Targeting MALT1 Suppresses the Malignant Progression of Colorectal Cancer via miR-375/miR-365a-3p/NF-κB Axis.

Rui Qian,Yinghui Wang,Zhi Guo,Xuyi Deng,Haijun Deng,Zhenhua Ding,Xinli Niu,Meijuan Zhou

doi:10.3389/fcell.2022.845048

Abstract

Colorectal cancer (CRC) is a malignant tumor with the second highest morbidity and the third highest mortality in the world, while the therapeutic options of targeted agents remain limited. Here, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), known as the upstream of the NF-κB signaling pathway, was identified to be highly upregulated in CRC tumors and cell lines. Furthermore, the downregulation of MALT1 or inhibition of its proteolytic function by MI-2 suppressed the cell proliferation and migration of CRC cells. In vivo, suppressing the MALT1 expression or its proteasome activity effectively reduced the size of the subcutaneous tumor in nude mice. Mechanistically, miR-375 and miR-365a-3p were identified to inhibit NF-κB activation via targeting MALT1. Overall, our results highlight that a novel regulatory axis, miRNA-MALT1-NF-κB, plays a vital role in the progression of CRC and provides novel and hopeful therapeutic targets for clinical treatment.

Highlights

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancerrelated deaths worldwide
To explore the relationship between mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and the malignant progression of CRC, we first analyzed the difference of the MALT1 mRNA level between CRC and adjacent tissues based on the Gene Expression Omnibus (GEO) database (GSE21510)
Another GEO series GSE17536 showed that patients with high MALT1 expression (n = 22) had a worse prognosis compared with those with low MALT expression (n = 123) (Figure 1B), which reminded us of the significance of MALT1 in CRC

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancerrelated deaths worldwide. In 2020, there were surprisingly about 1.9 million new cases of CRC and more than 935,000 deaths all over the world. The incidence rate of early-onset CRC is rising by 1%–4% per year (Sung et al, 2021), which is paralleled by the increasing mortality rate (Siegel et al, 2020). There is still a shortage of effective treatments in clinics. Traditional therapies, like endoscopic treatment and surgery, are limited for local and early-stage patients. Emerging immunotherapies still have not shown an increase of overall survival compared to chemotherapy alone (Dekker et al, 2019). It is necessary and imperative to put forward new treatment strategies to improve the outcomes of CRC and reduce its increasing mortality

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Results

Conclusion