulates glypican-3 mRNA expression | [189] |
miR-30d miR-181a miR-199a-5p | GRP78 | GRP78 | Prostate cancer | Suppresses GRP78 levels and GRP78-mediated chemoresistance | [190] |
Survival and apoptosis
Invasion and metastasis
Tumor microenvironment
Cancer stem cell characteristics
LncRNAs regulate the UPR in cancer progression
LncRNAs | Expression level | Tumor type | UPR-related mechanism | Biological process | References |
---|---|---|---|---|---|
MEG3 | Breast cancer | Increases ER stress-related proteins (GRP78, IRE1, PERK, ATF6, and CHOP) and NF-κB | Inhibits growth, induces apoptosis | [121] | |
Downregulated | ESCC | Increases ER stress-related proteins (GRP78, IRE1, PERK, ATF6, and CHOP), caspase-9, and cleaved caspase-3 | Inhibits cell growth, induces apoptosis | [122] | |
Downregulated | HCC | Increases ER stress-related proteins (GRP78, IRE1, PERK, ATF6, and CHOP) | Inhibits proliferation, induces apoptosis | [123] | |
Downregulated | Cervical carcinoma | Competing endogenous RNA of miR-7-5p | Accelerate ER stress-mediated apoptosis | [124] | |
Downregulated | Colorectal carcinoma | Increases ER stress-related proteins (GRP78, ATF6, and CHOP) | Suppresses proliferation and invasion | [125] | |
CASC2 | Downregulated | NSCLC | Increases PERK mRNA stability | Promotes radiation-induced apoptosis | [127] |
FOXD3-AS1 | Upregulated | NPC | Silencing FOXD3-AS1 promotes ER stress-induced apoptosis by competitively binding to let-7e-5p | Silencing of FOXD3-AS1 induces apoptosis | [128] |
LincRNA-p21 | Downregulated | HCC | Induces expression of IRE1, CHOP, and GRP78 and upregulates the phosphorylation level of PERK | Contributes to sorafenib-induced ER stress and apoptosis | [132] |
NORAD | Upregulated | Melanoma | Knockdown of NORAD can inhibit UPR-related genes including GRP78, CHOP, and eIF2α | Promotes invasion and migration | [136] |
NEAT1 | Upregulated | Multiple myeloma | Promotes expression of UPR-related proteins CHOP, XBP-1, and IRE1 | Promotes proliferation, migration, and invasion | [141] |
LUCRC | Upregulated | Colorectal cancer | Induces the expression of GRP78 | Promotes proliferation, migration, and invasion | [142] |
OR3A4 | Upregulated | Osteosarcoma | Knockdown of OR3A4 inhibits the expression of G6PD, blocking the pentose phosphate pathway and resulting in ER-stress | Promotes proliferation, colony formation | [145] |
Apoptosis
Invasion and metastasis
Tumor metabolism
CircRNAs regulate the UPR in cancer
CircRNAs | Expression level | Tumor type | UPR-related Mechanism | Biological process | References |
---|---|---|---|---|---|
Circ_002117 | Downregulated | Gastric cancer | Increases expression of GRP78, IRE1, eIF2α, and CHOP | Promotes apoptosis | [148] |
CircCDR1 | Upregulated | OSCC | Increases eIF2α expression | Inhibits apoptosis | [149] |
CircRNA_101036 | Downregulated | OSCC | Increases CHOP and ROS levels | Induces cell apoptosis | [150] |