The aryl hydrocarbon receptor in environmentally induced cervical cancer: A Narrative review

Abstract

The aryl hydrocarbon receptor (AhR) plays a crucial role in cellular responses to various environmental pollutants, including several known carcinogens. As a ligand-activated transcription factor, AhR activation modulates the expression of genes involved in critical cellular processes, including detoxification pathways, cell proliferation and differentiation, and immune system regulation. The AhR exhibits pleiotropic effects under normal physiological conditions, contributing to the development and function of various organ systems. AhR activity is important in angiogenesis, cardiomyocyte differentiation, oocyte maturation, oculomotor nerve formation, and hematopoietic stem cell maintenance. Additionally, AhR plays a role in regulating immune cell differentiation and function, maintaining the integrity of the intestinal epithelium and its associated immune system, and mediating UVB-induced DNA damage repair responses in the skin. It acts as a critical environmental sensor, mediating cellular responses to various exogenous ligands. Importantly, activation or inhibition of AhR affects distinct signaling pathways depending on the specific ligand and cellular context. Ligands for the AhR are divided into exogenous or endogenous and have agonistic or antagonistic activity. Recently, the AhR role was determined in cancer development. It can exert both tumor-promoting and tumor-suppressive effects depending on factors such as the specific ligand, cell type, and tissue microenvironment. Emerging evidence suggests that AhR may represent a promising target for immunotherapy and serve as a potential biomarker for cervical cancer. AhR interacts with apoptotic pathway, immune checkpoint system, steroid hormones, and immune cell regulation process in cervical cancer. Despite its potential significance, the precise role of AhR in cervical cancer development and progression is still unknown. In this review, we describe significant roles of AhR in gynecological cancers; e.g., in cervical cancer.

Keywords

Aryl hydrocarbon receptor / Gynecological cancer / Cervical cancer / Function / Immunotherapy target / Biomarker

ACKNOWLEDGEMENTS

None.

AUTHORS CONTRIBUTIONS

Authors have equal contribution for this manuscript includ-ing conceptualization, investigation, writing-original draft, and writing-review & editing.

ETHICAL STATEMENT

Ethical statement is not applicable for this review article.

FUNDING

None.

CONFLICTS OF INTEREST DISCLOSURE

The author declares that there is no conflicts of interest.

ETHICS APPROVAL

The Publication Ethics Committee of the Sciedu Press. The journal’s policies adhere to the Core Practices established by the Committee on Publication Ethics (COPE).

PROVENANCE AND PEER REVIEW

Not commissioned; externally double-blind peer reviewed.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

DATA SHARING STATEMENT

No additional data are available.

OPEN ACCESS

This is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

COPYRIGHTS

Copyright for this article is retained by the author(s), with first publication rights granted to the journal.

References

[1] Therachiyil L, Hussein OJ, Uddin S, et al. Regulation of the aryl hy-drocarbon receptor in cancer and cancer stem cells of gynecological malignancies: An update on signaling pathways. Seminars in Cancer Biology. 2022; 86(3): 1186-1202. https://doi.org/10.1016/j.semcancer.2022.10.003

[2] Wahid M, Dar SA, Jawed A, et al. Microbes in gynecologic cancers: causes or consequences and therapeutic potential. Semin. Cancer Biol. 2021; 86(2): 1179-1189. https://doi.org/10.1016/j.semcancer.2021.07.013

[3] Razavi ZS, Tajiknia V, Majidi S, et al. Gynecologic cancers and non-coding RNAs: Epigenetic regulators with emerging roles. Crit. Rev. Oncol. Hematol. 2021; 157: 103192. https://doi.org/10.1016/j.critrevonc.2020.103192

[4] Badaracco G, Savarese A, Micheli A, et al. Persistence of HPV after radio-chemotherapy in locally advanced cervical cancer. Oncol. Rep. 2020; 23: 1093-1099.

[5] Liu SY, Zheng PS. High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget. 2013; 4: 2462-2475. https://doi.org/10.18632/oncotarget.1578

[6] Yao T, Wu Z, Liu Y, et al. Aldehyde dehydrogenase 1 (ALDH1) positivity correlates with poor prognosis in cervical cancer. J. Int. Med. Res. 2014; 42(4): 1038-1042. https://doi.org/10.1177/0300060514527060

[7] Hou T, Zhang W, Tong C, et al. Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome. BMC Cancer. 2015; 15: 785. https://doi.org/10.1186/s12885-015-1826-4

[8] Xuan YH, Li GL, Jiang HY, et al. Relationship between hedgehog signaling pathway molecules and HPV16 infection in uterine cervical cancers. Chinese J. Pathol. 2009; 38 (3): 178-182.

