Abstract
BackgroundThe KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. The purpose of this study was to investigate the relationship between KRAS mutation and transgelin-2. Transgelin-2 is highly expressed in PDAC tissues compared with adjacent normal tissues. The underlying mechanism for upregulating transgelin-2 is largely unknown.MethodsExpression of transgelin-2 was analyzed by microarray data and qRT-PCR. The effect of KRAS signaling on transgelin-2 expression was examined in PDAC cells in the presence or absence of the ERK inhibitor. The interaction of transgelin-2 with ERK was confirmed by immunoprecipitation. ERK-mediated Phosphorylation of transglein-2 was detected by in vivo and in vitro kinase assays. The gain-of-function and loss-of-function approaches were used to examine the role of phosphorylation of transgelin-2 on cell proliferation. Phosphorylation of transgelin-2 was detected by immunohistochemistry in PDAC tissues.ResultsHere we found transgelin-2 expression was induced by KRAS mutation. In the case of KRAS mutation, ERK2 interacted with 29–31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC. In addition, S145 phosphorylation of transgelin-2 was associated with a poor prognosis in patients with PDAC.ConclusionsThis study indicated that KRAS-ERK-mediated transeglin-2 phosphorylation played an important role in the development of PDAC. Inhibition of transgelin-2 phosphorylation may be a potential therapeutic strategy for targeting PDAC with KRAS mutation.
Highlights
The KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC)
Transgelin-2 is up-regulated upon KRAS mutation In previous reports, we have shown increased expression of transgelin-2 in pancreatic cancer tissues compared with adjacent normal tissues [8]
By analyzing Haoqiang Ying ‘s dataset, we found that the level of transgelin-2 in doxycycline-induced mice was significantly higher than that in non-doxycycline-induced mice, suggesting that the KRASG12D mutation promotes the expression of transgelin-2 (Fig. 1a)
Summary
The KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of pancreatic cancer [2]. More than 90% of PDACs carry mutated KRAS alleles [4]. KRAS mutations have been shown to play a key role in the development of PDAC [5]. KRASG12D mutation is essential for the initiation and maintenance of pancreatic cancer [6]. KRAS mutations have been identified as a driver of PDAC, KRAS targeted therapy has not been successfully developed. Inhibition of KRAS downstream targets is an effective strategy for targeting KRAS mutations. KRAS activates different downstream effectors in a context specific manner.
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