HPV16相关宫颈癌中PI3K/Akt自噬通路与HIF-1α的关系

doi:10.12280/gjszjk.20210613

摘要/Abstract

摘要：

几乎90%以上的宫颈癌都有高危人乳头瘤病毒（high risk human papilloma virus,HR-HPV）的持续感染,尤其当患者感染HPV16时,高级别宫颈上皮内瘤变或宫颈癌的发生风险可进一步上升。研究表明人类肿瘤中存在低氧现象,缺氧诱导因子1α（hypoxia-inducible factor-1α,HIF-1α）与低氧微环境关系最为密切,HIF-1α的活化能促进肿瘤生长,已成为目前的研究热点。经典的磷脂酰肌醇3激酶（phosphoinositide 3-kinase,PI3K）/蛋白激酶B（protein kinase B,Akt）自噬通路抑制自噬,并且在多种人类肿瘤中表达失调,其异常活化使细胞异常增殖、分化,促进肿瘤生长。综述HPV16感染可能引起HIF-1α与PI3K/Akt自噬通路变化的不同机制,探讨HPV16相关宫颈癌中PI3K/Akt自噬通路及HIF-1α的表达意义。

关键词: 宫颈肿瘤, 人乳头瘤病毒16, 缺氧诱导因子1,α亚基, 磷酸肌醇3-激酶类, 蛋白激酶类, PI3K/Akt自噬通路

Abstract:

Almost 90% of cervical cancer has the high risk of human papilloma virus (HR-HPV) persistent infection. The risk of high-grade cervical intraepithelial neoplasia or cervical cancer can be further increased in patients with HPV16 persistent infection. Studies have shown that hypoxia exists in human tumors. Hypoxia-inducible factor-1α (HIF-1α) is closely related to hypoxia microenvironment. The activation of HIF-1α can promote tumor growth, which has become a research hotspot. The classic phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt) autophagy pathway inhibits autophagy, and the expression of this pathway is out of order in a variety of human tumors. Its abnormal activation makes abnormal cell proliferation and differentiation, which promotes the growth of tumor. This article reviews the different mechanisms of HPV16 infection that may cause the changes of HIF-1α and PI3K/Akt autophagy pathways, and their relationship in cervical cancer.

Key words: Uterine cervical neoplasms, Human papillomavirus 16, Hypoxia-inducible factor 1,alpha subunit, Phosphatidylinositol 3-kinases, Protein kinases, PI3K/Akt autophagy pathway

吴桐桐, 王志莲. HPV16相关宫颈癌中PI3K/Akt自噬通路与HIF-1α的关系[J]. 国际生殖健康/计划生育, 2022, 41(2): 172-176.

WU Tong-tong, WANG Zhi-lian. The Relationship between PI3K/Akt Autophagy Pathway and HIF-1α in HPV16 Related Cervical Cancer[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(2): 172-176.

