Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis
Abstract 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 underl...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-10-01
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| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12198 |
| _version_ | 1831763870588338176 |
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| author | Changqie Pan Jianhua Wu Siting Zheng Huiying Sun Yisheng Fang Zhenhua Huang Min Shi Li Liang Jianping Bin Yulin Liao Jinzhang Chen Wangjun Liao |
| author_facet | Changqie Pan Jianhua Wu Siting Zheng Huiying Sun Yisheng Fang Zhenhua Huang Min Shi Li Liang Jianping Bin Yulin Liao Jinzhang Chen Wangjun Liao |
| author_sort | Changqie Pan |
| collection | DOAJ |
| description | Abstract 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 (β2‐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, β2‐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, β2‐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 β2‐AR/MACC1 axis, while β2‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression. |
| first_indexed | 2024-12-22T05:34:11Z |
| format | Article |
| id | doaj.art-ff18b05c8c4e4e69872fc5348abb67d9 |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-12-22T05:34:11Z |
| publishDate | 2021-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-ff18b05c8c4e4e69872fc5348abb67d92022-12-21T18:37:23ZengWileyCancer Communications2523-35482021-10-0141101049107010.1002/cac2.12198Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axisChangqie Pan0Jianhua Wu1Siting Zheng2Huiying Sun3Yisheng Fang4Zhenhua Huang5Min Shi6Li Liang7Jianping Bin8Yulin Liao9Jinzhang Chen10Wangjun Liao11Department of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Pathology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Cardiology Nanfang Hospital, Sout4hern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Cardiology Nanfang Hospital, Sout4hern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaDepartment of Oncology Nanfang Hospital, Southern Medical University Guangzhou Guangdong 510515 P. R. ChinaAbstract 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 (β2‐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, β2‐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, β2‐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 β2‐AR/MACC1 axis, while β2‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.https://doi.org/10.1002/cac2.12198catecholaminesdepressiongastric cancerMACC1neuroendocrine phenotypepsychological stress |
| spellingShingle | Changqie Pan Jianhua Wu Siting Zheng Huiying Sun Yisheng Fang Zhenhua Huang Min Shi Li Liang Jianping Bin Yulin Liao Jinzhang Chen Wangjun Liao Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis Cancer Communications catecholamines depression gastric cancer MACC1 neuroendocrine phenotype psychological stress |
| title | Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis |
| title_full | Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis |
| title_fullStr | Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis |
| title_full_unstemmed | Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis |
| title_short | Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2‐AR/MACC1 axis |
| title_sort | depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine β2 ar macc1 axis |
| topic | catecholamines depression gastric cancer MACC1 neuroendocrine phenotype psychological stress |
| url | https://doi.org/10.1002/cac2.12198 |
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