2. Academic Validation
  3. TMEM65 promotes gastric tumorigenesis by targeting YWHAZ to activate PI3K-Akt-mTOR pathway and is a therapeutic target

TMEM65 promotes gastric tumorigenesis by targeting YWHAZ to activate PI3K-Akt-mTOR pathway and is a therapeutic target

  • Oncogene. 2024 Feb 10. doi: 10.1038/s41388-024-02959-9.
Lingxue Shi # 1 2 3,  Xiaohong Wang # 2 4,  Shang Guo 2 3 5,  Hongyan Gou 2,  Haiyun Shang 2,  Xiaojia Jiang 2,  Chunxian Wei 2,  Jia Wang 3,  Chao Li 1 3,  Lihong Wang 3,  Zengren Zhao 6 7,  Weifang Yu 8 9,  Jun Yu 10
Affiliations

Affiliations

  • 1 Departments of Endoscopy Center, The First Hospital of Hebei Medical University, Shijiazhuang, China.
  • 2 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 3 The First Hospital of Hebei Medical University, Shijiazhuang, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China.
  • 5 Gastrointestinal Disease Centre, Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China.
  • 6 The First Hospital of Hebei Medical University, Shijiazhuang, China. [email protected].
  • 7 Gastrointestinal Disease Centre, Hebei Key Laboratory of Colorectal Cancer Precision Diagnosis and Treatment, The First Hospital of Hebei Medical University, Shijiazhuang, China. [email protected].
  • 8 Departments of Endoscopy Center, The First Hospital of Hebei Medical University, Shijiazhuang, China. [email protected].
  • 9 The First Hospital of Hebei Medical University, Shijiazhuang, China. [email protected].
  • 10 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
  • # Contributed equally.
PMID: 38341472 DOI: 10.1038/s41388-024-02959-9
Abstract

Copy number alterations are crucial for the development of gastric Cancer (GC). Here, we identified Transmembrane Protein 65 (TMEM65) amplification by genomic hybridization microarray to profile copy-number variations in GC. TMEM65 mRNA level was significantly up-regulated in GC compared to adjacent normal tissues, and was positively associated with TMEM65 amplification. High TMEM65 expression or DNA copy number predicts poor prognosis (P < 0.05) in GC. Furtherly, GC patients with TMEM65 amplification (n = 129) or overexpression (n = 78) significantly associated with shortened survival. Ectopic expression of TMEM65 significantly promoted cell proliferation, cell cycle progression and cell migration/invasion ability, but inhibited Apoptosis (all P < 0.05). Conversely, silencing of TMEM65 in GC cells showed opposite abilities on cell function in vitro and suppressed tumor growth and lung metastasis in vivo (all P < 0.01). Moreover, TMEM65 depletion by VNP-encapsulated TMEM65-siRNA significantly suppressed tumor growth in subcutaneous xenograft model. Mechanistically, TMEM65 exerted oncogenic effects through activating PI3K-Akt-mTOR signaling pathway, as evidenced of increased expression of key regulators (p-Akt, p-GSK-3β, p-mTOR) by Western blot. YWHAZ (Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase) was identified as a direct downstream effector of TMEM65. Direct binding of TMEM65 with YWHAZ in the cytoplasm inhibited ubiquitin-mediated degradation of YWHAZ. Moreover, oncogenic effect of TMEM65 was partly dependent on YWHAZ. In conclusion, TMEM65 promotes gastric tumorigenesis by activating PI3K-Akt-mTOR signaling via cooperating with YWHAZ. TMEM65 overexpression may serve as an independent new biomarker and is a therapeutic target in GC.

Figures
Products