Cargando…

Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis

BACKGROUND: Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying dep...

Descripción completa

Detalles Bibliográficos
Autores principales: Pan, Changqie, Wu, Jianhua, Zheng, Siting, Sun, Huiying, Fang, Yisheng, Huang, Zhenhua, Shi, Min, Liang, Li, Bin, Jianping, Liao, Yulin, Chen, Jinzhang, Liao, Wangjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504143/
https://www.ncbi.nlm.nih.gov/pubmed/34288568
http://dx.doi.org/10.1002/cac2.12198
_version_ 1784581271950721024
author Pan, Changqie
Wu, Jianhua
Zheng, Siting
Sun, Huiying
Fang, Yisheng
Huang, Zhenhua
Shi, Min
Liang, Li
Bin, Jianping
Liao, Yulin
Chen, Jinzhang
Liao, Wangjun
author_facet Pan, Changqie
Wu, Jianhua
Zheng, Siting
Sun, Huiying
Fang, Yisheng
Huang, Zhenhua
Shi, Min
Liang, Li
Bin, Jianping
Liao, Yulin
Chen, Jinzhang
Liao, Wangjun
author_sort Pan, Changqie
collection PubMed
description BACKGROUND: Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression‐induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression‐associated catecholamines on GC. METHODS: Depression states of GC patients were graded using the Patient Health Questionnaire‐9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression‐like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT‐PCR, Western blotting, flow cytometry, and transmission electron microscopy. RESULTS: Fifty‐one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male‐to‐female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis‐associated in colon cancer‐1 (MACC1) level (P = 0.018), and metastasis (P < 0.001). Further, depression‐associated catecholamine specifically bound to the beta‐2 adrenergic receptor (β(2)‐AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β(2)‐AR antagonist ICI‐118,551 or MACC1 silencing effectively blocked the catecholamine‐induced neuroendocrine phenotypic transformation and eliminated depression‐enhanced GC migration and invasion. Moreover, β(2)‐AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model. CONCLUSIONS: Catecholamine‐induced neuroendocrine phenotypes of GC cells led to depression‐accelerated GC invasion and metastasis via the β(2)‐AR/MACC1 axis, while β(2)‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.
format Online
Article
Text
id pubmed-8504143
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-85041432021-10-18 Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis Pan, Changqie Wu, Jianhua Zheng, Siting Sun, Huiying Fang, Yisheng Huang, Zhenhua Shi, Min Liang, Li Bin, Jianping Liao, Yulin Chen, Jinzhang Liao, Wangjun Cancer Commun (Lond) Original Articles BACKGROUND: Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression‐induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression‐associated catecholamines on GC. METHODS: Depression states of GC patients were graded using the Patient Health Questionnaire‐9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression‐like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT‐PCR, Western blotting, flow cytometry, and transmission electron microscopy. RESULTS: Fifty‐one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male‐to‐female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis‐associated in colon cancer‐1 (MACC1) level (P = 0.018), and metastasis (P < 0.001). Further, depression‐associated catecholamine specifically bound to the beta‐2 adrenergic receptor (β(2)‐AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β(2)‐AR antagonist ICI‐118,551 or MACC1 silencing effectively blocked the catecholamine‐induced neuroendocrine phenotypic transformation and eliminated depression‐enhanced GC migration and invasion. Moreover, β(2)‐AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model. CONCLUSIONS: Catecholamine‐induced neuroendocrine phenotypes of GC cells led to depression‐accelerated GC invasion and metastasis via the β(2)‐AR/MACC1 axis, while β(2)‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression. John Wiley and Sons Inc. 2021-07-20 /pmc/articles/PMC8504143/ /pubmed/34288568 http://dx.doi.org/10.1002/cac2.12198 Text en © 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Pan, Changqie
Wu, Jianhua
Zheng, Siting
Sun, Huiying
Fang, Yisheng
Huang, Zhenhua
Shi, Min
Liang, Li
Bin, Jianping
Liao, Yulin
Chen, Jinzhang
Liao, Wangjun
Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title_full Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title_fullStr Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title_full_unstemmed Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title_short Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐AR/MACC1 axis
title_sort depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2)‐ar/macc1 axis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504143/
https://www.ncbi.nlm.nih.gov/pubmed/34288568
http://dx.doi.org/10.1002/cac2.12198
work_keys_str_mv AT panchangqie depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT wujianhua depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT zhengsiting depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT sunhuiying depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT fangyisheng depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT huangzhenhua depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT shimin depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT liangli depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT binjianping depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT liaoyulin depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT chenjinzhang depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis
AT liaowangjun depressionacceleratesgastriccancerinvasionandmetastasisbyinducinganeuroendocrinephenotypeviathecatecholamineb2armacc1axis