Abstract
Introduction: Gastric cancer is one of the common causes of cancer-related death in the world. Neurotransmitters have recently been related to the proliferation of cancer cells, but the role of neurotransmitters in the progression of gastric cancer is still unexplored. The cross-talk between the nervous system and immune cells through serotonin and its receptors in the tumor microenvironment can impact tumor progress. Our purpose is to expose probable changes in serotonin receptors, acetylcholinesterase, and monoamine oxidase A gene expression in gastric cancer. Methods: Transcript of serotonin receptors (5-HTR2A, 5-HTR2B, 5-HTR3A, 5-HTR7) and monoamine oxidase A genes in the peripheral blood mononuclear cells (40 patients and 40 control) and tissue (21 tumors and 21 normal adjacent tissues) were assessed. The gene expression was analyzed by quantitative real-time PCR using suitable primers. Statistical analysis was performed using appropriate software (REST, Prism). Results: Significantly higher amounts of 5-HTR2A, 5-HTR2B, 5-HTR3A, 5-HTR7, and acetylcholinesterase gene transcripts were found in the peripheral blood of gastric cancer patients compared with healthy individuals. The expression of 5-HTR2B and 5-HTR3A genes was significantly higher (p = 0.0250, p = 0.0005, respectively) and the acetylcholinesterase gene was lower in the tissue of patients (p = 0.0119) compared with adjacent normal tissue. Conclusion: This study highlights the role of serotonin receptors in gastric cancer that might have suggestions for the development of novel therapeutics and defensive approaches that target factors associated with the link between the nervous system, cancer cells, and the tumor microenvironment.
Journal Section:
Clinical Study
References
1.
Sung
H
, Ferlay
J
, Siegel
RL
, Laversanne
M
, Soerjomataram
I
, Jemal
A
. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
. CA Cancer J Clin
. 2021
;71
(3
):209
–49
.2.
Hojati
SA
, Kokabpeyk
S
, Yaghoubi
S
, Joukar
F
, Asgharnezhad
M
, Mansour-Ghanaei
F
. Helicobacter pylori infection in Iran: demographic, endoscopic and pathological factors
. BMC Gastroenterol
. 2021
;21
(1
):355
.3.
Kalan Farmanfarma
K
, Mahdavifar
N
, Hassanipour
S
, Salehiniya
H
. Epidemiologic study of gastric cancer in Iran: a systematic review
. Clin Exp Gastroenterol
. 2020
;13
:511
–42
.4.
Zhang
SX
, Liu
W
, Ai
B
, Sun
LL
, Chen
ZS
, Lin
LZ
Current advances and outlook in gastric cancer chemoresistance: a review
Recent Pat Anticancer Drug Discov
2021
.5.
Gao
YW
, Zhang
CH
, Zuo
XM
, Hui
XZ
. Genetic basis of gastric cancer
. Chin Med Sci J
. 2016
;31
(3
):192
–5
.6.
Wang
H
, Zheng
Q
, Lu
Z
, Wang
L
, Ding
L
, Xia
L
. Role of the nervous system in cancers: a review
. Cell Death Discov
. 2021
;7
(1
):76
.7.
Sarrouilhe
D
, Mesnil
M
. Serotonin and human cancer: a critical view
. Biochimie
. 2019
;161
:46
–50
.8.
Wang
K
, Zhao
XH
, Liu
J
, Zhang
R
, Li
JP
. Nervous system and gastric cancer
. Biochim Biophys Acta Rev Cancer
. 2020
;1873
(1
):188313
.9.
Fabà
L
, de Groot
N
, Ramis
G
, Cabrera-Gómez
CG
, Doelman
J
. Serotonin receptors and their association with the immune system in the gastrointestinal tract of weaning piglets
. Porcine Health Manag
. 2022
;8
(1
):8
.10.
Wan
M
, Ding
L
, Wang
D
, Han
J
, Gao
P
. Serotonin: a potent immune cell modulator in autoimmune diseases
. Front Immunol
. 2020
;11
:186
.11.
Ostadkarampour
M
, Putnins
EE
. Monoamine oxidase inhibitors: a review of their anti-inflammatory therapeutic potential and mechanisms of action
. Front Pharmacol
. 2021
;12
:676239
.12.
Pairet
M
, Meirieu
O
, Bardon
T
, Ruckebusch
Y
. Cholinergic modulation of the release of serotonin in the gastric interstitial fluid: an in vivo study in rabbits
. Gastroenterology
. 1986
;91
(5
):1250
–7
.13.
Schwörer
H
, Racké
K
, Kilbinger
H
. Cholinergic modulation of the release of 5-hydroxytryptamine from the Guinea pig ileum
. Naunyn Schmiedebergs Arch Pharmacol
. 1987
;336
(2
):127
–32
.14.
