Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production

被引：2

作者：

Cao, Mingxin ^{[1
,2
,3
,4
,5
,6
]}

Li, Xinming ^{[7
]}

Trinh, Duc-Anh ^{[1
]}

Yoshimachi, Shingo ^{[1
,8
]}

Goto, Kota ^{[1
]}

Sakata, Natsumi ^{[1
]}

Ishida, Masaharu ^{[8
]}

Ohtsuka, Hideo ^{[8
]}

Unno, Michiaki ^{[8
]}

Wang, Yuxia ^{[7
]}

Shirakawa, Ryutaro ^{[1
]}

Horiuchi, Hisanori ^{[1
,2
]}

机构：

[1] Tohoku Univ, Inst Dev Aging & Canc, Dept Mol & Cellular Biol, Sendai, Miyagi, Japan

[2] Tohoku Univ, Grad Sch Dent, Dept Oral Canc Therapeut, Sendai, Miyagi, Japan

[3] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu, Peoples R China

[4] Sichuan Univ, West China Hosp Stomatol, Natl Clin Res Ctr Oral Dis, Chengdu, Peoples R China

[5] Sichuan Univ, West China Hosp Stomatol, Dept Oral & Maxillofacial Surg, Chengdu, Peoples R China

[6] Tianjin Med Univ, Sch & Hosp Stomatol, Tianjin, Peoples R China

[7] Nankai Univ, Tianjin Stomatol Hosp, Affiliated Stomatol Hosp, Tianjin Key Lab Oral & Maxillofacial Funct Reconst, Tianjin, Peoples R China

[8] Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2023年 / 299卷 / 06期

基金：

日本学术振兴会;

关键词：

ACTIVATING PROTEINS; DOWN-REGULATION; C-JUN; CANCER; GROWTH;

D O I：

10.1016/j.jbc.2023.104754

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAP(3-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-(31 in RalGAP(3-deficient PDAC cells compared to control cells. Blockade of TGF-(31 signaling suppressed RalGAP(3 deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-(31 expression, was decreased by RalGAP(3 deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF(31 signaling at least in part by decreasing c-Jun N-terminal kinase activity.

引用

页数：10

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