A215: DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis

Chin Wen Png1,Madhushanee Weerasooriya1,Jing Guo2,Sharmy Jeniffer James1,Han Ming Poh1,Motomi Osato2,Richard Flavell3,Chen Dong4,Henry Yang2,Yongliang Zhang1

1Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, Singapore,2Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore, Singapore,3Department of Immunology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA,4Tsinghua University, Beijing, China

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

Dual specificity phosphatase 10 (DUSP10), also known as MAP kinase phosphatase 5 (MKP5), negatively regulates the activation of MAP kinases that are involved in various cellular signaling pathways. Genetic polymorphisms and aberrant expression of DUSP10 are associated with colorectal cancer (CRC) in humans. However, the role of DUSP10 in intestinal epithelial tumorigenesis is not fully understood.

 

Method

Dextran sulfate sodium (DSS)-induced colitis and AOM/DSS induced intestinal tumour model were employed to determine the role of DUSP10 in gut inflammation and colorectal cancer (CRC) development. Signaling pathways that were associated with DUSP10 function in intestinal epithelial cell (IEC) were examined in CMT93 cells. Furthermore, correlation analysis of DUSP10 expression and survival rate was carried out using publicly available data.

Results

In our study, DUSP10 knockout (KO) mice had increased IEC proliferation and migration and developed less severe colitis than wildtype (WT) mice in response to DSS treatment, which is associated with increased ERK1/2 activation and Krüppel-like factor 5 (KLF5) expression in IEC. In line with increased IEC proliferation, DUSP10 KO mice developed more colon tumours with increased severity compared to WT mice in response to administration of DSS and azoxymethane (AOM). Furthermore, survival analysis of CRC patients demonstrated that high DUSP10 expression in tumours was associated with significantly improved survival probability in two separate patient cohorts.

 

 

Conclusion

Our study showed that DUSP10 negatively regulates IEC growth and acts as a suppressor for colorectal cancer. Therefore, it could be an important target for the development of therapies for intestinal inflammation and CRC.