AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO025100047
Submit to EJMO
Cite this article
8
Download
260
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Investigating the role of neurotransmitter system and neurotrophic factor-related genes in human papillomavirus-associated cervical lesions

Ângela Inácio1,2,3* ,  Laura Aguiar1,2,3 ,  João Caldeira1,2 ,  Margarida Gato1,2 ,  Raquel Carrilho1,2 ,  Patrícia Pires1,2 ,  Joana Ferreira1,2,3 ,  Luís Coelho1,2 ,  Rui Medeiros4 ,  Manuel Bicho1,2,3 ,  Maria Clara Bicho3,5
Show Less
1 Bento da Rocha Cabral Scientific Research Institute, Lisbon, Portugal
2 Faculty of Medicine, University of Lisbon, Lisbon, Portugal
3 Institute of Environmental Health, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
4 Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Porto, Portugal
5 Institute of Preventive Medicine and Public Health, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
EJMO, 025100047 https://doi.org/10.36922/EJMO025100047
Received: 7 March 2025 | Revised: 16 April 2025 | Accepted: 23 April 2025 | Published online: 9 May 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
Cite
XML
Abstract

Human papillomavirus (HPV) infection plays a crucial role in cervical carcinogenesis. The link between the autonomic nervous system and tumor biology is increasingly being recognized. Understanding how neural signaling pathways interact with HPV oncogenesis could open new avenues for therapeutic intervention. We aim to study the contribution of the autonomic nervous system-related genes to the HPV-associated cervical lesions. A population of 140 HPV-infected women presenting cervical lesions was compared to a control population. Genes/variants under study were: BDNF/rs6265, NTRK2/rs2289656, NGF/rs6330, SLC6A4/5-HTT variable number tandem repeats intron 2, HTR2A/rs6313, ADRBR2/rs1042713, and CHRNA5/rs16969968. Samples were genotyped using polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism, and endpoint genotyping. Statistical analysis revealed a genetic contribution for SCL6A4, ADRB2, and CHRNA5. SCL6A4 showed statistically significant association in the codominant (p=0.003) and dominant models (p=0.024, odds ratio [OR] = 2.301). ADRB2 showed statistically significant association in the codominant (p<0.001), dominant (p=0.024, OR = 4.728), recessive (p<0.001, OR = 4.856), and allelic models (p<0.001, OR = 4.091), while CHRNA5 showed statistically significant association in the dominant model (p=0.030, OR = 0.529). We conclude that there is a genetic contribution of the adrenergic (ADRB2), cholinergic (CHRNA5), and serotonergic (SLC6A4) systems to cervical lesions associated with HPV infections.

Keywords
Human papillomavirus infection
Autonomic nervous system
Genetics
Funding
This research was funded by the Bento da Rocha Cabral Scientific Research Institute.
Conflict of interest
The authors declare they have no competing interests.
References
  1. WHO. Cancer Today; 2024. Available from: https://gco.iarc. who.int/today/en [Last accessed on 2025 Feb 20].

 

  1. Mlynarczyk-Bonikowska B, Rudnicka L. HPV Infections-classification, pathogenesis, and potential new therapies. Int J Mol Sci. 2024;25(14):7616. doi: 10.3390/ijms25147616

 

  1. Muñoz N, Castellsagué X, Berrington de González A, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006;24(Suppl 3):1-10. doi: 10.1016/j.vaccine.2006.05.115

 

  1. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393(10167):169-182. doi: 10.1016/S0140-6736(18)32470-X

 

  1. Dai S, Mo Y, Wang Y, et al. Chronic stress promotes cancer development. Front Oncol. 2020;19(10):1492. doi: 10.3389/fonc.2020.01492

 

  1. Wang C, Shen Y, Ni J, Hu W, Yang Y. Effect of chronic stress on tumorigenesis and development. Cell Mol Life Sci. 2022;79(9):485. doi: 10.1007/s00018-022-04455-3

 

  1. Kuebler U, Fischer S, Mernone L, Breymann C, Abbruzzese E, Ehlert U. Is stress related to the presence and persistence of oncogenic human papillomavirus infection in young women? BMC Cancer. 2021;21(1):419. doi: 10.1186/s12885-021-08010-4

 

  1. Oyola M, Handa R. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: Sex differences in regulation of stress responsivity. Physiol Behav. 2017;176(3):139-148. doi: 10.1080/10253890.2017.1369523

 

  1. Krizanova O, Babula P, Pacak K. Stress, catecholaminergic system and cancer. Stress. 2016;19(4):419-428. doi: 10.1080/10253890.2016.1203415

 

