雌激素受体信号通路与胃癌关系的研究进展

doi:10.3969/j.issn.1004-616x.2024.02.013

摘要/Abstract

摘要： 雌激素在人体内主要与核内雌激素受体(ER)α和ERβ特异性结合，通过调控下游靶基因表达发挥基因组效应。此外，雌激素还可与膜G蛋白偶联雌激素受体1(GPER1)结合，介导快速非基因组效应并对转录因子磷酸化修饰来调控基因表达。研究表明，ER受体和GPER1受体在胃癌发生发展中发挥着不可或缺的作用，雌激素结合相应的雌激素受体后激活不同的信号通路，影响胃癌细胞的增殖、侵袭和迁移等生物学行为。本文旨在总结分析不同的雌激素受体信号通路对胃癌组织细胞的作用及调控机制，这些信号通路包括磷脂酰肌醇3-激酶(PI3K)/Akt、丝裂原活化蛋白激酶(MAPK)、Wnt/β-catenin、核因子(NF)-κB等，为进一步研究雌激素及其受体在胃癌发生发展中的作用以及肿瘤的防治提供可能的线索和靶点。

关键词: 雌激素, 胃肿瘤, 核受体, 膜受体, 信号通路

中图分类号:

刘冠彤, 袁永轩, 高阳, 苏中静. 雌激素受体信号通路与胃癌关系的研究进展[J]. 癌变·畸变·突变, 2024, 36(2): 155-158.

