RIOK3 promotes pancreatic ductal adenocarcinoma cell invasion and metastasis by stabilizing FAK

Mengyuan Xu; Lei Fang; Xin Guo; Henan Qin; Rui Sun; Zhen Ning; Aman Wang

doi:10.1016/j.heliyon.2022.e10116

RIOK3 promotes pancreatic ductal adenocarcinoma cell invasion and metastasis by stabilizing FAK

Heliyon. 2022 Aug 3;8(8):e10116. doi: 10.1016/j.heliyon.2022.e10116. eCollection 2022 Aug.

Authors

Mengyuan Xu^{1

2}, Lei Fang¹, Xin Guo^{1

3}, Henan Qin¹, Rui Sun¹, Zhen Ning^{1

3}, Aman Wang^{1

3}

Affiliations

¹ The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian 116000, China.
² Hangzhou Medical College Affiliated Lin'an People's Hospital, Hangzhou 310000, China.
³ Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer, Dalian 116000, China.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, characterized by a high metastatic burden. RIO Kinase 3 (RIOK3) has been shown to promote invasion and metastasis of PDAC by cytoskeleton remodeling, but the exact mechanism is still unknown. In this study, we analyzed transcriptome sequencing data from RIOK3 stable knockdown PANC-1 cells and TCGA-PDAC data and discovered that RIOK3 was substantially related to focal adhesion signaling in PDAC. Additionally, silencing RIOK3 dramatically decreased Focal Adhesion Kinase (FAK) protein expression and phosphorylation (Tyr397 and Tyr925 sites). Immunoprecipitation assay verified the interaction of RIOK3 and FAK. Furthermore, RIOK3 considerably increased the protein stability of FAK protein but not FAK-Y925F protein. The biological function of RIOK3 in increasing PDAC cell invasion and migration was shown to be dependent on FAK activation. Moreover, we discovered that RIOK3 mutations were mainly characterized by amplification. RIOK3 mRNA was found to be significantly elevated in PDAC tissues and was associated with a poor prognosis. Furthermore, RIOK3 mRNA was significantly upregulated in later T-stage, pre-existing lymph node metastases, and later pathological stage samples. Overall, our study found that RIOK3 promotes PDAC cell invasion and metastasis by stabilizing FAK protein expression and upregulating its phosphorylation. This also provides a new target for therapeutic modalities targeting FAK.

Keywords: FAK; Invasion; Migration; Pancreatic ductal adenocarcinoma; RIOK3.