2. Academic Validation
  3. Guanine nucleotide exchange factor T exerts the cancer-promoting function in cholangiocarcinoma by enhancing the Wnt-GSK-3β-β-catenin cascade via regulation of Rac1/Cdc42

Guanine nucleotide exchange factor T exerts the cancer-promoting function in cholangiocarcinoma by enhancing the Wnt-GSK-3β-β-catenin cascade via regulation of Rac1/Cdc42

  • Toxicol Appl Pharmacol. 2023 Mar 26;116492. doi: 10.1016/j.taap.2023.116492.
Xifang Wang 1,  Xiaomin Zhang 2,  Jingying Sun 3,  Yang Sun 4,  Yuan Zhang 1,  Li He 1,  Ping Wang 5,  Feng Li 6,  Chao Sun 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
  • 2 Department of Orthopaedics, Xi'an International Medical Center Hospital, Xi'an 710100, China.
  • 3 Shaanxi Provincial Key Laboratory of Infectious and Immunological Diseases, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
  • 4 Data Center, Shaanxi Provincial People's Hospital, s 710068, China.
  • 5 Department of Pathology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
  • 6 Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China. Electronic address: [email protected].
  • 7 Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, China. Electronic address: [email protected].
PMID: 36977438 DOI: 10.1016/j.taap.2023.116492
Abstract

Guanine nucleotide exchange factor T (GEFT), which is frequently overexpressed in cancers, is closely related to tumorigenicity and metastasis. Up to now, little is known about the relationship between GEFT and cholangiocarcinoma (CCA). The work explored the expression and function of GEFT in CCA and revealed the underlying mechanisms. Both CCA clinical tissues and cell lines expressed higher levels of GEFT than normal controls. High GEFT levels were correlated with a low overall survival rate in CCA patients. A decrease in GEFT by RNA interference caused remarkable Anticancer effects in CCA cells, including retarded proliferation, delayed cell cycle progression, subdued metastatic potential and enhanced chemosensitivity. Mechanistically, GEFT mediated the Wnt-GSK-3β-β-catenin cascade associated with the regulation of Rac1/Cdc42. The inhibition of Rac1/Cdc42 markedly diminished the enhancing effect of GEFT on the Wnt-GSK-3β-β-catenin and reversed GEFT-mediated cancer-promoting effects in CCA. Moreover, the reactivation of β-catenin diminished GEFT-reduction-induced Anticancer effects. Critically, CCA cells with decreasing GEFT had a weakened ability to form xenografts in mouse models. Collectively, this work illustrates that GEFT-mediated Wnt-GSK-3β-β-catenin cascade represents a novel mechanism underlying CCA progression and propose a decrease in GEFT as a potential path for treatment in CCA patients.

Keywords

Cholangiocarcinoma; GEFT; Rac1/Cdc42; Wnt.

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