Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

被引：108

作者：

van Roosmalen, Wies ^{[1
]}

Le Devedec, Sylvia E. ^{[1
]}

Golani, Ofra ^{[2
]}

Smid, Marcel ^{[3
,4
]}

Pulyakhina, Irina ^{[5
]}

Timmermans, Annemieke M. ^{[3
,4
]}

Look, Maxime P. ^{[3
,4
]}

Zi, Di ^{[1
]}

Pont, Chantal ^{[1
]}

de Graauw, Marjo ^{[1
]}

Naffar-Abu-Amara, Suha ^{[6
]}

Kirsanova, Catherine ^{[7
]}

Rustici, Gabriella ^{[7
]}

't Hoen, Peter A. C. ^{[5
]}

Martens, John W. M. ^{[3
,4
]}

Foekens, John A. ^{[3
,4
]}

Geiger, Benjamin ^{[6
]}

van de Water, Bob ^{[1
]}

机构：

[1] Leiden Univ, Leiden Acad Ctr Drug Res, Div Toxicol, NL-2333 CC Leiden, Netherlands

[2] Weizmann Inst Sci, Dept Biol Serv, IL-76100 Rehovot, Israel

[3] Erasmus Univ, Erasmus MC Canc Inst, Dept Med Oncol, Med Ctr, Rotterdam, Netherlands

[4] Erasmus Univ, Med Ctr, Canc Genom Netherlands, Rotterdam, Netherlands

[5] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 CC Leiden, Netherlands

[6] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[7] European Bioinformat Inst EMBL EBI, Funct Genom Grp, Cambridge, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2015年 / 125卷 / 04期

基金：

欧洲研究理事会;

关键词：

RON RECEPTOR; PROTEIN; KINASE; GENES; REGULATOR; PHOSPHORYLATION; OVEREXPRESSION; MOTILITY;

D O I：

10.1172/JCI74440

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin beta(3)-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

引用

页码：1648 / 1664

页数：17

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