[9] Groeneweg JW, Foster R, Growdon WB, et al. Notch signaling in serous ovarian cancer. J. Ovarian Res. 2014; 7: 95. https://doi.org/10.1186/s13048-014-0095-1

[10] Yan B, Liu S, Shi Y, et al. Activation of AhR with nuclear IKK regulates cancer stem-like properties in the occurrence of radioresis-tance. Cell Death Dis. 2018; 9(5): 490. https://doi.org/10.1038/s41419-018-0542-9

[11] Wu C, Yu S, Tan Q, et al. Role of AhR in regulating cancer stem cell-like characteristics in choriocarcinoma. Cell Cycle. 2018; 17: 2309-2320. https://doi.org/10.1080/15384101.2018.1535219

[12] Fan Y, Boivin GP, Knudsen ES, et al. The Ah receptor has a tumor sup-pressor function in liver carcinogenesis. Cancer Res. 2010; 70: 212-220. https://doi.org/10.1158/0008-5472.CAN-09-3090

[13] Paris A, Tardif N, Galibert MD, et al. AhR and cancer: From gene profiling to targeted therapy. Int. J. Mol. Sci. 2021; 22(2): 752. https://doi.org/10.3390/ijms22020752

[14] Denison MS, Soshilov AA, He G, et al. Exactly the same but differ-ent: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 2011; 124: 1-22. https://doi.org/10.1093/toxsci/kfr218

[15] Singh D, Vignat J, Lorenzoni V, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. The Lancet Global Health. 2023; 11(2): e197-e206. https://doi.org/10.1016/S2214-109X(22)00501-0

[16] Gardner AB, Charo LM, Mann AK, et al. Ovarian, uterine, and cervical cancer patients with distant metastases at diagnosis: most common locations and outcomes. Clin. Exp. Metastasis. 2020; 37(1):107-113. https://doi.org/10.1007/s10585-019-10007-0

[17] Bolhassani A, Mohit E, Rafati S. Different spectra of therapeutic vaccine development against HPV infections. Hum. Vaccin. 2009; 5(10): 671-689. https://doi.org/10.4161/hv.5.10.9370

[18] Khairkhah N, Bolhassani A, Rajaei F, et al. Systemic delivery of spe-cific and efficient CRISPR/Cas9 system targeting HPV16 oncogenes using LL-37 antimicrobial peptide in C57BL/6 mice. J. Med. Virol. 2023; 95(7): e28934. https://doi.org/10.1002/jmv.28934

[19] Abbasifarid E, Bolhassani A, Irani S, et al. Synergistic effects of exo-somal crocin or curcumin compounds and HPV L1-E 7 polypeptide vaccine construct on tumor eradication in C57BL/6 mouse model. PLoS One. 2021; 16(10): e0258599. https://doi.org/10.1371/journal.pone.0258599

[20] Burmeister CA, Khan SF, Schäfer G, et al. Cervical cancer therapies: Current challenges and future perspectives. Tumour Virus Res. 2022; 13: 200238. https://doi.org/10.1016/j.tvr.2022.200238

[21] Ramos A, Sadeghi S, Tabatabaeian H. Battling chemoresistance in cancer: Root causes and strategies to uproot them. Int. J. Mol. Sci. 2021; 22(17): 9451.https://doi.org/10.3390/ijms22179451

[22] Wang J, Mijiti Y, Chen Y, et al. Aryl hydrocarbon receptor is a prognostic biomarker and is correlated with immune responses in cervical cancer. Bioengineered. 2021; 12(2): 11922-11935. https://doi.org/10.1080/21655979.2021.2006953

[23] Paris A, Tardif N, Galibert MD, et al. AhR and cancer: from gene profiling to targeted therapy. Int. J. Mol. Sci. 2021; 22(2): 752. https://doi.org/10.3390/ijms22020752

