Open Access

ARTICLE

USP13 Suppresses Colorectal Cancer Angiogenesis by Downregulating VEGFA Expression through Inhibition of the PTEN-AKT Pathway

Guo-Zhi Xu^1,2, Han-Yang Guan¹, Yan-Guan Guo¹, Yi-Ran Zhang¹, Jing-Hua Pan¹, Simin Luo³, Hui Ding¹, Yunlong Pan^1,*, Qi Yao^4,*

1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
2 Department of Hepatobiliary Gastrointestinal Surgery, Xinyi People’s Hospital, Maoming, Xinyi, 525300, China
3 Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, China
4 Department of Anorectal Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, 518000, China

* Corresponding Authors: Yunlong Pan. Email: ; Qi Yao. Email:

(This article belongs to the Special Issue: Advances and Innovations in Colorectal Cancer Research and Treatment)

Oncology Research 2025, 33(8), 1947-1967. https://doi.org/10.32604/or.2025.060440

Received 01 November 2024; Accepted 10 April 2025; Issue published 18 July 2025

Abstract

Background: Tumor angiogenesis is related to solid tumor occurrence. Ubiquitin-specific peptidase 13 (USP13) is a deubiquitinating enzyme with a pivotal effect on tumor proliferation, metastasis, and tumorigenesis. Nonetheless, its effect on colorectal cancer (CRC) angiogenesis remains poorly understood. Methods: Human umbilical vein endothelial cells (HUVECs) and CRC cells were cultivated, followed by USP13 knockdown/overexpression using shRNA lentiviral vectors or plasmids. Conditioned media (CM) from treated CRC cells were collected to assess HUVEC migration, invasion, and tube formation. Phosphatase and tensin homolog (PTEN) overexpression and recombinant vascular endothelial growth factor A (VEGFA) rescue experiments were performed. Molecular mechanisms were analyzed via Western blot (PTEN, p-AKT, VEGFA), co-immunoprecipitation (PTEN ubiquitination), and in vivo nude mice study to detect the role of USP13 in tumor angiogenesis. Results: USP13 expression in CRC cells is downregulated and negatively related to platelet endothelial cell adhesion molecule-1 (CD31) expression. Furthermore, the conditioned medium from CRC cells with USP13 knockdown significantly promoted HUVEC migration, invasion, and tube formation, while USP13 overexpression exerted the opposite effect. Additionally, USP13 overexpression significantly increased PTEN expression while decreasing protein kinase B (AKT) phosphorylation levels. Concurrently, USP13 overexpression significantly reduced PTEN ubiquitination, whereas USP13 knockdown remarkably increased this modification. Overexpression of PTEN in sh-USP13 CRC cells decreased the expression levels of VEGFA and p-AKT. USP13 also inhibited tumor angiogenesis through downregulating VEGFA, and recombinant VEGFA blocked the inhibition of the conditioned medium from USP13-overexpressing CRC cells against HUVEC angiogenesis in vivo. Conclusions: USP13 downregulated VEGFA and inhibited tumor angiogenesis via the PTEN-AKT pathway.

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