2. Academic Validation
  3. Enhanced ZBTB10 expression induced by betulinic acid inhibits gastric cancer progression by inactivating the ARRDC3/ITGB4/PI3K/AKT pathway

Enhanced ZBTB10 expression induced by betulinic acid inhibits gastric cancer progression by inactivating the ARRDC3/ITGB4/PI3K/AKT pathway

  • Cell Oncol (Dordr). 2025 Jan 28. doi: 10.1007/s13402-025-01039-8.
Zhixin Huang # 1 2,  Ying Li # 3,  Zeyu Zhao # 1 2,  Linying Ye # 1 2,  Tianhao Zhang 1 2,  Zihan Yu 1 2,  Ertao Zhai 1,  Yan Qian 1,  Xiang Xu 1 2,  Risheng Zhao 1,  Shirong Cai 4,  Jianhui Chen 5 6
Affiliations

Affiliations

  • 1 Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 2 Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 3 Guangdong Provincial Key Laboratory of Microbial Safety and Health, National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China.
  • 4 Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. caishr@mail.sysu.edu.cn.
  • 5 Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. chenjh45@mail.sysu.edu.cn.
  • 6 Department of General Surgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, Guangxi, 530000, China. chenjh45@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39873948 DOI: 10.1007/s13402-025-01039-8
Abstract

Background: Gastric Cancer (GC) ranks as the fourth leading cause of cancer-related deaths worldwide, with most patients diagnosed at advanced stages due to the absence of reliable early detection biomarkers.

Methods: RNA-sequencing was conducted to identify the differentially expressed genes between GC tissues and adjacent normal tissues. CCK8, EdU, colony formation, transwell, flow cytometry and xenograft assays were adopted to explore the biological function of ZBTB10 and betulinic acid (BA) in GC progression. RNA-sequencing and phospho-proteomic profiling were performed to analyze the signaling pathways associated with ZBTB10-inhibiting GC progression. Chromatin immunoprecipitation, Co-immunoprecipitation and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of ZBTB10 in GC.

Results: ZBTB10 was one of the most significantly downregulated genes in GC tissues, and higher expression levels of ZBTB10 was correlated with better prognosis in patients with GC. Functional studies revealed that ZBTB10 overexpression and BA inhibited GC progression both in vitro and in vivo. Mechanistically, ZBTB10 enhanced ARRDC3 expression by binding to a specific response element in the ARRDC3 promoter region. Elevated ARRDC3 then directly interacted with β-4 Integrin (ITGB4), leading to its ubiquitination and degradation. This cascade ultimately resulted in the downregulation of PI3K and Akt phosphorylation level. Moreover, ZBTB10 was a key target for BA in GC and BA inhibited GC progression through regulating the ZBTB10/ARRDC3/ITGB4/PI3K/Akt axis.

Conclusions: Our findings reveal that BA holds promise as an effective therapeutic strategy for GC, and the ZBTB10/ARRDC3/ITGB4/PI3K/Akt axis may serve as a novel diagnostic and therapeutic target.

Keywords

ARRDC3; Betulinic acid; Gastric cancer; Malignant progression; PI3K/AKT pathway; ZBTB10.

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