[24] Organista Nava J, Gómez Gómez Y, Garibay-Cerdenares OL, et al. Cervical cancer stem cell-associated genes: Prognostic impli-cations in cervical cancer. Oncology Letters. 2019; 18(1): 7-14. https://doi.org/10.3892/ol.2019.10307

[25] Olivero C, Lanfredini S, Borgogna C, et al. HPV-induced field cancerisation: transformation of adult tissue stem cell into can-cer stem cell. Frontiers in Microbiology. 2018; 9: 546. https://doi.org/10.3389/fmicb.2018.00546

[26] Vishnoi K, Mahata S, Tyagi A, et al. Cross-talk between human pa-pillomavirus oncoproteins and hedgehog signaling synergistically promotes stemness in cervical cancer cells. Scientific Reports. 2016; 6(1): 34377. https://doi.org/10.1038/srep34377

[27] Liu SY, Zheng PS. High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget. 2013; 4(12): 2462. https://doi.org/10.18632/oncotarget.1578

[28] Yao T, Lu R, Li Y, et al. ALDH 1 might influence the metastatic capability of HeLa cells. Tumor Biology. 2015; 36: 7045-7051. https://doi.org/10.1007/s13277-015-3398-y

[29] Hou T, Zhang W, Tong C, et al. Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome. BMC Cancer. 2015; 15: 1-8. https://doi.org/10.1186/s12885-015-1826-4

[30] Wu C, Yu S, Tan Q, et al. Role of AhR in regulating cancer stem cell-like characteristics in choriocarcinoma. Cell Cycle. 2018; 17(18): 2309-2320. https://doi.org/10.1080/15384101.2018.1535219

[31] To KK, Yu L, Liu S, et al. Constitutive AhR activation leads to con-comitant ABCG2-mediated multidrug resistance in cisplatin-resistant esophageal carcinoma cells. Mol. Carcinog. 2012; 51(6): 449-464. https://doi.org/10.1002/mc.20810

[32] Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer. 2014; 14(12):801-814. https://doi.org/10.1038/nrc3846

[33] Hidaka T, Fujimura T, Aiba S. Aryl hydrocarbon receptor modulates carcinogenesis and maintenance of skin cancers. Front. Med. 2019; 6: 194. https://doi.org/10.3389/fmed.2019.00194

[34] Wang Z, Snyder M, Kenison JE, et al. How the AHR became im-portant in cancer: The role of chronically active AHR in cancer aggression. Int. J. Mol. Sci. 2021; 22: 387. https://doi.org/10.3390/ijms22010387

[35] Giannone JV, Li W, Probst M, et al. Prolonged depletion of AH recep-tor without alteration of receptor mRNA levels after treatment of cells in culture with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Biochemical Pharmacology. 1998; 55(4): 489-497. https://doi.org/10.1016/S0006-2952(97)00493-0

[36] Li EY, Huang WY, Chang YC, et al. Aryl hydrocarbon receptor ac-tivates NDRG 1 transcription under hypoxia in breast cancer cells. Scientific Reports. 2016; 6: 20808. https://doi.org/10.1038/srep20808

[37] Hernandez-Ochoa I, Karman BN, Flaws JA. The role of the Aryl hydrocarbon receptor in the female reproductive system. Biochem. Pharm. 2009; 77: 547-559. https://doi.org/10.1016/j.bcp.2008.09.037

[38] Bian Y, Li Y, Shrestha G, et al. ITE, an endogenous aryl hydrocarbon receptor ligand, suppresses endometrial cancer cell proliferation and migration. Toxicology. 2019; 421: 1-8. https://doi.org/10.1016/j.tox.2019.03.017

[39] Ding B, Sun W, Han S, et al. Cytochrome P 450 1A1 gene poly-morphisms and cervical cancer risk: A systematic review and meta-analysis. Medicine. 2018; 97(13): e0210. https://doi.org/10.1097/MD.0000000000010210

[40] Wongpratate M, Settheetham-Ishida W, Phuthong S, et al. Genetic polymorphisms of the human cytochrome P 450 1A1 (CYP1A1) and cervical cancer susceptibility among Northeast Thai women. Asian Pacific Journal of Cancer Prevention. 2020; 21(1): 243. https://doi.org/10.31557/APJCP.2020.21.1.243