Ming
Z
, Wotton
CA
, Appleton
RT
, Ching
JC
, Loewen
ME
, Sawicki
G
. Systemic lipopolysaccharide-mediated alteration of cortical neuromodulation involves increases in monoamine oxidase-A and acetylcholinesterase activity
. J Neuroinflammation
. 2015
;12
(1
):37
.15.
Liu
W
, Wang
Y
, Youdim
MBH
. A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson’s disease
. Ageing Neurodegener Dis
. 2022
;2
(1
):1
.16.
Wang
Y
, Jia
Z
, Gao
J
, Zhou
T
, Zhang
X
, Zu
G
. Clinicopathological and prognostic value of USP22 expression in gastric cancer: a systematic review and meta-analysis and database validation
. Front Surg
. 2022
;9
:920595
.17.
Shah
PA
, Park
CJ
, Shaughnessy
MP
, Cowles
RA
. Serotonin as a mitogen in the gastrointestinal tract: revisiting a familiar molecule in a new role
. Cell Mol Gastroenterol Hepatol
. 2021
;12
(3
):1093
–104
.18.
Neshan
M
, Campbell
A
, Malakouti
SK
, Zareii
M
, Ahangari
G
. Gene expression of serotonergic markers in peripheral blood mononuclear cells of patients with late-onset Alzheimer’s disease
. Heliyon
. 2020
;6
(8
):e04716
.19.
Choi
JR
, Jeon
M
, Koh
SB
. Association between serotonin 2A receptor (HTR2A) genetic variations and risk of hypertension in a community-based cohort study
. BMC Med Genet
. 2020
;21
(1
):5
.20.
Rébé
C
, Ghiringhelli
F
. Interleukin-1β and cancer
. Cancers
. 2020
;12
(7
):1791
.21.
Laha
D
, Grant
R
, Mishra
P
, Nilubol
N
. The role of tumor necrosis factor in manipulating the immunological response of tumor microenvironment
. Front Immunol
. 2021
;12
:656908
.22.
Rinaldi
A
, Chiaravalli
AM
, Mian
M
, Zucca
E
, Tibiletti
MG
, Capella
C
. Serotonin receptor 3A expression in normal and neoplastic B cells
. Pathobiology
. 2010
;77
(3
):129
–35
.23.
Murakami
Y
, Saito
H
, Shimizu
S
, Kono
Y
, Shishido
Y
, Miyatani
K
. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer
. Sci Rep
. 2019
;9
(1
):13083
.24.
Amedei
A
, Della Bella
C
, Silvestri
E
, Prisco
D
, D’Elios
MM
. T cells in gastric cancer: friends or foes
. Clin Dev Immunol
. 2012
;2012
:690571
.25.
Tone
M
, Tahara
S
, Nojima
S
, Motooka
D
, Okuzaki
D
, Morii
E
. HTR3A is correlated with unfavorable histology and promotes proliferation through ERK phosphorylation in lung adenocarcinoma
. Cancer Sci
. 2020
;111
(10
):3953
–61
.26.
Szabo
A
, Gogolak
P
, Koncz
G
, Foldvari
Z
, Pazmandi
K
, Miltner
N
. Immunomodulatory capacity of the serotonin receptor 5-HT2B in a subset of human dendritic cells
. Sci Rep
. 2018
;8
(1
):1765
.27.
Nieto
C
, Rayo
I
, de Las Casas-Engel
M
, Izquierdo
E
, Alonso
B
, Béchade
C
. Serotonin (5-HT) shapes the macrophage gene profile through the 5-HT(2B)-Dependent activation of the aryl hydrocarbon receptor
. J Immunol
. 2020
;204
(10
):2808
–17
.28.
Xiao
GG
. Targeting serotonin system in pancreatic cancer
. Pancreas
. 2020
;49
(1
):e1
.29.
Kwiecień
I
, Rutkowska
E
, Raniszewska
A
, Rzepecki
P
, Domagała-Kulawik
J
. Modulation of the immune response by heterogeneous monocytes and dendritic cells in lung cancer
. World J Clin Oncol
. 2021
;12
(11
):966
–82
.30.
Zamarron
BF
, Chen
W
. Dual roles of immune cells and their factors in cancer development and progression
. Int J Biol Sci
. 2011
;7
(5
):651
–8
.31.
Pan
Y
, Yu
Y
, Wang
X
, Zhang
T
. Tumor-associated macrophages in tumor immunity
. Front Immunol
. 2020
11
32.
Domínguez-Soto
Á
, Usategui
A
, Casas-Engel
Md L
, Simón-Fuentes
M
, Nieto
C
, Cuevas
VD
. Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis
. Sci Rep
. 2017
;7
(1
):14761
.33.
