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KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK–ERK pathway in pancreatic cancer

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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… Click to show full abstract

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.

Keywords: cancer; expression; metastasis chemoresistance; rkip

Journal Title: International Journal of Cancer
Year Published: 2018

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