[41] Alshammari FO, Al-Saraireh YM, Youssef AM, et al. Cytochrome P 450 1B1 overexpression in cervical cancers: cross-sectional study. Interactive Journal of Medical Research. 2021; 10(4): e31150. https://doi.org/10.2196/31150

[42] Helaoui A, Sfar S, Boudhiba N, et al. Association of xenobiotic-metabolizing genes polymorphisms with cervical cancer risk in the Tunisian population. Molecular Biology Reports. 2022; 50(2): 949-959. https://doi.org/10.1007/s11033-022-07945-6

[43] Ishihara Y, Kado SY, Bein KJ, et al. Aryl hydrocarbon receptor sig-naling synergizes with TLR/NF-B-signaling for induction of IL-22 through canonical and non-canonical AhR pathways. Frontiers in Toxicology. 2022; 3: 787360. https://doi.org/10.3389/ftox.2021.787360

[44] Kenison JE, Wang Z, Yang K, et al. The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through im-mune checkpoint regulation. P.N.A.S. 2021; 118(19): e2012692118. https://doi.org/10.1073/pnas.2012692118

[45] Stockinger B, Meglio PD, Gialitakis M, et al. The aryl hydrocarbon receptor: multitasking in the immune system. Annual Review of Immunology. 2014; 32: 403-432. https://doi.org/10.1146/annurev-immunol-032713-120245

[46] Low HY, Lee YC, Lee YJ, et al. Reciprocal regulation between Indoleamine 2, 3-dioxigenase 1 and Notch 1 involved in radiation response of cervical cancer stem cells. Cancers. 2020; 12(6): 1547. https://doi.org/10.3390/cancers12061547

[47] Mnif W, Zidi I, Balaguer P. Potential anti-cervical carcinoma drugs with agonist and antagonist AhR/PXR activities. European Society of Medicine. 2017; 4(8): 1-16. https://doi.org/10.18103/mra.v4i8.899

[48] Sasaki-Kudoh E, Kudo I, Kakizaki Y, et al. Cisplatin Inhibits AhR Activation. American Journal of Molecular Biology. 2018; 8: 69-82. https://doi.org/10.4236/ajmb.2018.81006

[49] Arellano-Gutiérrez CV, Quintas-Granados LI, Cortés H, et al. Indole-3-Carbinol, a phytochemical aryl hydrocarbon receptor-ligand, in-duces the mRNA overexpression of UBE2L3 and cell prolifera-tion arrest. Curr. Issues Mol. Biol. 2022; 44: 2054-2068. https://doi.org/10.3390/cimb44050139

[50] Chen B, Ye P, Chen Y, et al. Involvement of the estrogen and proges-terone axis in cancer stemness: elucidating molecular mechanisms and clinical significance. Frontiers in Oncology. 2020; 10: 1657. https://doi.org/10.3389/fonc.2020.01657

[51] van den Brand A, Rubinstein E, de Jong P, et al. Assessing anti-estrogenic effects of AHR ligands in primary human and rat endome-trial epithelial cells. Reproductive Toxicology. 2020; 96: 202-208. https://doi.org/10.1016/j.reprotox.2020.07.003

[52] Gardner AB, Charo LM, Mann AK, Ovarian, uterine, and cervical cancer patients with distant metastases at diagnosis: most common lo-cations and outcomes. Clinical & Experimental Metastasis. 2020; 37:107-113. https://doi.org/10.1007/s10585-019-10007-0

[53] Dunlap TL, Howell CE, Mukand N, et al. Red clover aryl hydro-carbon receptor (AhR) and estrogen receptor (ER) agonists enhance genotoxic estrogen metabolism. Chemical Research in Toxicology. 2017; 30(11): 2084-2092. https://doi.org/10.1021/acs.chemrestox.7b00237

[54] Wagage S, John B, Krock BL, et al. The aryl hydrocarbon receptor promotes IL-10 production by NK cells. The Journal of Immunology. 2014; 192(4): 1661-1670. https://doi.org/10.4049/jimmunol.1300497

[55] Funatake CJ, Marshall NB, Kerkvliet NI. 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin alters the differentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mecha-nism that is dependent on aryl hydrocarbon receptor in CD4+ T cells. Journal of Immunotoxicology. 2008; 5(1); 81-91. https://doi.org/10.1080/15476910802019037

