Depletion of p21-activated kinase 1 up-regulates the immune system of APCΔ14/+ mice and inhibits intestinal tumorigenesis

被引:33
作者
Huynh, Nhi [1 ]
Wang, Kai [1 ]
Yim, Mildred [1 ]
Dumesny, Chelsea J. [1 ]
Sandrin, Mauro S. [1 ]
Baldwin, Graham S. [1 ]
Nikfarjam, Mehrdad [1 ]
He, Hong [1 ]
机构
[1] Univ Melbourne, Austin Hlth, Dept Surg, Studley Rd, Heidelberg, Vic 3084, Australia
来源
BMC CANCER | 2017年 / 17卷
基金
英国医学研究理事会;
关键词
PAK1; Intestinal tumour; APC; Lymphocytes; FAMILIAL ADENOMATOUS POLYPOSIS; COLORECTAL-CANCER; MOUSE MODEL; PANCREATIC-CANCER; BETA-CATENIN; RESISTANCE; MUTATION; KINASES; GROWTH; TUMORS;
D O I
10.1186/s12885-017-3432-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC(Delta 14/+) mice. Methods: The PAK1 KO APC(Delta 14/+) mice were generated by cross-breeding of PAK1 KO mice with APC(Delta 14/+) mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. Results: Compared to APC(+/+) mice, the numbers of both T- and B-lymphocytes were reduced in the spleen of APC(Delta 14/+) mice. Depletion of PAK1 in APC(Delta 14/+) mice increased the numbers of splenic T- and B-lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC(Delta 14/+) mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. Conclusion: Depletion of active PAK1 up-regulates the immune system of APC(Delta 14/+) mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.
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页数:9
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