A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling
A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling
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PTPN12 中的错义变异通过修饰 Ras/MEK/ERK 信号传导与结直肠癌风险相关。
DOI：
10.1016/j.canep.2019.01.013
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发表时间：
2019-04-01
影响因子：
2.6
通讯作者：
Miao, Xiaoping
中科院分区：
文献类型：
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作者：
Shen, Na;Li, Lu;Miao, Xiaoping
背景：经典蛋白酪氨酸磷酸酶（PTPs）已被广泛报道与包括结直肠癌（CRC）在内的多种人类恶性肿瘤有关。然而，很少有关于经典PTP基因与结直肠癌风险之间关系的综合分析。方法：首先，进行生物信息学分析，以确定经典PTP基因家族中的错义变异。其次，采用全外显子组关联数据和独立人群研究来评估候选变异对结直肠癌风险的影响。最后，应用基于信号通路的功能分析来揭示潜在的致病机制。结果：在联合分析的加性模型下，我们发现PTPN12 rs3750050 G等位基因使结直肠癌的风险增加19%，OR为1.19 （95% CI= 1.09-1.30, P = 1.015 × 10(-4)）。此外，生化实验表明，rs3750050可通过阻碍SHC去磷酸化，削弱PTPN12对Ras/MEK/ERK信号的抑制作用，增加cyclin D1的表达，最终导致细胞异常增殖，从而参与CRC的发病机制。结论：本研究提示PTPN12 rs3750050可能通过改变Ras/MEK/ERK信号通路增加结直肠癌风险。这项工作为PTP基因变异在结直肠癌发病机制中的作用提供了新的见解。
Background: The classical protein tyrosine phosphatases (PTPs) have been widely reported to be associated with various human malignancies including colorectal cancer (CRC). However, there are few comprehensive analyses of the association between the classical PTP genes and CRC risk.Methods: First, a bioinformatics analysis was performed to identify missense variants within the classical PTP gene family. Second, exome-wide association data and an independent population study were conducted to evaluate effects of candidate variants on CRC risk. Finally, functional assays based on signaling pathways were applied to uncover the potential pathogenic mechanism.Results: We identified that PTPN12 rs3750050 G allele presented a 19% increase the risk of CRC, with an OR of 1.19 (95% CI= 1.09-1.30, P = 1.015 x 10(-4)) under an additive model in the combined analysis. Furthermore, biochemical assays illustrated that rs3750050 could impair the inhibitory effect of PTPN12 on Ras/MEK/ERK signaling by impeding SHC dephosphorylation, increase the expression of cyclin D1 and ultimately lead to aberrant cell proliferation, thus contributing to CRC pathogenesis.Conclusion: Our study highlights that PTPN12 rs3750050 could increase CRC risk by modifying Ras/MEK/ERK signaling. This work provides a novel insight into the roles of genetic variants within PTP genes in the pathogenesis of CRC.