[56] Li J, Bhattacharya S, Zhou J, et al. Aryl hydrocarbon receptor ac-tivation suppresses EBF1 and PAX5 and impairs human B lym-phopoiesis. The Journal of Immunology. 2017; 199(10): 3504-3515. https://doi.org/10.4049/jimmunol.1700289

[57] Goudot C, Coillard A, Villani AC, et al. Aryl hydrocarbon recep-tor controls monocyte differentiation into dendritic cells versus macrophages. Immunity. 2017; 47(3): 582-596. https://doi.org/10.1016/j.immuni.2017.08.016

[58] Hollingshead BD, Beischlag TV, DiNatale BC, et al. Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of Interleukin 6 in MCF-7 cells. Cancer Res. 2008; 68(10): 3609-3617. https://doi.org/10.1158/0008-5472.CAN-07-6168

[59] Poland A, Glover E.Chlorinated dibenzo-p-dioxins: Potent induc-ers of delta-aminolevulinic acid synthetase and aryl hydrocarbon hydroxylase. II. A study of the structure-activity relationship. Mol. Pharmacol. 1973; 9: 736-747.

[60] Poland A, Glover E. Studies on the mechanism of toxicity of the chlorinated dibenzo-p-dioxins. Environ. Health Perspect. 1973; 5:245-251. https://doi.org/10.1289/ehp.7305245

[61] Poland A, Glover E. 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin: A po-tent inducer of aminolevulinic acid synthetase. Science. 1973; 179:476-477. https://doi.org/10.1126/science.179.4072.476

[62] Poland A, Glover E, Robinson J, et al. Genetic expression of aryl hydrocarbon hydroxylase activity: Induction of monooxy-genase activites and cytochrome P1-450 formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice genetically “nonresponsive” to other aromatic hydrocarbons. J. Biol. Chem. 1974; 249: 5599-5606. https://doi.org/10.1016/S0021-9258(20)79769-3

[63] Perdew GH, Poland A. Purification of the Ah receptor from C57BL/6J mouse liver. J. Biol. Chem. 1988; 263: 9848-9852. https://doi.org/10.1016/S0021-9258(19)81594-6

[64] Bradfield CA, Glover E, Poland A. Purification and N-terminal amino acid sequence of the Ah receptor from the C57BL/6J mouse. Mol. Pharmacol. 1991; 39: 13-19.

[65] Burbach KM, Poland A, Bradfield CA.Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc. Natl. Acad. Sci. USA. 1992; 89: 8185-8189. https://doi.org/10.1073/pnas.89.17.8185

[66] Ema M, Sogawa K, Watanabe N, et al. cDNA cloning and structure of mouse putative Ah receptor. Biochem. Biophys. Res. Commun. 1992; 184: 246-253. https://doi.org/10.1016/0006-291X(92)91185-S

[67] Wang J, Li Z, Gao A, et al. The prognostic landscape of tumor-infiltrating immune cells in cervical cancer. Biomed. Pharmacother. 2019; 120: 109444. https://doi.org/10.1016/j.biopha.2019.109444

[68] Baba T, Mimura J, Gradin K, et al. Structure and expression of the Ah receptor repressor gene. J. Biol. Chem. 2001; 276: 33101-33110. https://doi.org/10.1074/jbc.M011497200

[69] Mimura J, Ema M, Sogawa K, et al. Identification of a novel mech-anism of regulation of Ah (dioxin) receptor function. Genes Dev. 1999; 13: 20-25. https://doi.org/10.1101/gad.13.1.20

[70] Evans BR, Karchner SI, Allan LL, et al. Repression of aryl hydro-carbon receptor (AHR) signaling by AHR repressor: Role of DNA binding and competition for AHR nuclear translocator. Mol. Phar-macol. 2008; 73: 387-398. https://doi.org/10.1124/mol.107.040204

[71] Hahn ME, Allan LL, Sherr DH. Regulation of constitutive and in-ducible AHR signaling: Complex interactions involving the AHR repressor. Biochem. Pharmacol. 2009; 77: 485-497. https://doi.org/10.1016/j.bcp.2008.09.016

[72] Zudaire E, Cuesta N, Murty V, et al. The aryl hydrocarbon recep-tor repressor is a putative tumor suppressor gene in multiple hu-man cancers. J. Clin. Investig. 2008; 118 (2): 640-650. https://doi.org/10.1172/JCI30024