  1. Sam C, Bordoni B. Physiology, acetylcholine. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.

 

  1. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389. doi: 10.1126/science.1083968

 

  1. Paine NJ, Watkins LL, Blumenthal JA, Kuhn CM, Sherwood A. Associations of depressive and anxiety symptoms with 24-hour urinary catecholamines in individuals with untreated high blood pressure. Psychosom Med. 2016;77(2):136-144. doi: 10.1097/PSY.0000000000000144

 

  1. Shioda N, Imai Y, Yabuki Y, Sugimoto W, Yamaguchi K, Wang Y. Dopamine D2L receptor deficiency causes stress vulnerability through 5-HT1A receptor dysfunction in serotonergic neurons. J Neurosci. 2019;39(38):7551-7563. doi: 10.1523/JNEUROSCI.0079-19.2019

 

  1. Brindley RL, Bauer MB, Walker LA, et al. Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter. Pharmacol Res. 2019;140:56-66. doi: 10.1016/j.phrs.2018.06.008

 

  1. Cao Y. Tumorigenesis as a process of gradual loss of original cell identity and gain of properties of neural precursor/ progenitor cells. Cell Biosci. 2017;7(1):61. doi: 10.1186/s13578-017-0188-9

 

  1. Li Y, Yang S, Sadaoui NC, et al. Sustained adrenergic activation of YAP1 induces anoikis resistance in cervical cancer cells. iScience. 2020;24;23(7):101289. doi: 10.1016/j.isci.2020.101289

 

  1. Lutfy K, Aimiuwu O, Mangubat M, et al. Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors. J Neurochem. 2012;120(6):1108-1116. doi: 10.1111/j.1471-4159.2011.07633.x

 

  1. Weisstaub NV, Zhou M, Lira A, et al. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science. 2006;313(5786):536-540. doi: 10.1126/science.1123432

 

  1. Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: From regeneration to cancer. Cancer Cell. 2017;31(3):342-354. doi: 10.1016/j.ccell.2017.02.005

 

  1. Mancino M, Ametller E, Gascón P, Almendro V. The neuronal influence on tumor progression Biochim Biophys. 2011;1816(2):105-118. doi: 10.1016/j.bbcan.2011.04.005

 

  1. Benzaquen D, Lawrence YR, Taussky D, Zwahlen D, Oehler C, Champion A. The crosstalk between nerves and cancer-a poorly understood phenomenon and new possibilities. Cancers (Basel). 2024;6(10):1875. doi: 10.3390/cancers16101875

 

  1. Bernstock JD, Gerstl JVE, Chen JA, et al. The case for neurosurgical intervention in cancer neuroscience. Neurosurgery. 2025;96(1):10-17. doi: 10.1227/neu.0000000000003039

 

  1. Le TT, Oudin MJ. Understanding and modeling nerve-cancer interactions. Dis Model Mech. 2023;16(1):dmm049729. doi: 10.1242/dmm.049729

 

  1. Magnon C, Hall SJ, Lin J, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142):1236361. doi: 10.1126/science.1236361

 

  1. Zhao CM, Hayakawa Y, Kodama Y, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med. 2014;6(250):250ra115. doi: 10.1126/scitranslmed.3009569

 

  1. Peterson SC, Eberl M, Vagnozzi AN, et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell. 2015;16(4):400-412. doi: 10.1016/j.stem.2015.02.006

 

  1. Roda N, Blandano G, Pelicci PG. Blood vessels and peripheral nerves as key players in cancer progression and therapy resistance. Cancers (Basel). 2021;13(17):4471. doi: 10.3390/cancers13174471

 

  1. Silverman DA, Martinez VK, Dougherty PM, Myers JN, Calin GA, Amit M. Cancer-associated neurogenesis and nerve-cancer cross-talk. Cancer Res. 2021;81(6):1431-1440. doi: 10.1158/0008-5472.CAN-20-2793

 

  1. Adriaenssens E, Vanhecke E, Saule P, et al. Nerve growth factor is a potential therapeutic target in breast cancer. Cancer Res. 2008;68(2):346-351. doi: 10.1158/0008-5472.CAN-07-1183

 

  1. Watanabe T, Katayama Y, Kimura S, Yoshino A. Control of proliferation and survival of C6 glioma cells with modification of the nerve growth factor autocrine system. J Neurooncol. 1999;41(2):121-128. doi: 10.1023/a:1006127624487

 

  1. Demir IE, Tieftrunk E, Schorn S, Friess H, Ceyhan GO. Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochim Biophys Acta. 2016;1866(1):37-50. doi: 10.1016/j.bbcan.2016.05.003

 

