Abstract
Peritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.
Highlights
Gastric cancer remains one of the most common cancer and the third leading cause of cancer-related deathsThese authors contributed : Xi Kang, Weilin Li
Transcriptomic sequencing identified unique gene expression profiles of gastric cancer peritoneal metastasis expression profiles compared to primary gastric tumors or normal stomach tissues (Fig. 1B and 1C)
4 candidate genes were selected from the top up-regulated genes in peritoneal metastasis compared to primary gastric cancer, which were S100A13 (S100 calcium-binding protein A13), BCHE (Butyrylcholinesterase), ITGA4 (Integrin alpha 4) and LIMK1 (LIM domain kinase 1) (Fig. 1D)
Summary
We aim to identify genes uniquely up-regulated in peritoneal metastasis that could be targeted by readily available drugs
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