2. Academic Validation
  3. HECW1-Mediated Ubiquitination of HIPK2 Drives Metastasis in Gastric Cancer Through the AKT Signaling Pathway

HECW1-Mediated Ubiquitination of HIPK2 Drives Metastasis in Gastric Cancer Through the AKT Signaling Pathway

  • Lab Invest. 2024 Nov 28;105(2):102202. doi: 10.1016/j.labinv.2024.102202.
Guangze Zhang 1,  Weilong Qu 2,  Xinkun Huang 3,  Jianfeng Yi 1,  Hanxu Gao 1,  Jiancheng He 4,  Wanjiang Xue 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China; Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, China.
  • 2 Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Nantong Hospital of Traditional Chinese Medicine, Nantong, China.
  • 3 Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China.
  • 4 Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China; Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, China. Electronic address: ntdxhjc@stmail.ntu.edu.cn.
  • 5 Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, China. Electronic address: xuewanjiang@ntu.edu.cn.
PMID: 39615883 DOI: 10.1016/j.labinv.2024.102202
Abstract

E3 ubiquitin ligases, crucial Enzymes in the ubiquitination pathway, significantly influence the development of malignant tumors, including gastric Cancer (GC), by regulating the stability of oncogenic and tumor-suppressive proteins. This study employed bioinformatics analysis of public databases alongside various experimental techniques-tissue arrays, real-time reverse-transcription polymerase chain reaction, western blot, immunofluorescence, and coimmunoprecipitation-to identify and explore the role of HECW1, a pivotal NEDD4 family E3 ubiquitin Ligase, in GC progression. The results demonstrated that HECW1 is markedly overexpressed in GC tissues relative to normal gastric tissues, and its elevated expression correlates with poor prognosis in GC patients. In vitro experiments revealed that HECW1 overexpression significantly enhances the metastatic capabilities of GC cells. Mechanistically, HECW1 interacts with HIPK2 to facilitate its ubiquitination and degradation, thereby activating Akt and promoting the expression of downstream epithelial mesenchymal transition-related genes. In vivo experiments confirmed HECW1's role in promoting GC cell metastasis, highlighting the HECW1-HIPK2-AKT signaling axis as critical in GC metastasis. These findings not only elucidate a novel metastasis mechanism of GC but also suggest potential molecular targets for developing new therapeutic strategies against GC.

Keywords

AKT; HECW1; HIPK2; gastric cancer; ubiquitination.

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