  1. Bapat AA, Munoz RM, Von Hoff DD, Han H. Blocking nerve growth factor signaling reduces the neural invasion potential of pancreatic cancer cells. PLoS One. 2016;11(10):e0165586. doi: 10.1371/journal.pone.0165586

 

  1. Lei Y, Tang L, Xie Y, et al. Gold nanoclusters-assisted delivery of NGF siRNA for effective treatment of pancreatic cancer. Nat Commun. 2017;8:15130. doi: 10.1038/ncomms15130

 

  1. Brodeur GM. Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer. 2003;3(3):203-216. doi: 10.1038/nrc1014

 

  1. Wang L, Li J, Wang R, et al. NGF signaling interacts with the Hippo/YAP pathway to regulate cervical cancer progression. Front Oncol. 2021;11:688794. doi: 10.3389/fonc.2021.688794

 

  1. Yuan Y, Ye HQ, Ren QC. Proliferative role of BDNF/TrkB signaling is associated with anoikis resistance in cervical cancer. Oncol Rep. 2018;40(2):621-634. doi: 10.3892/or.2018.6515

 

  1. Aziz AUR, Zhang J, Zhang C, Yu X, Wang D. The mutual interplay between NTRK fusion genes and human papillomavirus infection in cervical cancer progression. Mol Clin Oncol. 2024;21(4):67. doi: 10.3892/mco.2024.2765

 

  1. Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol. 2000;38(1):357-361. doi: 10.1128/JCM.38.1.357-361.2000

 

  1. Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Futur Oncol. 2010;6(12):1863-1881. doi: 10.2217/fon.10.142

 

  1. Iftikhar A, Islam M, Shepherd S, Jones S, Ellis I. Cancer and stress: Does it make a difference to the patient when these two challenges collide? Cancers (Basel). 2021;13(2):1-29. doi: 10.3390/cancers13020163

 

  1. Chen G, Qiu L, Gao J, et al. Stress hormones: Emerging targets in gynecological cancers. Front Cell Dev Biol. 2021;9:699487. doi: 10.3389/fcell.2021.699487

 

  1. Lai LP, Mitchell J. β2-adrenergic receptors expressed on murine chondrocytes stimulate cellular growth and inhibit the expression of Indian hedgehog and collagen type XJ. Cell Biochem. 2008;104(2):545-553. doi: 10.1002/jcb.21646

 

  1. Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci. 2006;119(3):592-602. doi: 10.1242/jcs.02772

 

  1. Floras JS. Epinephrine and the genesis of hypertension. Hypertension. 1992;19(1):1-18. doi: 10.1161/01.hyp.19.1.1

 

  1. Carlos-Escalante JA, de Jesús-Sánchez M, Rivas-Castro A, Pichardo-Rojas PS, Arce C, Wegman-Ostrosky T. The use of antihypertensive drugs as coadjuvant therapy in cancer. Front Oncol. 2021;11:660943. doi: 10.3389/fonc.2021.660943

 

  1. Fan Y, Khan NH, Farhan Ali Khan M, et al. Association of hypertension and breast cancer: Antihypertensive drugs as an effective adjunctive in breast cancer therapy. Cancer Manag Res. 2022;14:1323-1329. doi: 10.2147/CMAR.S350854

 

  1. Liggett SB. The pharmacogenetics of beta2-adrenergic receptors: Relevance to asthma. J Allergy Clin Immunol. 2000;105(2):S487-S492. doi: 10.1016/s0091-6749(00)90048-4

 

  1. Green SA, Liggett SB. A proline-rich region of the third intracellular loop imparts phenotypic β1- versus β2-adrenergic receptor coupling and sequestration. J Biol Chem. 1994;269(42):26215-26219. doi: 10.1016/s0021-9258(18)47181-5

 

  1. Bierut LJ, Stitzel JA, Wang JC, et al. Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry. 2008;165(9):1163-1171. doi: 10.1176/appi.ajp.2008.07111711

 

  1. Carhart-Harris RL, Nutt DJ. Serotonin and brain function: A tale of two receptors. J Psychopharmacol. 2017;31(9): 1091-1120. doi: 10.1177/0269881117725915

 

  1. Siwiec M, Hess G. The use of serotonin type 7 receptor antagonists as a pharmacological intervention in chronic stress. Insights from animal studies. Int J Biochem Cell Biol. 2024;175:106647. doi: 10.1016/j.biocel.2024.106647

 

  1. Bauer MB, Currie KPM. Serotonin and the serotonin transporter in the adrenal gland. Vitam Horm. 2024;124: 39-78. doi: 10.1016/bs.vh.2023.06.002

 

