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∆14/+ mice. METHODS:The PAK1 KO APC∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC∆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∆14/+ mice. Depletion of PAK1 in APC∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC∆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∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.

译文

背景:P21激活的激酶1(PAK1)通过多种信号通路的激活刺激结直肠癌(CRC)的生长和转移。 PAK1对CRC干细胞标志物的上调也有助于CRC对5-氟尿嘧啶的抗性。这项研究的目的是研究PAK1的消耗和抑制对APC∆14 /小鼠免疫系统和肠道肿瘤形成的影响。
方法:PAK1 KO APC∆14 /小鼠是通过将PAK1 KO小鼠与APC∆14 /小鼠杂交而产生的。通过流式细胞术和免疫组织化学染色分析脾淋巴细胞。计算肠道肿瘤的数量。还对血细胞计数。
结果:与APC /小鼠相比,APC∆14 /小鼠脾脏中T淋巴细胞和B淋巴细胞的数量均减少。 APC∆14 /小鼠中PAK1的消耗增加了脾脏T-和B-淋巴细胞的数量,并减少了肠肿瘤的数量。用PAK抑制剂PF-3758309治疗APC∆14 /小鼠,可减少肠肿瘤的数量并增加血淋巴细胞的数量。
结论:活性PAK1的耗尽可上调APC∆14 /小鼠的免疫系统,并抑制肠道肿瘤的发展。这些观察结果表明PAK1在对肿瘤的免疫应答中起重要作用。

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