2. Academic Validation
  3. Transglutaminase 2 facilitates metastasis of basal-like bladder cancer by sustaining MVP-mediated MAPK/ERK1/2 signaling activation

Transglutaminase 2 facilitates metastasis of basal-like bladder cancer by sustaining MVP-mediated MAPK/ERK1/2 signaling activation

  • Cancer Lett. 2026 Jan 1:636:218146. doi: 10.1016/j.canlet.2025.218146.
Daihui Chen 1,  Xinyuan Li 2,  Guozhi Zhao 1,  Chen Zhang 3,  Junlin Gan 2,  Tinghao Li 1,  Ning Xu 4,  Qingshu Li 5,  Ziying Yi 6,  Yongpeng Xie 1,  Fangchao Yuan 1,  Jing Fan 1,  Hongya Ou 1,  Xin Gou 1,  Hang Tong 1,  Weiyang He 7,  Hubin Yin 8
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 3 State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 5 Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China.
  • 6 Breast and Thyroid Surgery, Chongqing General Hospital, Chongqing University, Chongqing, 400016, China.
  • 7 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].
  • 8 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].
PMID: 41238097 DOI: 10.1016/j.canlet.2025.218146
Abstract

Basal-like bladder Cancer is a subtype of bladder Cancer (BC) with a high risk of invasion and metastasis, for which there are currently no approved or clinically validated targeted therapies. Transglutaminase 2 (TG2) is dysregulated in various solid tumors, including muscle-invasive BC, but its role in the progression of basal-like BC remains unexplored. In this study, we revealed that TG2 is overexpressed in basal-like BC and correlates with basal/squamous cell differentiation, advanced clinical stage, poor prognosis, and lymphatic metastasis. Functional studies demonstrate that TG2 promotes epithelial-mesenchymal transition (EMT), cell migration, invasion, lymphangiogenesis, lymphatic and distant metastasis both in vitro and in vivo. Mechanistically, TG2 binds to major vault protein (MVP), which stabilizes MVP by inhibiting ubiquitin-proteasomal degradation. This process is dependent on the cross-linking activity of the transamidase of TG2. Accumulation of MVP protein facilitates MAPK/ERK1/2 signaling activation, thereby inducing EMT and malignant phenotypes. Pharmacological inhibition of TG2's catalytic activity with NC9 reduces MVP protein stability, ERK1/2 activation, and aggressive behaviors. Crucially, administration of NC9 retards the growth and EMT of patient-derived organoids (PDOs) from basal-like BC in a dose-dependent manner. Furthermore, in vivo studies validated that NC9 significantly reduces lung metastasis and is well-tolerated, with no observed significant organ toxicity. Our findings establish TG2 as a prognostic biomarker and therapeutic target, with its transamidase-dependent MVP-ERK1/2 axis offering a novel therapeutic strategy against basal-like BC.

Keywords

Basal-like bladder cancer; Metastasis; Organoids; TG2; Targeted therapy.

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