参考文献 35

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660. doi: 10.3322/caac.21660 URL
[2]	Zhang M, Song Y, Yu L. LncRNA PTCSC3 suppressed cervical carcinoma cell invasion and proliferation via regulating miR-574-5p[J]. Am J Transl Res, 2019, 11(11):7186-7194. pmid: 31814920
[3]	Kim HJ, Cho HS, Ban HS, et al. Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer[J]. Biochem Biophys Res Commun, 2020, 523(3):726-732. doi: 10.1016/j.bbrc.2020.01.031. doi: 10.1016/j.bbrc.2020.01.031 URL
[4]	Bossler F, Hoppe-Seyler K, Hoppe-Seyler F. PI3K/AKT/mTOR Signaling Regulates the Virus/Host Cell Crosstalk in HPV-Positive Cervical Cancer Cells[J]. Int J Mol Sci, 2019, 20(9):2188. doi: 10.3390/ijms20092188. doi: 10.3390/ijms20092188 URL
[5]	Yun CW, Lee SH. The Roles of Autophagy in Cancer[J]. Int J Mol Sci, 2018, 19(11):3466. doi: 10.3390/ijms19113466. doi: 10.3390/ijms19113466 URL
[6]	Infantino V, Santarsiero A, Convertini P, et al. Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target[J]. Int J Mol Sci, 2021, 22(11):5703. doi: 10.3390/ijms22115703. doi: 10.3390/ijms22115703 URL
[7]	Silva N, Sabino AP, Tafuri A, et al. Lack of association between methylenetetrahydrofolate reductase C677T polymorphism, HPV infection and cervical intraepithelial neoplasia in Brazilian women[J]. BMC Med Genet, 2019, 20(1):100. doi: 10.1186/s12881-019-0831-x. doi: 10.1186/s12881-019-0831-x URL
[8]	Molijn A, Jenkins D, Chen W, et al. The complex relationship between human papillomavirus and cervical adenocarcinoma[J]. Int J Cancer, 2016, 138(2):409-416. doi: 10.1002/ijc.29722. doi: 10.1002/ijc.29722 pmid: 26334557
[9]	Zacapala-Gómez AE, Del Moral-Hernández O, Villegas-Sepúlveda N, et al. Changes in global gene expression profiles induced by HPV 16 E6 oncoprotein variants in cervical carcinoma C33-A cells[J]. Virology, 2016, 488:187-195. doi: 10.1016/j.virol.2015.11.017. doi: 10.1016/j.virol.2015.11.017 pmid: 26655236
[10]	Li X, Gong Z, Zhang L, et al. Autophagy knocked down by high-risk HPV infection and uterine cervical carcinogenesis[J]. Int J Clin Exp Med, 2015, 8(7):10304-10314.
[11]	Arizmendi-Izazaga A, Navarro-Tito N, Jiménez-Wences H, et al. Metabolic Reprogramming in Cancer: Role of HPV 16 Variants[J]. Pathogens, 2021, 10(3):347. doi: 10.3390/pathogens10030347. doi: 10.3390/pathogens10030347 URL
[12]	Jiang L, Shi S, Shi Q, et al. Similarity in the functions of HIF-1α and HIF-2α proteins in cervical cancer cells[J]. Oncol Lett, 2017, 14(5):5643-5651. doi: 10.3892/ol.2017.6837. doi: 10.3892/ol.2017.6837
[13]	Xu S, Catapang A, Braas D, et al. A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers[J]. Cancer Metab, 2018, 6:7. doi: 10.1186/s40170-018-0181-8. doi: 10.1186/s40170-018-0181-8 URL
[14]	Tang X, Zhang Q, Nishitani J, et al. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells[J]. Clin Cancer Res, 2007, 13(9):2568-2576. doi: 10.1158/1078-0432.CCR-06-2704. doi: 10.1158/1078-0432.CCR-06-2704 URL
[15]	Xu X, Liu T, Wu J, et al. Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer[J]. Cancer Gene Ther, 2019, 26(11/12):356-365. doi: 10.1038/s41417-019-0078-x. doi: 10.1038/s41417-019-0078-x URL
[16]	Wang F, Tan WH, Liu W, et al. Effects of miR-214 on cervical cancer cell proliferation, apoptosis and invasion via modulating PI3K/AKT/mTOR signal pathway[J]. Eur Rev Med Pharmacol Sci, 2018, 22(7):1891-1898. doi: 10.26355/eurrev_201804_14711. doi: 10.26355/eurrev_201804_14711
[17]	Hao Y, Huang J, Ma Y, et al. Asiatic acid inhibits proliferation, migration and induces apoptosis by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway in human colon carcinoma cells[J]. Oncol Lett, 2018, 15(6):8223-8230. doi: 10.3892/ol.2018.8417. doi: 10.3892/ol.2018.8417
[18]	Zhang W, Zhou Q, Wei Y, et al. The exosome-mediated PI3k/Akt/mTOR signaling pathway in cervical cancer[J]. Int J Clin Exp Pathol, 2019, 12(7):2474-2484.
