MICALL2 as a substrate of ubiquitinase TRIM21 regulates tumorigenesis of colorectal cancer

Abstract

Background Molecule interacting with CasL-like protein 2 (MICALL2) is believed to regulate cytoskeleton dynamics, tight junction formation, and neurite outgrowth. However, its biological role and the underlying mechanism in colorectal cancer (CRC) remain largely elusive. Methods qRT-PCR, Western blotting and immunohistochemistry assays were used to detect the expression levels of different genes. Next, mass spectrometry, co-immunoprecipitation and immunofluorescence staining were used to detect the interactions of proteins. Furthermore, MTT assay, colony formation assay, wound-healing assays and xenograft tumor models were performed to demonstrate the functions of MICALL2 in CRC. In addition, transcriptome sequencing and Western blotting were conducted to verify the mechanism of MICALL2 in CRC. Results We found that both mRNA and protein levels of MICALL2 are up-regulated in colorectal cancer tissues compared with non-tumor tissues and that its overexpression is closely correlated with poor prognosis. Ubiquitin E3 ligase Tripartite motif-containing protein 21 (TRIM21) mediated MICALL2 ubiquitination and proteasome-dependent degradation, negatively correlated with MICALL2 levels, and reversely regulated the tumorigenic activity of MICALL2 in CRC. Functional studies confirmed that MICALL2 promoted colorectal cancer cell growth and migration via the Wnt/β-catenin signaling pathway. Conclusions As a substrate of ubiquitinase TRIM21, MICALL2 enhances the growth and migration of colorectal cancer cells and activates the Wnt/β-catenin signaling pathway.

Identification of a tissue resident memory CD8 T cell-related risk score signature for colorectal cancer, the association with TME landscapes and therapeutic responses

“…By contrast, Trm cluster B was characterized by enhanced tumor purity and a paucity of immune and stromal contents in TME. Notably, Wnt_β-catenin pathway, a canonical carcinogenic pathway for malignancies in digestive system ( Xue et al, 2021 ; Wen et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ; Zhu et al, 2022 ), was the Hallmark item with the highest enrichment level in Trm cluster B ( Figure 3B ), which reflected the high tumor purity of this cluster.…”

High MICAL-L2 promotes cancer progression and drug resistance of renal clear cell carcinoma cell via stabilization of ACTN4 and following vimentin expression

“…For example, MICAL-L2 may interact with c-myc, which in turn may induce lung cancer cell proliferative behaviour [6]. TRIM21 binds to and mediates MICAL-L2 ubiquitination, reversely regulated the tumorigenic activity of MICAL-L2 in colorectal cancer [7]. Although in ammation and T Cell exhaustion by MICAL-L2 in KIRC have been well studied [8], for potential clinical implementation, further investigation is needed to determine the exact role and detailed mechanisms of MICAL-L2 in KIRC for potential clinical translation.…”