Page 259 - EJMO-9-2

Eurasian Journal of
Medicine and Oncology The genetics of chronic stress in cervical lesions

1. Introduction tumor cell proliferation or modulate immune responses
within the tumor microenvironment.
Cervical cancer, a malignancy of the uterus, accounted for
approximately 6.9% of all malignancies in females in 2022, Peripheral nerves play a crucial role in the early stages
making it the fourth most common cancer in women and a of tumorigenesis. 19-23 Adrenergic nerve denervation
significant global public health challenge. While high-risk or inhibition of adrenergic signaling delays tumor
1
24
human papillomavirus (HPV) infection is a primary trigger formation in prostate cancer, while in pancreatic
of cervical cancer, it is important to recognize that HPV ductal adenocarcinoma, sympathetic neuron-derived
infection alone is not sufficient to drive the development of catecholamines promote neoplastic lesions through
this cancer or its pre-cursors. Factors contributing to its adrenergic receptors. Similarly, stomach denervation
2-4
25
incidence include early sexual activity, multiple partners, reduces gut cancer incidence, and sensory nerve ablation
26
inadequate clinical follow-up, and tobacco use. 4 in basal cell carcinoma models decreases tumor size.
Tumors interact with nerves through neurotransmitters,
Chronic stress is linked to tumorigenesis and cancer such as epinephrine, norepinephrine, serotonin, and
progression, as well as the persistence of HPV infection. acetylcholine, while overexpressing neurotrophic factors,
7
5,6
27
It disrupts the hypothalamic-pituitary-adrenal axis (HPA), such as nerve growth factor (NGF), which drive growth
increasing cortisol, epinephrine, and norepinephrine through tropomyosin receptor kinase (Trk) A-mediated
levels. Catecholamines, key mediators of the stress signaling. 28-34 Studies have shown that NGF promotes
8
response, act through β-adrenergic receptors and are the proliferation and metastasis of cervical cancer cells
released through nicotinic cholinergic receptor activation through the Hippo/Yes-associated protein (YAP) signaling
in the adrenal glands and peripheral sympathetic ganglia. pathway. The brain-derived neurotrophic factor/TrkB
9,10
35
Dysregulation of this system is associated with conditions, signaling pathway activates downstream cascades such as
such as depression and anxiety, which involve serotonergic the phosphoinositide 3-kinase/protein kinase B pathway,
signaling. 11,12 Serotonin receptors and solute carrier family which contributes to tumor proliferation and resistance
proteins, essential for serotonin transport, may modulate to anoikis. Notably, NTRK2 gene fusions are linked to a
36
the sympathetic stress response. 13-15 subtype of cervical cancer. 37
A previous study demonstrated that chronic stress, We aim to investigate the association between
through the release of norepinephrine, can protect neurotransmitter systems and neurotrophic factor-related
cervical cancer cells from anoikis. This protective effect is genes in HPV-infected women by examining genetic
mediated by the activation of the beta-adrenergic receptor variations in key components of the nervous system.
2 (β2-AR)/cyclic adenosine monophosphate (cAMP)/ Specifically, we focus on genes involved in neurotransmitter
protein kinase A (PKA) signaling pathway. The nicotinic systems – adrenergic (ADRB2/rs1042713), cholinergic
16
acetylcholine receptor system, including CHRNA5, plays (CHRNA5/rs16969968), and serotonergic (SLC6A4/5-
a role in activating corticotropin-releasing hormone HTT VNTR intron 2 and HTR2A/rs6313) – as well as genes
neurons, which regulate the HPA axis. This axis controls encoding neurotrophic factors, which play critical roles
cortisol secretion in response to psychological stress. in neuronal growth, survival, development, and function
Dysregulation of this system has been associated with (BDNF/rs6265, NTRK2/rs2289656, and NGF/rs6330).
impaired immune surveillance, increased inflammation,
and tumor-supportive environments. Specifically, 2. Materials and methods
17
rs16969968 has been associated with altered HPA axis
activation, heightened stress sensitivity, anxiety-related 2.1. Study participants
traits, and an enhanced cortisol response under stress. The A total of 140 women infected with HPV and presenting
SLC6A4 gene, particularly the variable number tandem cervical lesions were included in this study. Women
repeat (VNTR) polymorphism in intron 2, can influence were followed in the Portuguese Oncological Institutes
serotonin transporter expression levels. HTR2A plays in Lisbon and Porto. All women underwent cytologic
a critical role in mood and anxiety regulation as well as and histopathologic analyses. HPV detection was
HPA axis function. Activation of the 5-hydroxytryptamine performed using polymerase chain reaction (PCR) using
receptor 2A stimulates the release of corticotropin- the PGMY09/11 primer set (STABVIDA, Portugal)
38
releasing hormone, subsequently regulating cortisol and hybridization using the Digene Hybrid Capture 2
18
secretion. While these genes are well-documented in (QIAGEN, United States) methods. Inclusion criteria for
psychiatric disorders, their role in cancer is an emerging the HPV group were women older than 18 years who were
area of research. Although direct evidence in cancer is HPV positive and presented with cervical lesions. Pregnant
limited, altered serotonin uptake could potentially affect women were excluded. The pathological group’s age ranged

Volume 9 Issue 2 (2025) 251 doi: 10.36922/EJMO025100047