ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer

Abstract

Angiopoietin-like protein 1 (ANGPTL1) is a member of the ANGPTL family that suppresses angiogenesis, cancer invasion, metastasis, and cancer progression. ANGPTL1 is down-regulated in various cancers including colorectal cancer (CRC); however, the effects and mechanisms of ANGPTL1 on liver metastasis and cancer stemness in CRC are poorly understood. In the present study, we identified that ANGPTL1 was down-regulated in CRC and inversely correlated with metastasis and poor clinical outcomes in CRC patients form the ONCOMINE database and Human Tissue Microarray staining. ANGPTL1 significantly suppressed the migration/invasion abilities, the expression of cancer stem cell (CSC) markers, and sphere formation by enhancing FOXO3a expression, which contributed to the reduction of stem cell transcription factor SOX2 expression in CRC cells. Consistently, overexpression of ANGPTL1 reduced liver metastasis, tumor growth, and tumorigenicity in tumor-bearing mice. ANGPTL1 expression was negatively correlated with CSC markers expression and poor clinical outcomes in CRC patients. Taken together, these findings demonstrate that the molecular mechanisms of ANGPTL1 in colorectal cancer stem cell progression may provide a novel therapeutic strategy for CRC.

ANGPTL1, Foxo3a-Sox2, and colorectal cancer metastasis

“…Fan et al reported that ANGPTL1-positive expression was negatively associated with tumor size, lymph node metastasis, and TNM stage, and poor prognosis of CRC patients [ 15 ]. In the present article, the author supported the above findings through the ONCOMINE database analysis and Human Tissue Microarray staining [ 4 ]. Above findings made ANGPTL1 more attractive either as cancer prognostic or predictive biomarkers.…”

“…Nowadays, several target genes and signaling pathways involved in CRC metastasis have been elucidated, but none was selected as an effective treatment target [ 3 ]. In this issue of Clinical Science [ 4 ], Chang et al demonstrated the effects of angiopoietin-like protein 1 (ANGPTL1) on CRC, as they found that increased ANGPTL1 expression was associated with less metastasis and better clinical outcomes. What is more, Forkhead box O-3a (Foxo3a)–SRY-related HMG-box-2 (Sox2) axis was first explored as the mechanism of ANGPTL1 regulated cancer migration, invasion, and stemness.…”

Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity

“…AARS2 and FOXO3 are protective factors in the prognostic model of CRC, and the former regulates the proliferation of colorectal cancer by affecting mitochondrial respiration [ 32 ]. The latter is associated with morbidity and mortality in CRC [ 33 ] and can modulate its mediated SOX2 expression to affect cancer migration, invasion, and stem cell proliferation [ 34 ]. ATF4 regulates tumor autophagy in CRC and affects tumor survival [ 35 ].…”

Sequential Treatment with Activin and Hepatocyte Growth Factor Induces FOXM1 to Promote Colorectal Cancer Liver Metastasis

“…Te precise mechanism of CRC liver metastasis has yet to be determined. CSCs play an important role in primary tumor initiation, development, and metastasis [21]. Many regulators of CSCs have been found to be involved in CRC liver metastasis [22][23][24].…”