参考文献

[1] RUGGIERO R J, LIKIS F E. Estrogen:physiology, pharmacology, and formulations for replacement therapy[J]. J Midwifery Womens Health, 2002, 47(3):130-138.
[2] KNOWLTON A A, LEE A R. Estrogen and the cardiovascular system[J]. Pharmacol Ther, 2012, 135(1):54-70.
[3] WOOLLEY C S. Effects of estrogen in the CNS[J]. Curr Opin Neurobiol, 1999, 9(3):349-354.
[4] PATEL S, HOMAEI A, RAJU A B, et al. Estrogen:the necessary evil for human health, and ways to tame it[J]. Biomed Pharmacother, 2018, 102:403-411.
[5] JIA M, DAHLMAN-WRIGHT K, GUSTAFSSON J Å. Estrogen receptor alpha and beta in health and disease[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29(4):557-568.
[6] CARMECI C, THOMPSON D A, RING H Z, et al. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer[J]. Genomics, 1997, 45(3):607-617.
[7] OLDE B,LEEB-LUNDBERG L M. GPR30/GPER1:searching for a role in estrogen physiology[J]. Trends Endocrinol Metab, 2009, 20(8):409-416.
[8] PROSSNITZ E R,BARTON M. The G-protein-coupled estrogen receptor GPER in health and disease[J]. Nat Rev Endocrinol, 2011, 7(12):715-726.
[9] BOON W C,CHOW J D Y,SIMPSON E R. The multiple roles of estrogens and the enzyme aromatase[J]. Prog Brain Res, 2010, 181:209-232.
[10] FUENTES N, SILVEYRA P. Estrogen receptor signaling mechanisms[J]. Adv Protein Chem Struct Biol, 2019, 116:135-170.
[11] JEMAL A, BRAY F, CENTER M M, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011, 61(2):69-90.
[12] QIN J, LIU M, DING Q S, et al. The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells[J]. Mol Cell Biochem, 2014, 395(1/2):99-107.
[13] RYU W S, KIM J H, JANG Y J, et al. Expression of estrogen receptors in gastric cancer and their clinical significance[J]. J Surg Oncol, 2012, 106(4):456-461.
[14] YI J H, DO I G, JANG J, et al. Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer[J]. Sci Rep, 2014, 4:7592.
[15] TIAN S, ZHAN N, LI R X, et al. Downregulation of G protein-coupled estrogen receptor (GPER) is associated with reduced prognosis in patients with gastric cancer[J]. Med Sci Monit, 2019, 25:3115-3126.
[16] LEE S J,KIM T W,PARK G L,et al. G protein-coupled estrogen receptor-1 agonist induces chemotherapeutic effect via ER stress signaling in gastric cancer[J]. BMB Rep, 2019, 52(11):647-652.
[17] FATTAHI S, AMJADI-MOHEB F, TABARIPOUR R, et al. PI3K/AKT/mTOR signaling in gastric cancer:Epigenetics and beyond[J]. Life Sci, 2020, 262:118513.
[18] PENG X R, SHI J Y, ZHAO Z P, et al. Emetine, a small molecule natural product,displays potent anti-gastric cancer activity via regulation of multiple signaling pathways[J]. Cancer Chemother Pharmacol, 2023, 91(4):303-315.
[19] WANG Y, CHU F H, LIN J, et al. Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification[J]. J Ethnopharmacol, 2021, 279:114399.
[20] BARZI A,LENZ A M,LABONTE M J,et al. Molecular pathways:Estrogen pathway in colorectal cancer[J]. Clin Cancer Res,2013,19(21):5842-5848.
[21] GE H, LIANG C J, LI Z X, et al. DcR3 induces proliferation, migration, invasion, and EMT in gastric cancer cells via the PI3K/AKT/GSK-3β/β-catenin signaling pathway[J]. Onco Targets Ther, 2018, 11:4177-4187.
[22] XU E, XIA X F, JIANG C Y, et al. GPER1 silencing suppresses the proliferation,migration,and invasion of gastric cancer cells by inhibiting PI3K/AKT-mediated EMT[J]. Front Cell Dev Biol, 2020, 8:591239.
[23] XU H W,CHEN Y R,OUYANG S S,et al. HOTAIR plays an oncogenic role in gastric cancer through microRNA and SNP[J]. Neoplasma, 2021, 68(3):465-471.
[24] KANG S,PARK M,CHO J Y,et al. Tumorigenic mechanisms of estrogen and Helicobacter pylori cytotoxin-associated gene A in estrogen receptor α-positive diffuse-type gastric adenocarcinoma[J]. Gastric Cancer, 2022, 25(4):678-696.
[25] KIM H S,KIM M H,JEONG M,et al. EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells[J]. Anticancer Res, 2004, 24(2B):747-753.
[26] LEI Y,CHEN X,MO J L,et al. Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the MAPK/Erk-Pax6 signal pathway[J]. Glia, 2023, 71(7):1648-1666.
[27] GUO Y J, PAN W W, LIU S B, et al. ERK/MAPK signalling pathway and tumorigenesis[J]. Exp Ther Med, 2020, 19(3):1997-2007.
[28] DOS SANTOS E G, DIEUDONNE M N, PECQUERY R, et al. Rapid nongenomic E2 effects on p42/p44 MAPK,activator protein-1,and cAMP response element binding protein in rat white adipocytes[J]. Endocrinology, 2002, 143(3):930-940.
[29] UR RAHMAN M S,CAO J. Estrogen receptors in gastric cancer:advances and perspectives[J]. World J Gastroenterol, 2016, 22(8):2475-2482.
[30] WANG Y, ZHENG L X, SHANG W J, et al. Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer[J]. Cell Death Differ, 2022, 29(11):2190-2202.
[31] AKHAVANFAR R, SHAFAGH S G, MOHAMMADPOUR B, et al. A comprehensive insight into the correlation between ncRNAs and the Wnt/β-catenin signalling pathway in gastric cancer pathogenesis[J]. Cell Commun Signal, 2023, 21(1):166.
[32] ZHANG L, XIONG W Q, XIONG Y, et al. 17β-Estradiol promotes vascular endothelial growth factor expression via the Wnt/β-catenin pathway during the pathogenesis of endometriosis[J]. Mol Hum Reprod, 2016, 22(7):526-535.
[33] YU Z Y, JIANG X Y, QIN L, et al. Correction:a novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination[J]. Oncogene, 2021, 40(14):2622-2623.
[34] ABANCENS M,HARVEY B J,MCBRYAN J. GPER agonist G1 prevents wnt-induced JUN upregulation in HT29 colorectal cancer cells[J]. Int J Mol Sci, 2022, 23(20):12581.
[35] SOKOLOVA O, NAUMANN M. NF-κB signaling in gastric cancer[J]. Toxins, 2017, 9(4):119.
[36] LI S N,KHOI P N,YIN H,et al. Sulforaphane suppresses the nicotine-induced expression of the matrix metalloproteinase-9 via inhibiting ROS-mediated AP-1 and NF-κB signaling in human gastric cancer cells[J]. Int J Mol Sci, 2022, 23(9):5172.
[37] HAZAFA A, REHMAN K U, JAHAN N, et al. The role of polyphenol (flavonoids) compounds in the treatment of cancer cells[J]. Nutr Cancer, 2020, 72(3):386-397.
[38] YANG X F,ZHANG J Q,MA J,et al. GPER governs the immune infiltration of gastric cancer and activates the NF-κB/ROS/Apoptosis pathway in gastric mucosal epithelium[J]. Int Immunopharmacol, 2023, 122:110641.
[39] MORGAN M J,LIU Z G. Crosstalk of reactive oxygen species and NF-κB signaling[J]. Cell Res, 2011, 21(1):103-115.