KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer
KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer
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KRAS 通过 MAPK-ERK 通路抑制胰腺癌中的 RKIP，从而促进肿瘤转移和化疗耐药
DOI：
10.1002/ijc.31248
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发表时间：
2018-06-01
影响因子：
6.4
通讯作者：
Chen, Yinting
中科院分区：
文献类型：
--
作者：
Yang, Kege;Li, Yaqing;Chen, Yinting
致癌性KRAS在胰腺导管腺癌（PDAC）的发生和发展中起着至关重要的作用。然而，其机制尚未明确阐明。RKIP是一种肿瘤抑制因子，在PDAC中已经显示了RKIP的缺失。在这里，我们发现，无论KRAS突变状态如何，PDAC新鲜组织中KRAS表达与RKIP表达呈负相关。PDAC组织芯片进一步证实了KRAS和RKIP之间的负相关性。KRAS过度表达和RKIP下调与不良临床结局相关。PDAC细胞系中KRAS的敲低或过表达分别显著增加或降低RKIP蛋白和mRNA水平。此外，MAPK-ERK通路参与了RKIP的调节。KRAS调节RKIP表达，进而影响关键上皮-间质转化（EMT）和凋亡因子的表达。KRAS-RKIP轴的生物学功能在体外和体内的人胰腺癌细胞中得到证实。KRAS敲低增加RKIP表达，抑制转移和化疗耐药性。此外，通过RNA干扰抑制RKIP，在KRAS敲减细胞中挽救了转移和化学抗性的特征。总之，我们的研究证明了KRAS如何抑制肿瘤抑制因子RKIP，从而为靶向RKIP作为克服PDAC中KRAS诱导的肿瘤转移和化疗耐药性的策略提供了新的理由。
Oncogenic KRAS plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. However, the mechanism has not been clearly elucidated. RKIP is a tumor repressor, and loss of RKIP has been shown in PDAC. Here, we found that KRAS expression was inversely correlated with RKIP expression in PDAC fresh tissue regardless of the KRAS mutant status. The negative correlation between KRAS and RKIP was further confirmed in our PDAC tissue microarray. KRAS overexpression and RKIP downregulation were associated with poor clinical outcomes. Knockdown or overexpression of KRAS in PDAC cell lines robustly increased or decreased, respectively, RKIP protein and mRNA levels. Furthermore, the MAPK–ERK pathway was involved in the regulation of RKIP. KRAS‐regulated RKIP expression, which in turn affected the expression of pivotal epithelial–mesenchymal transition (EMT) and apoptosis factors. The biological function of the KRAS–RKIP axis was demonstrated in human pancreatic cancer cells in vitro and in vivo. KRAS knockdown increased RKIP expression and inhibited metastasis and chemoresistance. Moreover, the feature of metastasis and chemoresistance was rescued in the KRAS‐knockdown cells through the inhibition of RKIP by RNA interference. In conclusion, our studies demonstrate how KRAS inhibits the tumor suppressor RKIP, thus offering novel justification for targeting RKIP as a strategy to overcome KRAS‐induced tumor metastasis and chemoresistance in PDAC.