2. Academic Validation
  3. RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation

RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation

  • Drug Resist Updat. 2025 Dec 4:85:101339. doi: 10.1016/j.drup.2025.101339.
Mengyuan Wu 1,  Xu Huang 1,  Miao Lin 1,  Zhiyun Duan 1,  Zitao Jian 1,  Runze You 1,  Peiyi Xie 2,  Zhiwei Wu 1,  Siyun Lin 1,  Shaoyuan Zhang 1,  Wenyi Xu 1,  Heng Jiao 1,  Han Tang 1,  Lei Guo 2,  Hao Wang 3,  Weigang Guo 4,  Lijie Tan 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
  • 3 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 4 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 5 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 41411970 DOI: 10.1016/j.drup.2025.101339
Abstract

Aims: Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various Cancer types. However, the role of RCN2 in ESCC remains unexplored.

Methods: The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both in vitro and in vivo. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.

Results: We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein Phosphatase 2 A (PP2A), and ubiquitin protein Ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.

Conclusions: Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.

Keywords

Cisplatin resistance; Esophageal squamous cell carcinoma; Metastasis; PI3K-AKT signaling pathway; RCN2.

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