Title: | ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer |
Authors: | Hashimoto, Shigeru Browse this author |
Furukawa, Shotaro Browse this author |
Hashimoto, Ari Browse this author →KAKEN DB |
Tsutaho, Akio Browse this author |
Fukao, Akira Browse this author →KAKEN DB |
Sakamura, Yurika Browse this author |
Parajuli, Gyanu Browse this author |
Onodera, Yasuhito Browse this author →KAKEN DB |
Otsuka, Yutaro Browse this author |
Handa, Haruka Browse this author |
Oikawa, Tsukasa Browse this author →KAKEN DB |
Hata, Soichiro Browse this author |
Nishikawa, Yoshihiro Browse this author →KAKEN DB |
Mizukami, Yusuke Browse this author →KAKEN DB |
Kodama, Yuzo Browse this author |
Murakami, Masaaki Browse this author →KAKEN DB |
Fujiwara, Toshinobu Browse this author →KAKEN DB |
Hirano, Satoshi Browse this author →KAKEN DB |
Sabe, Hisataka Browse this author →KAKEN DB |
Keywords: | ARF6 |
mRNA translation |
pancreatic driver oncogenes |
PD-L1 |
mevalonate pathway |
Issue Date: | 27-Aug-2019 |
Publisher: | National Academy of Sciences. |
Journal Title: | Proceedings of the National Academy of Sciences of the United States of America (PNAS) |
Volume: | 116 |
Issue: | 35 |
Start Page: | 17450 |
End Page: | 17459 |
Publisher DOI: | 10.1073/pnas.1901765116 |
PMID: | 31399545 |
Abstract: | Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor beta (PDGFR beta) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, elF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among elF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands. |
Rights: | https://creativecommons.org/licenses/by-nc-nd/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/75628 |
Appears in Collections: | 国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc) 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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