1. Academic Validation
  2. MicroRNA-621 functions as a metastasis suppressor in colorectal cancer by directly targeting LEF1 and suppressing Wnt/β-catenin signaling

MicroRNA-621 functions as a metastasis suppressor in colorectal cancer by directly targeting LEF1 and suppressing Wnt/β-catenin signaling

  • Life Sci. 2022 Nov 1;308:120941. doi: 10.1016/j.lfs.2022.120941.
Xinyi Chen 1 Jingyao Tu 1 Chaofan Liu 1 Lu Wang 2 Xianglin Yuan 3
Affiliations

Affiliations

  • 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang road 1095, Wuhan, Hubei Province, China.
  • 2 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang road 1095, Wuhan, Hubei Province, China. Electronic address: [email protected].
  • 3 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang road 1095, Wuhan, Hubei Province, China. Electronic address: [email protected].
Abstract

Aims: Colorectal liver metastasis (CRLM) is the leading death-causing among colorectal Cancer (CRC) patients. Recently, a novel tumor-related MicroRNA, miR-621, has been identified as a tumor suppressor in diverse tumor types, but its role in CRLM remains unclear and requires further investigation.

Main methods: To elucidate novel regulators of CRLM progression, we used a well-established CRLM animal model. After serially transplanting human colon carcinoma cell lines Caco-2 into the liver, we obtained liver metastatic variants that exhibited a strong ability for invasion and metastasis. High-throughput sequencing was conducted on these newly established cell lines. After comparison and prediction between the two cell lines: parental Caco-2 (hereafter referred to as F0) and F3, miR-621 was identified as a candidate regulator for lymphoid enhancer-binding factor 1 (LEF1) expression. Further validation was achieved with dual-luciferase reporter assay.

Key findings: The gain- and loss-of-function validation showed that miR-621 inhibits cell viability, cell cycle progression, colony formation, and proliferation in vitro. Meanwhile, miR-621 could reverse EMT malignant phenotype. LEF1, an important downstream mediator of activated Wnt/β-catenin signaling pathway, was validated as the direct functional target of miR-621. miR-621 interacts directly with the LEF1 3'-UTR and post-transcriptionally suppresses LEF1 expression. Moreover, LEF1 overexpression reversed the effect of miR-621. LEF1 silencing counteracted miR-621 down-regulation-induced effects. Further in vivo experiments revealed that miR-621 over-expression suppressed CRLM, but LEF1 abrogated the inhibitory effect of miR-621.

Significance: MiR-621 is a vital tumor suppressor in CRC and could be a promising anti-cancer therapeutic target.

Keywords

Colorectal liver metastasis; Epithelial-mesenchymal transition; LEF1; MiRNA-621; Tumor growth; Wnt/β-catenin pathway.

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