TRIB3 Interacts with STAT3 to Promote Cancer Angiogenesis

Qian-Zhi Chen; Yan Chen; Xia Li; Hao Liu; Xu-Ling Sun

doi:10.1007/s11596-022-2655-8

TRIB3 Interacts with STAT3 to Promote Cancer Angiogenesis

Curr Med Sci. 2022 Oct;42(5):932-940. doi: 10.1007/s11596-022-2655-8. Epub 2022 Oct 17.

Authors

Qian-Zhi Chen^#¹, Yan Chen^#², Xia Li³, Hao Liu⁴, Xu-Ling Sun⁵

Affiliations

¹ Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
² Department of Hematology, Wuhan No. 1 Hospital, Wuhan, 430022, China.
³ Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, China.
⁴ Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, China. liuhao850619@sina.com.
⁵ Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, China. tjhsxl@126.com.

^# Contributed equally.

PMID: 36245025
DOI: 10.1007/s11596-022-2655-8

Abstract

Objective: Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis, which is a hallmark of cancer that promotes cancer growth and metastasis. It is of great significance to find new intervention targets and related regulatory mechanisms of VEGFA related angiogenesis for the treatment of tumors. This study focuses on the role of tribbles pseudokinase 3 (TRIB3)/signal transducer and activator of transcription 3 (STAT3)/VEGFA signaling axis in colon cancer angiogenesis.

Methods: This study investigated the expression level of TRIB3 in colon cancer through database analysis and tissue microarray analysis. The effect of TRIB3 on proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) was further confirmed by CCK8 assay, scratch-wound assay/migration assay and tube formation assay respectively. The regulatory relationship of TRIB3/VEGFA signaling axis was identified by qPCR and Western blotting, which was further confirmed through animal experiments, and the specific regulatory mechanism was explored by immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) with colon cancer cell lines.

Results: TRIB3 was increased in colon cancer tissues compared to normal tissues, and elevated TRIB3 expression indicated a poor prognosis in colon cancer patients. Moreover, it was found that silencing TRIB3 could inhibit cancer angiogenesis, whereas overexpressing TRIB3 promoted cancer angiogenesis in vitro and in vivo. Mechanistically, TRIB3 physically interacted with STAT3 and enhanced STAT3-mediated transcriptional activity. Furthermore, the function of TRIB3 in cancer angiogenesis was through cooperating with STAT3 to increase the VEGFA expression.

Conclusion: Our study provides insights into cancer angiogenesis and offers a potential therapeutic strategy for TRIB3-overexpressed cancer.

Keywords: angiogenesis; cancer; signal transducer and activator of transcription 3; tribbles pseudo-kinase 3; vascular endothelial growth factor.

MeSH terms

Animals
Cell Cycle Proteins / metabolism
Colonic Neoplasms* / genetics
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Neovascularization, Pathologic / genetics
Protein Serine-Threonine Kinases / genetics
Repressor Proteins / metabolism
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Vascular Endothelial Growth Factor A* / genetics
Vascular Endothelial Growth Factor A* / metabolism

Substances

Vascular Endothelial Growth Factor A
STAT3 Transcription Factor
TRIB3 protein, human
Repressor Proteins
Protein Serine-Threonine Kinases
Cell Cycle Proteins
STAT3 protein, human