癌症研究
鸟嘌呤核苷酸交换因子
生物
转移
癌症
GTPase激活蛋白
GTP酶
胰腺
细胞生物学
内分泌学
G蛋白
信号转导
遗传学
作者
Shingo Yoshimachi,Ryutaro Shirakawa,Mingxin Cao,Duc Anh Trinh,Pan Gao,Natsumi Sakata,Kento Miyazaki,Kunihiko Goto,Takayuki Miura,Kyohei Ariake,Shin Maeda,Koichi Masuda,Masaharu Ishida,Hideo Ohtsuka,Michiaki Unno,Hisanori Horiuchi
出处
期刊:Cancer Science
[Wiley]
日期:2021-06-15
卷期号:112 (8): 3064-3073
被引量:7
摘要
The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common β subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPβ-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPβ-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPβ-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPβ-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPβ deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo.
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