Metabolic enzyme PFKFB3 mediates matrix stiffness-potentiated tumour growth and radiotherapeutic resistance in HCC

  • Clin Transl Med. 2025 Dec;15(12):e70509. doi: 10.1002/ctm2.70509.
Mimi Wang  1 ,  Jiajun Li  1 ,  Jiali Qian  2 ,  Xi Zhang  1 ,  Miao Li  1 ,  Yingying Zhao  1 ,  Zhiming Wang  3 ,  Kun Guo  1 ,  Dongmei Gao  1 ,  Yan Zhao  1 ,  Rongxin Chen  1 ,  Zhenggang Ren  1 ,  Taiwei Sun  4 ,  Fan Wang  5 ,  Jiefeng Cui  1
Affiliations
  • 1. Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, PR China.
  • 2. Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, PR China.
  • 3. Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
  • 4. Department of Radiotherapy, Zhongshan Hospital, Fudan University, Shanghai, PR China.
  • 5. Department of Oncology, Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
PMID: 41292194 DOI: 10.1002/ctm2.70509
Abstract

Background: Although the contribution of matrix stiffness to aggravating the malignant features of HCC cells has been well documented, the effects of matrix stiffness on chemoradiotherapy resistance and its underlying mechanism remain largely elusive.

Methods: To delineate the role of matrix stiffness in HCC progression, we engineered novel in vivo animal models with defined liver stiffness and a complementary tunable hydrogel culture system. This integrated approach enabled a comprehensive investigation into how biomechanical cues modulate HCC cell proliferation and DNA repair both in vitro and in vivo.

Results: High stiffness stimulation noticeably enhanced cell proliferation and cell survival from DNA damage through changing the expression and distribution of metabolic enzyme PFKFB3. Specifically, high stiffness stimulation prominently suppressed PFKFB3 ubiquitination by downregulating E3 ubiquitin Ligase NEDD4, and then increased the stability of PFKFB3 protein to enhance glycolysis, ultimately promoted HCC growth. Meanwhile, high matrix stiffness stimulation also effectively strengthened the DNA damage repair ability of irradiated HCC cells, and PFKFB3 nuclear translocation mediated in matrix stiffness-regulated DNA damage repair by interacting with Ku70.

Conclusions: Our results delineate a PFKFB3-mediated pathway that underpins how increased matrix stiffness potentiates HCC growth and compromises radiotherapy efficacy. These findings not only highlight the contribution of matrix stiffness to tumor growth and DNA damage repair in HCC, but also disclose a previously unidentified nonmetabolic function of PFKFB3.

Key points: Increased matrix stiffness significantly promoted glycolysis in HCC cells via upregulating PFKFB3 expression. High stiffness stimulation suppressed PFKFB3 ubiquitination by downregulating E3 ubiquitin Ligase NEDD4 expression. PFKFB3 participated in DNA damage repair by translocating into nuclear and interacting with Ku70, which strengthened by matrix stiffness.

Keywords
DNA repair; PFKFB3; hepatocellular carcinoma; matrix stiffness.
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