Abstract
Endoplasmic reticulum oxidoreductin 1α (ERO1α) is an oxidase that exists in the endoplasmic reticulum and plays an important role in regulating oxidized protein folding and tumor malignant progression. However, the specific role and mechanism of ERO1α in the progression of colorectal cancer (CRC) have not yet been fully elucidated. In this study, 280 specimens of CRC tissues and adjacent noncancerous tissues were collected to detect the expression of ERO1α and analyze the clinical significance. ERO1α was stably knocked-down in RKO and HT29 CRC cells to investigate its function and mechanism in vitro and in vivo. We found that ERO1α was remarkably upregulated in CRC tissues and high ERO1α expression is associated with N stage and poor prognosis of CRC patients. ERO1α knockdown in CRC cells significantly inhibited the proliferation and induced apoptosis while inactivating the PI3K/AKT pathway. Rescue assays revealed that AKT activator 740Y-P could reverse the effects on proliferation and apoptosis of ERO1α knockdown in CRC cells. In vivo tumorigenicity assay also confirmed that ERO1α knockdown suppressed tumor growth. Taken together, our findings demonstrated ERO1α promotes the proliferation and inhibits apoptosis of CRC cells by regulating the PI3K/AKT pathway. High expression of ERO1α is associated with poor prognosis in CRC patients, and ERO1α could be a potential therapeutic target for CRC.
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References
Chen F, Wang Y, Liu Q et al (2020a) ERO1α promotes testosterone secretion in hCG-stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway. J Cell Physiol 235(7–8):5666–5678. https://doi.org/10.1002/jcp.29498
Chen M, Yang J, Li L et al (2020b) Metabolomics reveals that cysteine metabolism plays a role in celastrol-induced mitochondrial apoptosis in HL-60 and NB-4 cells. Sci Rep 10(1):471. https://doi.org/10.1038/s41598-019-57312-y
Elsayed AM, Bayraktar E, Amero P et al (2021) PRKAR1B-AS2 long noncoding RNA promotes tumorigenesis, survival, and chemoresistance via the PI3K/AKT/mTOR pathway. Int J Mol Sci. https://doi.org/10.3390/ijms22041882
Hayes KE, Batsomboon P, Chen WC et al (2019) Inhibition of the FAD containing ER oxidoreductin 1 (Ero1) protein by EN-460 as a strategy for treatment of multiple myeloma. Bioorg Med Chem 27(8):1479–1488. https://doi.org/10.1016/j.bmc.2019.02.016
Hu J, Jin J, Qu Y et al (2020) ERO1α inhibits cell apoptosis and regulates steroidogenesis in mouse granulosa cells. Mol Cell Endocrinol 511:110842. https://doi.org/10.1016/j.mce.2020.110842
Huang K, Zhao W, Wang X et al (2021) Akt inhibition enhanced the growth inhibition effects of low-dose heavy-ion radiation via the PI3K/Akt/p53 signaling pathway in C6 glioblastoma cells. Front Oncol 11:649176. https://doi.org/10.3389/fonc.2021.649176
Jha V, Kumari T, Manickam V et al (2021) ERO1-PDI redox signaling in health and disease. Antioxid Redox Signal 35(13):1093–1115. https://doi.org/10.1089/ars.2021.0018
Jin C, Li Y, Su Y et al (2020) Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26. Cell Death Dis 11(10):844. https://doi.org/10.1038/s41419-020-03048-x
Ke F, Lancaster GI, Grabow S et al (2020) Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice. Cell Death Dis 11(3):185. https://doi.org/10.1038/s41419-020-2376-5
Lei Y, Zang R, Lu Z et al (2020) ERO1L promotes IL6/sIL6R signaling and regulates MUC16 expression to promote CA125 secretion and the metastasis of lung cancer cells. Cell Death Dis 11(10):853. https://doi.org/10.1038/s41419-020-03067-8
Li Z, Zhao S, Zhu S et al (2021) MicroRNA-153-5p promotes the proliferation and metastasis of renal cell carcinoma via direct targeting of AGO1. Cell Death Dis 12(1):33. https://doi.org/10.1038/s41419-020-03306-y
Liu J, Duan Z, Guo W et al (2018) Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nat Commun 9(1):5200. https://doi.org/10.1038/s41467-018-07258-y
Polčic P, Mentel M (2020) Reconstituting the mammalian apoptotic switch in yeast. Genes (Basel). https://doi.org/10.3390/genes11020145
Saaranen MJ, Ruddock LW (2019) Applications of catalyzed cytoplasmic disulfide bond formation. Biochem Soc Trans 47(5):1223–1231. https://doi.org/10.1042/BST20190088
