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

Author:

Yu Hao1,Qin Xiao-Kang1,Yin Kai-Wen1,Li Zi-Ming2,Ni En-De1,Yang Jian-Ming2,Liu Xun-Hua3,Zhou Ai-Jun1,Li Shu-Ji2,Gao Tian-Ming2,Li Ying1,Li Jian-Ming14ORCID

Affiliation:

1. Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People’s Republic of China

2. State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515 , People’s Republic of China

3. Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University , Guangzhou 510080 , People’s Republic of China

4. Department of Pathology, Soochow University Medical School , Suzhou 215123 , People’s Republic of China

Abstract

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.

Funder

National Natural Foundation of China

Key-Area Research and Development Program of Guangdong Province

Basic and Applied Basic Research Foundation of Guangdong Province

Natural Science Foundation of Guangdong Province

Fundamental Research Funds for the Central Universities

National Sun Yat-sen University

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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