León-Ponte
M
, Ahern
GP
, O’Connell
PJ
. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor
. Blood
. 2007
;109
(8
):3139
–46
.34.
Luo
J
, Chen
X-Q
, Li
P
. The role of TGF-β and its receptors in gastrointestinal cancers
. Transl Oncol
. 2019
;12
(3
):475
–84
.35.
Hejazi
SH
, Ahangari
G
, Pornour
M
, Deezagi
A
, Aminzadeh
S
, Ahmadkhaniha
HR
. Evaluation of gene expression changes of serotonin receptors, 5-HT3AR and 5-HT2AR as main stress factors in breast cancer patients
. Asian Pac J Cancer Prev
. 2014
;15
:4455
–8
.36.
Razavi
SA
, Rahimi
B
, Gholipour
N
, Ahangari
F
, Ahangari
G
Serotonin (5HTR2A and 5HTR3A) and GABA (GABAB) receptor genes overexpression are correlated with non-small cell lung cancer (NSCLC)
Current Cancer Therapy Reviews
2019
.37.
Jayachandran
P
, Battaglin
F
, Strelez
C
, Lenz
A
, Algaze
S
, Soni
S
. Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions
. Oncogene
. 2023
;42
(9
):627
–37
.38.
Xi
H-J
, Wu
R-P
, Liu
J-J
, Zhang
L-J
, Li
Z-S
. Role of acetylcholinesterase in lung cancer
. Thorac Cancer
. 2015
;6
(4
):390
–8
.39.
Peters
MAM
, Meijer
C
, Fehrmann
RSN
, Walenkamp
AME
, Kema
IP
, de Vries
EGE
. Serotonin and dopamine receptor expression in solid tumours including rare cancers
. Pathol Oncol Res
. 2020
;26
(3
):1539
–47
.40.
Razavi
SA
, Rahimi
B
, Gholipour
N
, Ahangari
F
, Ahangari
G
. Serotonin (5HTR2A and 5HTR3A) and GABA (GABAB) receptor genes overexpression are correlated with non-small cell lung cancer (NSCLC)
. Curr Cancer Ther Rev
. 2019
;15
(2
):155
–61
.41.
Wu
C
, Ma
L
, Wei
H
, Nie
F
, Ning
J
, Jiang
T
. MiR-1256 inhibits cell proliferation and cell cycle progression in papillary thyroid cancer by targeting 5-hydroxy tryptamine receptor 3A
. Hum Cell
. 2020
;33
(3
):630
–40
.42.
Huang
G-W
, Chen
Q-Q
, Ma
C-C
, Xie
L-H
, Gu
J
. linc01305 promotes metastasis and proliferation of esophageal squamous cell carcinoma through interacting with IGF2BP2 and IGF2BP3 to stabilize HTR3A mRNA
. Int J Biochem Cell Biol
. 2021
;136
:106015
.43.
Le-Bel
G
, Benhassine
M
, Landreville
S
, Guérin
SL
. Analysis of the proteasome activity and the turnover of the serotonin receptor 2B (HTR2B) in human uveal melanoma
. Exp Eye Res
. 2019
;184
:72
–7
.44.
Shakoori
A
, Mahasti
P
, Moradi
V
. Determination of twenty organophosphorus pesticides in wheat samples from different regions of Iran
. Int J Technoethics
. 2017
;11
(5
):37
–44
.45.
Senarathne
R
, Hettiaratchi
U
, Athiththan
L
, Peiris
H
, Sarathchandra
C
, Senanayake
H
. Selected liver markers in predicting the severity of organophosphate and carbamate poisoning
. J Environ Public Health
. 2022
;2022
:7826396
.46.
Li
Y
, Fu
Y
, Hu
K
, Zhang
Y
, Chen
J
, Zhang
S
. Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China
. Ecotoxicol Environ Saf
. 2020
;196
:110548
.47.
Yu
H
, Xia
H
, Tang
Q
, Xu
H
, Wei
G
, Chen
Y
. Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation
. Sci Rep
. 2017
;7
:40802
.48.
Xu
H
, Shen
Z
, Xiao
J
, Yang
Y
, Huang
W
, Zhou
Z
. Acetylcholinesterase overexpression mediated by oncolytic adenovirus exhibited potent anti-tumor effect
. BMC Cancer
. 2014
;14
(1
):668
.49.
Pérez-Aguilar
B
, Vidal
CJ
, Palomec
G
, García-Dolores
F
, Gutiérrez-Ruiz
MC
, Bucio
L
. Acetylcholinesterase is associated with a decrease in cell proliferation of hepatocellular carcinoma cells
. Biochim Biophys Acta
. 2015
;1852
(7
):1380
–7
.© 2023 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2023
You do not currently have access to this content.
