2. Academic Validation
  3. SERPINE1-Driven MAPK Activation Enhances Cuproptosis Resistance and Angiogenic Potential in Colorectal Cancer

SERPINE1-Driven MAPK Activation Enhances Cuproptosis Resistance and Angiogenic Potential in Colorectal Cancer

  • Dig Dis Sci. 2026 Feb 9. doi: 10.1007/s10620-026-09721-z.
Piyao Gao # 1,  Haoyang Li # 2,  Jie Luo 3 4,  Cheng Zhang 5,  Jianbao Wei 1,  Xuejuan Li 1,  Hui Ma 6
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning City, 530011, Guangxi Zhuang Autonomous Region, China.
  • 2 Guangxi University of Chinese Medicine, Nanning City, 530001, Guangxi Zhuang Autonomous Region, China.
  • 3 Guilin Tourism University, Guilin City, 541006, Guangxi Zhuang Autonomous Region, China.
  • 4 Lincoln University, Lincoln, 7647, Canterbury, New Zealand.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning City, 530021, Guangxi Zhuang Autonomous Region, China.
  • 6 Department of Medical Research, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyuan Road, Qingxiu District,, Nanning City, 530021, Guangxi Zhuang Autonomous Region, China. [email protected].
  • # Contributed equally.
PMID: 41661494 DOI: 10.1007/s10620-026-09721-z
Abstract

Background: Colorectal Cancer (CRC) is a significant health challenge with high incidence and mortality rates. While SERPINE1 is overexpressed in CRC and linked to poor patient outcomes, the detailed mechanisms by which it promotes tumor progression remain poorly understood.

Methods: SERPINE1 was identified as a cuproptosis-related angiogenic protein using the GEO database. Expression and prognostic impact of SERPINE1 in CRC were analyzed with the TCGA database. To forecast the pathways SERPINE1 might enrich, we deployed gene set enrichment analysis. SERPINE1 mRNA levels were quantified via qPCR. Co-immunoprecipitation (Co-IP) assay was performed to analyze the interaction between SERPINE1 and uPA/uPAR. Western blot (WB) was conducted to gauge protein expression of MAPK signaling components, Cuproptosis markers, and SERPINE1 itself. Changes in cell viability were assessed using CCK-8. Angiogenesis assays probed how SERPINE1 may impact the angiogenic CA of CRC cells. Xenograft tumor models were established in adult nude mice to track tumor growth and volume changes.

Results: SERPINE1 was highly expressed in CRC, with substantial enrichment in the MAPK signaling pathway, and this overexpression is associated with unfavorable prognoses. CRC cells overexpressing SERPINE1 showed increased cell viability and angiogenic capacity, while expression of cuproptosis-related genes was markedly reduced. Mechanistically, SERPINE1 activates p38/MAPK pathway, thereby enhancing angiogenesis and Cuproptosis resistance in CRC. This process may be associated with the interaction between SERPINE1 and uPA/uPAR.

Conclusion: Our study illuminates how SERPINE1, often overexpressed in CRC, leverages the p38/MAPK pathway to bolster Cuproptosis resistance and angiogenesis, offering a promising avenue for anti-angiogenic strategies in CRC treatment.

Keywords

Angiogenesis; Colorectal cancer; Cuproptosis; P38/MAPK signaling pathway; SERPINE1.

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