Seol SY, Kim C, Lim JY et al (2016) Overexpression of endoplasmic reticulum oxidoreductin 1-α (ERO1L) is associated with poor prognosis of gastric cancer. Cancer Res Treat 48(4):1196–1209. https://doi.org/10.4143/crt.2015.189
Shergalis AG, Hu S, Bankhead A et al (2020) Role of the ERO1-PDI interaction in oxidative protein folding and disease. Pharmacol Ther 210:107525. https://doi.org/10.1016/j.pharmthera.2020.107525
Shi X, Wu J, Liu Y et al (2020) ERO1L promotes NSCLC development by modulating cell cycle-related molecules. Cell Biol Int 44(12):2473–2484. https://doi.org/10.1002/cbin.11454
Siegel RL, Miller KD, Goding Sauer A et al (2020) Colorectal cancer statistics. CA Cancer J Clin 70(3):145–164. https://doi.org/10.3322/caac.21601
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
Takei N, Yoneda A, Sakai-Sawada K et al (2017) Hypoxia-inducible ERO1α promotes cancer progression through modulation of integrin-β1 modification and signalling in HCT116 colorectal cancer cells. Sci Rep 7(1):9389. https://doi.org/10.1038/s41598-017-09976-7
Tanaka T, Kajiwara T, Torigoe T et al (2015) Cancer-associated oxidoreductase ERO1-α drives the production of tumor-promoting myeloid-derived suppressor cells via oxidative protein folding. J Immunol 194(4):2004–2010. https://doi.org/10.4049/jimmunol.1402538
Tanaka T, Kutomi G, Kajiwara T et al (2016) Cancer-associated oxidoreductase ERO1-α drives the production of VEGF via oxidative protein folding and regulating the mRNA level. Br J Cancer 114(11):1227–1234. https://doi.org/10.1038/bjc.2016.105
Tanaka T, Kutomi G, Kajiwara T et al (2017) Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer. Oncotarget 8(15):24706–24718. https://doi.org/10.18632/oncotarget.14960
Ushioda R, Nagata K (2019) Redox-mediated regulatory mechanisms of endoplasmic reticulum homeostasis. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a033910
Varone E, Decio A, Chernorudskiy A et al (2021) The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions. Oncogene 40(9):1721–1736. https://doi.org/10.1038/s41388-021-01659-y
Wen XQ, Qian XL, Sun HK et al (2020) MicroRNAs: multifaceted regulators of colorectal cancer metastasis and clinical applications. OncoTargets Ther 13:10851–10866. https://doi.org/10.2147/OTT.S265580
Xie H, Li X, Yang W et al (2020a) N6-(2-hydroxyethyl)-adenosine induces apoptosis via ER stress and autophagy of gastric carcinoma cells in vitro and in vivo. Int J Mol Sci. https://doi.org/10.3390/ijms21165815
Xie S, Ni J, Mcfaline-Figueroa JR et al (2020b) Divergent roles of PI3K isoforms in PTEN-deficient glioblastomas. Cell Rep 32(13):108196. https://doi.org/10.1016/j.celrep.2020.108196
Xing J, Bhuria V, Bui KC et al (2020) Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition. Cancers (Basel). https://doi.org/10.3390/cancers12030615
Yan W, Wang X, Liu T et al (2019) Expression of endoplasmic reticulum oxidoreductase 1-α in cholangiocarcinoma tissues and its effects on the proliferation and migration of cholangiocarcinoma cells. Cancer Manag Res 11:6727–6739. https://doi.org/10.2147/CMAR.S188746
Yang S, Yang C, Yu F et al (2018) Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway. Cell Death Dis 9(11):1105. https://doi.org/10.1038/s41419-018-1134-4
Zhang Y, Li T, Zhang L et al (2019) Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer. EBioMedicine 41:408–419. https://doi.org/10.1016/j.ebiom.2019.02.041
Zhang J, Yang J, Lin C et al (2020) Endoplasmic reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in pancreatic cancer. Theranostics 10(18):8400–8414. https://doi.org/10.7150/thno.45124
Zhou H, Li L, Xie W et al (2020) TAGLN and high-mobility group AT-hook 2 (HMGA2) complex regulates TGF-β-induced colorectal cancer metastasis. OncoTargets Ther 13:1049–10498. https://doi.org/10.2147/OTT.S263090
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This work was supported by the National Natural Science Foundation of China (No. 81660417).
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Wu, M., Li, R., Qin, J. et al. ERO1α promotes the proliferation and inhibits apoptosis of colorectal cancer cells by regulating the PI3K/AKT pathway. J Mol Histol 54, 621–631 (2023). https://doi.org/10.1007/s10735-023-10149-2
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DOI: https://doi.org/10.1007/s10735-023-10149-2