Extracellular Matrix Protein 1 Regulates Colorectal Cancer Cell Proliferative, Migratory, Invasive and Epithelial-Mesenchymal Transition Activities Through the PI3K/AKT/GSK3β/Snail Signaling Axis

Abstract

In prior reports, extracellular matrix protein 1 (ECM1) upregulation has been reported in colorectal cancer (CRC) patient tumor tissues, and has been suggested to be related to the metastatic progression of CRC, although the underlying mechanisms have yet to be clarified. In this study, we found that ECM1 was overexpressed in both CRC tissues and cell lines. Upregulation of ECM1 was correlated with tumor size, lymph node status and TNM stage in CRC patients. Knocking down ECM1 suppressed CRC cell growth, migration and invasion, in addition to reducing the expression of Vimentin and increasing E-cadherin expression. The overexpression of ECM1, in contrast, yielded the opposite phenotypic outcomes while also promoting the expression of p-AKT, p-GSK3β, and Snail, which were downregulated when ECM1 was knocked down. Treatment with LY294002 and 740 Y-P reversed the impact upregulation and downregulation of ECM1 on CRC cell metastasis and associated EMT induction. In vivo analyses confirmed that ECM1 overexpression was able to enhance EMT induction and CRC tumor progression. In conclusion, ECM1 influences CRC development and progression in an oncogenic manner, and regulates CRC metastasis and EMT processes via the PI3K/AKT/GSK3β/Snail signaling axis.

ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction

“…In our previous study, we found that ECM1 could promote CRC progression by influencing cell growth, metastasis and the process of EMT ( Long et al, 2022 ). As a result, we postulated that cell apoptotic evasion and EMT might be regulated by ECM1 in the HCT15/FU cells with mesenchymal-like phenotypes.…”

“…Additionally, AKT/GSK3β signaling was found to be activated in CRC-resistant cells and controlled HIF1α expression ( Shi et al, 2022 ). Moreover, ECM1 has been shown to regulate PI3K/AKT/GSK3β/Snail signaling in CRC ( Long et al, 2022 ). In line with these investigations, we found that ECM1-regulated 5-FU resistance in CRC was mediated through PI3K/AKT/GSK3β.…”

“…The expression of ECM1 is much higher in a variety of tumor tissues, such as ovarian cancer ( Yin et al, 2021 ), CRC ( Long et al, 2022 ), breast cancer ( Steinhaeuser et al, 2020 ), gastric cancer ( Wu et al, 2014 ; Liu et al, 2019 ), etc., when compared with normal tissues. In our previous study, we found that high expression of ECM1 was correlated with tumor size, lymph node status and TNM stage in CRC patients and functionally promoted CRC cells proliferation, invasion and migration ( Long et al, 2022 ). However, whether ECM1 also influence the procession of CRC resistance to 5-FU has not been clarified.…”

Depletion of Fibroblast Growth Factor 12 Restrains the Viability, Stemness, and Motility of Colorectal Cancer

“…In addition, more and more studies have shown that EMT is involved in the proliferation of CSCs, which further promotes cancer progression [ 14 ]. In previous studies, the PI3K/AKT signaling axis was found to be indispensable for EMT induction and subsequent tumor progression [ 15 ]. The PI3K/Akt pathway is related with CRC progression, but the specific molecular mechanism is unclear [ 16 , 17 ].…”

PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells

“…ECM1 inhibition down regulated Snail, pGSK3β, and p-AKT in CRC cells. Additionally, ECM1 induced CRC metastasis by promoting EMT via modulating the PI3K/AKT/GSK3β/Snail pathway [ 42 ]. P2X purine receptors are ATP-dependent cation channel receptors that regulate potassium ions outflow and sodium and calcium ions influx [ 114 – 116 ].…”