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

doi:10.1038/s41420-022-00824-w

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

Cell Death Discov. 2022 Jan 24;8(1):35. doi: 10.1038/s41420-022-00824-w.

Authors

Yan Chen^{1

2}, Danqi Chen², Ying Qin³, Cheng Qiu⁴, Yaoyao Zhou⁴, Mengmeng Dai², Lulu Li², Qinsheng Sun², Yuyang Jiang^{5

6

7}

Affiliations

¹ School of Life Sciences, Tsinghua University, Beijing, China.
² State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong, China.
³ Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China.
⁴ National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong, China.
⁵ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong, China. jiangyy@sz.tsinghua.edu.cn.
⁶ Shenzhen Bay Laboratory, Shenzhen, Guangdong, China. jiangyy@sz.tsinghua.edu.cn.
⁷ School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. jiangyy@sz.tsinghua.edu.cn.

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.