  1. Tjurmina OA, Armando I, Saavedra JM, Goldstein DS, Murphy DL. Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology. 2002;143(12):4520-4526. doi: 10.1210/en.2002-220416

 

  1. Murphy DL, Lesch KP. Targeting the murine serotonin transporter: Insights into human neurobiology. Nat Rev Neurosci. 2008;9(2):85-96. doi: 10.1038/nrn2284

 

  1. Brindley RL, Bauer MB, Blakely RD, Currie KPM. An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells. Neuropharmacology. 2016;110:438-448. doi: 10.1016/j.neuropharm.2016.08.015

 

  1. Brindley RL, Bauer MB, Blakely RD, Currie KPM. Serotonin and serotonin transporters in the adrenal medulla: A potential hub for modulation of the sympathetic stress response. ACS Chem Neurosci. 2017;8(5):943-954. doi: 10.1021/acschemneuro.7b00026

 

  1. Hranilovic D, Stefulj J, Schwab S, et al. Serotonin transporter promoter and intron 2 polymorphisms: Relationship between allelic variants and gene expression. Biol Psychiatry. 2004;55(11):1090-1094. doi: 10.1016/j.biopsych.2004.01.029

 

  1. Lovejoy EA, Scott AC, Fiskerstrand CE, Bubb VJ, Quinn JP. The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit. Eur J Neurosci. 2003;17(2):417-420. doi: 10.1046/j.1460-9568.2003.02446.x

 

  1. Garrido MP, Torres I, Vega M, Romero C. Angiogenesis in gynecological cancers: Role of neurotrophins. Front Oncol. 2019;9:913. doi: 10.3389/fonc.2019.00913

 

  1. Moon A, Won KY, Lee JY, Kang I, Lee SK, Lee J. Expression of BDNF, TrkB, and p53 in early-stage squamous cell carcinoma of the uterine cervix. Pathology. 2011;43(5): 453-458. doi: 10.1097/PAT.0b013e3283484a3a

 

  1. Laganà AS, Monti N, Fedeli V, Gullo G, Bizzarri M. Does Alpha-lipoic acid improve effects on polycystic ovary syndrome? Eur Rev Med Pharmacol Sci. 2022;26(4): 1241-1247. doi: 10.26355/eurrev_202202_28116

 

  1. Coldebella D, Buzzaccarini G, Ferrari J, et al. Inositols administration: Further insights on their biological role. Ital J Gynaecol Obstet. 2023;35(1):30-36.

 

  1. Habib N, Buzzaccarini G, Centini G, et al. Impact of lifestyle and diet on endometriosis: A fresh look to a busy corner. Prz Menopauzalny. 2022;21(2):124-132. doi: 10.5114/pm.2022.116437

 

  1. Chen S, Wu F, Zhang J, Zhu J, Zhou X, Zhi X. ADRB2 regulates the proliferation and metastasis of gastrointestinal stromal tumor cells by enhancing the ETV1-c-KIT signaling. J Oncol. 2023;2023:6413796. doi: 10.1155/2023/6413796

 

  1. Ji L, Xu F, Zhang J, et al. ADRB2 expression predicts the clinical outcomes and is associated with immune cells infiltration in lung adenocarcinoma. Sci Rep. 2022;12(1):15994. doi: 10.1038/s41598-022-19991-y

 

  1. Tu Y, Yao S, Chen Q, Li W, Song Y, Zhang P. 5-Hydroxytryptamine activates a 5-HT/c-Myc/SLC6A4 signaling loop in non-small cell lung cancer. Biochim Biophys. 2022;1866(4):130093. doi: 10.1016/j.bbagen.2022.130093

 

  1. Li Q, Li J, Wang J, et al. PLEK2 mediates metastasis and invasion via α5-nAChR activation in nicotine-induced lung adenocarcinoma. Mol Carcinog. 2024;63(2):253-265. doi: 10.1002/mc.23649

 

  1. Kang G, Jiao Y, Pan P, et al. α5-nAChR/STAT3/CD47 axis contributed to nicotine-related lung adenocarcinoma progression and immune escape. Carcinogenesis. 2023;44(10-11):773-784. doi: 10.1093/carcin/bgad061

 

  1. Feng C, Mao W, Yuan C, Dong P, Liu Y. Correction: Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway. Cell Death Dis. 2024;12(12):922. doi: 10.1038/s41419-024-07261-w

 

  1. Fu Y, Ci H, Du W, Dong Q, Jia H. CHRNA5 contributes to hepatocellular carcinoma progression by regulating YAP activity. Pharmaceutics. 2022;12(2):275. doi: 10.3390/pharmaceutics14020275
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept