Mol Carcinog. 2023 Nov;62(11):1659-1672.doi: 10.1002/mc.23606. Epub 2023 Jul 14.

本文采用的英格恩产品: 增强型ECL发光液

LKB1 loss promotes colorectal cancer cell metastasis through regulating TNIK expression and actin cytoskeleton remodeling

Affiliations

Affiliations

  • 1 Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Panjiayuan, Chaoyang District, Beijing, People’s Republic of China.

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors. Approximately 5%-6% of CRC cases are associated with hereditary CRC syndromes, including the Peutz-Jeghers syndrome (PJS). Liver kinase B1 (LKB1), also known as STK11, is the major gene responsible for PJS. LKB1 heterozygotic deficiency is involved in intestinal polyps in mice, while the mechanism of LKB1 in CRC remains elusive. In this study, we generated LKB1 knockout (KO) CRC cell lines by using CRISPR-Cas9. LKB1 KO promoted CRC cell motility in vitro and tumor metastases in vivo. LKB1 attenuated expression of TRAF2 and NCK-interacting protein kinase (TNIK) as accessed by RNA-seq and western blots, and similar suppression was also detected in the tumor tissues of azoxymethane/dextran sodium sulfate-induced intestinal-specific LKB1-KO mice. LKB1 repressed TNIK expression through its kinase activity. Moreover, attenuating TNIK by shRNA inhibited cell migration and invasion of CRC cells. LKB1 loss-induced high metastatic potential of CRC cells was depended on TNIK upregulation. Furthermore, TNIK interacted with ARHGAP29 and further affected actin cytoskeleton remodeling. Taken together, LKB1 deficiency promoted CRC cell metastasis via TNIK upregulation and subsequently mediated cytoskeleton remodeling. These results suggest that LKB1-TNIK axis may play a crucial role in CRC progression.

Keywords: LKB1; TNIK; actin cytoskeleton; colorectal cancer; metastasis.

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