LIM domain only protein 7 promotes metastasis in colorectal cancer by TGF-β/ZEB1 pathway

Abstract

BACKGROUND

Tumor metastasis is the main cause of death in patients with colorectal cancer (CRC). Despite the rapid development of new therapeutic methods and drugs in recent years, the survival rate of patients with metastatic CRC has not improved significantly. Proteins play pivotal roles in CRC development and progression. Thus, studying their expression profiles and regulatory mechanisms in CRC may facilitate the development of novel diagnostic and therapeutic strategies.

AIM

To explore the role and regulatory mechanism of LIM domain only protein 7 (LMO7) in CRC metastasis.

METHODS

We screened differentially expressed proteins associated with CRC through proteomics and verified the expression and clinical significance of LMO7 in CRC. The biological role of LMO7 in CRC was assessed in vitro and in vivo and further analyzed by transcriptome sequencing. In addition, we investigated the effects of LMO7 on epithelial-mesenchymal transition (EMT) in CRC cells and the underlying mechanisms.

RESULTS

Data-independent acquisition proteomic analysis of 78 paired CRC tissues and adjacent normal tissues identified 1144 differentially expressed proteins, among which LMO7 was significantly upregulated in CRC. We found that the expression of LMO7 in CRC tissues was increased and correlated with the clinical stage of CRC. Additionally, compared with that in primary colon cancer sites or negative lymph nodes, the protein expression of LMO7 in metastatic lymph nodes was greater. LMO7 promoted CRC cell proliferation, migration, and invasion, as well as the growth and metastasis of CRC tumors. Transcriptome sequencing revealed that LMO7 is associated with cell migration and EMT. We also confirmed that LMO7 promoted the EMT ability of CRC cells by regulating the expression of E-cadherin, N-cadherin, and vimentin. Furthermore, we found that LMO7 could bind to zinc finger E-box binding homeobox 1 (ZEB1) and regulate the expression of LMO7 through ZEB1. Moreover, induction with transforming growth factor (TGF)-β led to increased expression of ZEB1 and LMO7 proteins in CRC cells, and knockdown of ZEB1 attenuated this induction effect of TGF-β on LMO7 protein expression.

CONCLUSION

This study demonstrated that LMO7 facilitates EMT, as well as cell migration and invasion, ultimately driving the progression and metastasis of CRC cells. Furthermore, the TGF-β/ZEB1 signaling pathway positively regulates LMO7 expression in CRC.

Keywords: LIM domain only protein 7; Colorectal cancer; Metastasis; Epithelial-mesenchymal transition; Transforming growth factor-β; Zinc finger E-box binding homeobox 1

Core Tip: LIM domain only protein 7 (LMO7) is upregulated in colorectal cancer (CRC), and is correlated with clinical stage and metastasis. It promotes CRC cell proliferation, migration, invasion, epithelial-mesenchymal transition and tumor metastasis. transforming growth factor-β induces LMO7 expression by upregulating zinc finger E-box binding homeobox 1, which binds to the LMO7 promoter, forming a transforming growth factor-β/zinc finger E-box binding homeobox 1/LMO7 axis that drives CRC progression, highlighting LMO7 as a potential therapeutic target for CRC.