2. Academic Validation
  3. Comprehensive pan-cancer analysis of USP35 and validation of its role in gastric cancer

Comprehensive pan-cancer analysis of USP35 and validation of its role in gastric cancer

  • Hum Genomics. 2025 Nov 12;19(1):134. doi: 10.1186/s40246-025-00850-6.
Lirong Yan # 1 2,  Yuzhe Zhang # 1,  Shubao Wang # 3,  Jiahui Qin 4,  Moye Chen 5,  Dan Zou 6,  Lulu Zhang 7,  Lina Wu 8,  Ye Zhang 9
Affiliations

Affiliations

  • 1 The First Laboratory of Cancer Institute, The First Hospital of China Medical University, North Nanjing Street 155#, Heping District, Shenyang, 110001, China.
  • 2 Department of Pharmacy, Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
  • 3 Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China.
  • 4 Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, 110004, Liaoning, People's Republic of China.
  • 5 Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 6 Department of Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.
  • 7 Central Hospital Affiliated to Shenyang Medical College, No. 5 South Qi West Road, Tiexi District, Shenyang, China.
  • 8 Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, 110004, Liaoning, People's Republic of China. [email protected].
  • 9 The First Laboratory of Cancer Institute, The First Hospital of China Medical University, North Nanjing Street 155#, Heping District, Shenyang, 110001, China. [email protected].
  • # Contributed equally.
PMID: 41225657 DOI: 10.1186/s40246-025-00850-6
Abstract

In this study, we systematically revealed the expression characteristics, clinical relevance, and potential molecular mechanisms of the ubiquitin-specific processing protease 35 (USP35) in 33 cancers for the first time by integrating pan-cancer data from TCGA, GTEx, and Other databases. Bioinformatics analysis showed that USP35 was significantly highly expressed in nine cancers, including gastric Cancer (GC) and thyroid Cancer, and its expression level was closely related to the tumor stage, metastasis, and a poor prognosis. Diagnostic value analysis showed that the area under the curve (AUC) value of USP35 exceeded 0.7 for four cancers, including rectal adenocarcinoma, suggesting its potential as a diagnostic marker. Mechanistic studies revealed that USP35 may affect tumor progression by regulating myogenesis, the epithelial–mesenchymal transition (EMT), and Other pathways, and is significantly associated with Apoptosis, cell cycles, and Other activities. Experimental validation partially confirmed that USP35 is strongly associated with cancer-associated fibroblasts in GC. Knockdown of USP35 inhibited GC cell migration/invasion, down-regulated vimentin, and blocked energy metabolism reprogramming through the inhibition of glycolysis. In combination with USP35 knockdown, 2-DG further exacerbated the metabolic inhibitory effects, and the reversal of the EMT was even more significant. USP35 enhanced the tumorigenic capacity and the EMT of GC cells in vivo. This study demonstrates that USP35 may promote GC progression through metabolic reprogramming, exhibiting potential as a diagnostic and prognostic tumor marker.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40246-025-00850-6.

Keywords

Energy metabolism reprogramming; Epithelial–mesenchymal transition; Pan-cancer; Tumor immune microenvironment; USP35.

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