EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling

Abstract EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But h...

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Published in:Carcinogenesis (New York) 2023-12, Vol.44 (8-9), p.682-694
Main Authors: Yu, Hao, Qin, Xiao-Kang, Yin, Kai-Wen, Li, Zi-Ming, Ni, En-De, Yang, Jian-Ming, Liu, Xun-Hua, Zhou, Ai-Jun, Li, Shu-Ji, Gao, Tian-Ming, Li, Ying, Li, Jian-Ming
Format: Article
Language:English
Subjects:
Animals
Cell Communication
Colorectal Neoplasms - metabolism
gamma-Aminobutyric Acid
Humans
Intestines - pathology
Mice
Neurons - metabolism
Neurons - pathology
Tumor Microenvironment
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Summary:Abstract EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons. EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. Our study found EphB6 regulates GABA release in intestinal neurons and then modulates tumor progression in CRC in a way that is dependent on intestinal neurons. Graphical Abstract Graphical Abstract
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgad041