TRIP13, identified as a hub gene of tumor progression, is the target of microRNA-4693-5p and a potential therapeutic target for colorectal cancer

Yan Chen,Cheng Qiu,Ying Qin,Yuyang Jiang,Lulu Li,Danqi Chen,Mengmeng Dai,Qinsheng Sun,Yaoyao Zhou

doi:10.1038/s41420-022-00824-w

Abstract

Colorectal cancer (CRC) is one of the digestive tract malignancies whose early symptoms are not obvious. This study aimed to identify novel targets for CRC therapy, especially early-stage CRC, by reanalyzing the publicly available GEO and TCGA databases. Thyroid hormone receptor interactor 13 (TRIP13) correlated with tumor progression and prognosis of patients after several rounds of analysis, including weighted gene correlation network analysis (WGCNA), and further chosen for experimental validation in cancer cell lines and patient samples. We identified that mRNA and protein levels of TRIP13 increased in CRC cells and tumor tissues with tumor progression. miR-4693-5p was significantly downregulated in CRC tumor tissues and bound to the 3′ untranslated region (3′UTR) of TRIP13, downregulating TRIP13 expression. DCZ0415, a small molecule inhibitor targeting TRIP13, induced anti-tumor activity in vitro and in vivo. DCZ0415 markedly suppressed CRC cell proliferation, migration, and tumor growth, promoted cell apoptosis, and resulted in the arrest of the cell cycle. Our research suggests that TRIP13 might play a crucial role in CRC progression and could be a potential target for CRC therapy.

Highlights

Colorectal cancer (CRC) is a malignant tumor of the colon and rectum
To further explore the biological roles of the blue module genes, the STRING database was used to apply the protein−protein interaction (PPI) enrichment analysis and the network constructed by Cytoscape (Fig. 2B)
Among the top 20 hub genes, only the Hormone Receptor Interactor 13 (TRIP13) expression increased continuously from normal tissue to polyp to early-stage tumor to the late-stage tumor in the GSE41258 dataset, suggesting that Thyroid hormone receptor interactor 13 (TRIP13) might play an essential part in tumor progression (Fig. 2D, E)

Summary

Introduction

Colorectal cancer (CRC) is a malignant tumor of the colon and rectum. When first diagnosed, the tumor stage had a significant influence on the prognosis of CRC patients [2]. 70–80% of CRC are sporadic tumors, which develop through the polypoid adenomas and progress into malignant forms [4, 5]. It often takes decades before final malignancies develop; early diagnosis and endoscopic resection of the primary tumor is essential to control CRC [6]. The molecular biomarkers of CRC tumors were tested for assistance in disease prognosis, surveillance, and treatment. There remains an urgent need to appraise valuable clinical entities and biomarkers for CRC therapy, especially early-stage CRC

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Conclusion