Your browser doesn't support javascript.
loading
Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC.
Wang, Shunxi; Yuan, Xiaoxue; Yang, Zetao; Zhang, Xuan; Xu, Zhiling; Yang, Li; Yang, Xian; Zhou, Wei; Liu, Wanqian.
Afiliación
  • Wang S; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Yuan X; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Yang Z; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Zhang X; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Xu Z; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Yang L; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Yang X; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • Zhou W; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China; Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China. Electronic address: zhouwei998@cqu.edu.cn.
  • Liu W; Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China. Electronic address: wqliu@cqu.edu.cn.
J Adv Res ; 2024 Aug 17.
Article en En | MEDLINE | ID: mdl-39159723
ABSTRACT

INTRODUCTION:

Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear.

OBJECTIVES:

This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC.

METHODS:

Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo.

RESULTS:

Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC.

CONCLUSION:

These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Egipto
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Adv Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Egipto