LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

• Published in: Oncogene 2021-05, Vol.40 (19), p.3422-3433
• Main Authors: Kang, Xi, Li, Weilin, Liu, Weixin, Liang, Han, Deng, Jingyu, Wong, Chi Chun, Zhao, Sinan, Kang, Wei, To, Ka Fai, Chiu, Philip Wai Yan, Wang, Guiying, Yu, Jun, Ng, Enders Kwok Wai
• Format: Article
• Language: English
• Subjects: 13/51; 631/337; 631/67/322; 64/60; 82/80; 96/106; 96/109; 96/95; Animals; Apoptosis; Care and treatment; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Cell migration; Cell Proliferation; Cofilin; Development and progression; Gastric cancer; Genetic aspects; Health aspects; Human Genetics; Humans; Imidazoles - pharmacology; Immunohistochemistry; Internal Medicine; LIM kinase; Lim Kinases - antagonists & inhibitors; Lim Kinases - genetics; Lim Kinases - metabolism; Liver cancer; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neoplasm Metastasis; Oncology; Oximes - pharmacology; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - secondary; Peritoneum; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein kinases; Sequence Analysis, RNA; Stomach cancer; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Survival Rate; Therapeutic applications; Therapeutic targets; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01656-1

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.