The abnormal expression of protein tyrosine phosphatase nonreceptor type 6 (PTPN6) has been proved to be associated with the progression of colorectal cancer. However, its role in chemosensitivity and related molecular mechanism have not been clarified. It has been reported that PTPN6 was down‐regulated in colorectal cancer cells compared with the normal colorectal cells. To evaluate the effects of PTPN6 on the proliferation and survival of colorectal cancer cells, PTPN6 was overexpressed in colorectal cancer cells in the present study. We found that cell proliferation and viability were both decreased after overexpression of PTPN6. The IC50 of 5‐Fu against colorectal cells was also declined in PTPN6 transfected cells. And further, we verified that PTPN6 could down‐regulate the expression of P‐gp and MRP‐1. Moreover, SP1 was the target protein of PTPN6 predicated by ChIPBase software and confirmed through Co‐immunoprecipitation assay and it was negatively regulated by PTPN6. To further verify the effect of SP1 on chemoresistance, SP1 was overexpressed. SP1 overexpression enhanced the drug‐resistance to 5‐Fu and abrogated the effects of PTPN6 upregulation on 5‐Fu resistance. All the above changes were associated with the down‐regulation of proteins related to MAPK signalling pathway, such as phosphorylation of extracellular regulated protein kinases (ERK) and p38. In summary, PTPN6 promoted chemosensitivity of colorectal cancer cells by targeting SP1 and inhibiting the activation of MAPK signalling pathway.

中文翻译：

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PTPN6通过抑制SP1/MAPK信号通路提高结直肠癌细胞的化疗敏感性


蛋白酪氨酸磷酸酶非受体6型（PTPN6）的异常表达已被证明与结直肠癌的进展有关。但其在化疗敏感性中的作用及相关分子机制尚未阐明。据报道，与正常结直肠细胞相比，结直肠癌细胞中 PTPN6 表达下调。为了评估PTPN6对结直肠癌细胞增殖和存活的影响，本研究在结直肠癌细胞中过表达PTPN6。我们发现过表达 PTPN6 后细胞增殖和活力均下降。在 PTPN6 转染细胞中，5-Fu 对结直肠细胞的 IC50 也有所下降。此外，我们验证了 PTPN6 可以下调 P-gp 和 MRP-1 的表达。此外，通过ChIPBase软件预测并通过免疫共沉淀实验证实SP1是PTPN6的靶蛋白，并且SP1受到PTPN6的负调控。为了进一步验证SP1对化疗耐药的影响，SP1被过表达。 SP1过表达增强了对5-Fu的耐药性，并消除了PTPN6上调对5-Fu耐药性的影响。上述变化均与MAPK信号通路相关蛋白的下调有关，如细胞外调节蛋白激酶（ERK）和p38的磷酸化。综上所述，PTPN6通过靶向SP1并抑制MAPK信号通路的激活来促进结直肠癌细胞的化疗敏感性。