[19]	Rahmani F, Ferns GA, Talebian S, et al. Role of regulatory miRNAs of the PI3K/AKT signaling pathway in the pathogenesis of breast cancer[J]. Gene, 2020, 737:144459. doi: 10.1016/j.gene.2020.144459. doi: S0378-1119(20)30128-1 pmid: 32045660
[20]	方瑾, 罗泳仪, 易佰蓉. 宫颈上皮内瘤变临床特点及预后情况分析[J]. 河北医药, 2017, 39(8):1137-1140. doi: 10.3969/j.issn.1002-7386.2017.08.004. doi: 10.3969/j.issn.1002-7386.2017.08.004
[21]	Cuninghame S, Jackson R, Lees SJ, et al. Two common variants of human papillomavirus type 16 E6 differentially deregulate sugar metabolism and hypoxia signalling in permissive human keratinocytes[J]. J Gen Virol, 2017, 98(9):2310-2319. doi: 10.1099/jgv.0.000905. doi: 10.1099/jgv.0.000905 pmid: 28857035
[22]	Cuninghame S, Jackson R, Lees SJ, et al. Two common variants of human papillomavirus type 16 E6 differentially deregulate sugar metabolism and hypoxia signalling in permissive human keratinocytes[J]. J Gen Virol, 2017, 98(9):2310-2319. doi: 10.1099/jgv.0.000905. doi: 10.1099/jgv.0.000905 pmid: 28857035
[23]	Guo Y, Meng X, Ma J, et al. Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction[J]. Int J Mol Sci, 2014, 15(5):7974-7986. doi: 10.3390/ijms15057974. doi: 10.3390/ijms15057974 pmid: 24810689
[24]	Gu NJ, Wu MZ, He L, et al. HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells[J]. J Cancer, 2019, 10(27):6903-6909. doi: 10.7150/jca.37070. doi: 10.7150/jca.37070 URL
[25]	Reyes A, Corrales N, Gálvez N, et al. Contribution of hypoxia inducible factor-1 during viral infections[J]. Virulence, 2020, 11(1):1482-1500. doi: 10.1080/21505594.2020.1836904. doi: 10.1080/21505594.2020.1836904 URL
[26]	Mattoscio D, Medda A, Chiocca S. Human Papilloma Virus and Autophagy[J]. Int J Mol Sci, 2018, 19(6):1775. doi: 10.3390/ijms19061775. doi: 10.3390/ijms19061775 URL
[27]	Poillet-Perez L, White E. Role of tumor and host autophagy in cancer metabolism[J]. Genes Dev, 2019, 33(11/12):610-619. doi: 10.1101/gad.325514.119. doi: 10.1101/gad.325514.119 URL
[28]	Li Z, Liu J, Que L, et al. The immunoregulatory protein B7-H3 promotes aerobic glycolysis in oral squamous carcinoma via PI3K/Akt/mTOR pathway[J]. J Cancer, 2019, 10(23):5770-5784. doi: 10.7150/jca.29838. doi: 10.7150/jca.29838 URL
[29]	Gao T, Zhang X, Zhao J, et al. SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer[J]. Cancer Lett, 2020, 469:89-101. doi: 10.1016/j.canlet.2019.10.029. doi: 10.1016/j.canlet.2019.10.029 URL
[30]	Coppock JD, Lee JH. mTOR, metabolism, and the immune response in HPV-positive head and neck squamous cell cancer[J]. World J Otorhinolaryngol Head Neck Surg, 2016, 2(2):76-83. doi: 10.1016/j.wjorl.2016.05.010. doi: 10.1016/j.wjorl.2016.05.010 URL
[31]	Zhang W, Xiong Z, Wei T, et al. Nuclear factor 90 promotes angiogenesis by regulating HIF-1α/VEGF-A expression through the PI3K/Akt signaling pathway in human cervical cancer[J]. Cell Death Dis, 2018, 9(3):276. doi: 10.1038/s41419-018-0334-2. doi: 10.1038/s41419-018-0334-2 URL
[32]	Ma D, Li Y, Xiao W, et al. Achyranthes bidentata extract protects chondrocytes functions through suppressing glycolysis and apoptosis via MAPK/AKT signaling axis[J]. Am J Transl Res, 2020, 12(1):142-152.
[33]	Dayer G, Masoom ML, Togtema M, et al. Virus-Host Protein-Protein Interactions between Human Papillomavirus 16 E6 A1 and D2/D3 Sub-Lineages: Variances and Similarities[J]. Int J Mol Sci, 2020, 21(21):7980. doi: 10.3390/ijms21217980. doi: 10.3390/ijms21217980 URL
[34]	Bossler F, Kuhn BJ, Günther T, et al. Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling[J]. mBio, 2019, 10(1):e02323-18. doi: 10.1128/mBio.02323-18. doi: 10.1128/mBio.02323-18
[35]	No YR, Lee SJ, Kumar A, et al. HIF1α-Induced by Lysophosphatidic Acid Is Stabilized via Interaction with MIF and CSN5[J]. PLoS One, 2015, 10(9):e0137513. doi: 10.1371/journal.pone.0137513. doi: 10.1371/journal.pone.0137513 URL