CEBPB regulates the migration, invasion and EMT of breast cancer cells by inhibiting THBS2 expression and O-fucosylation

Abstract

Breast cancer (bc) is the second most common type of human malignancies with highest morbidity and mortality in the female population. Therefore, it is essential to develop novel and effective therapies for bc treatment. The main aim of current study is to investigate the functions of CEBPB and THBS2 in bc and the underlying mechanism. RT-qPCR and western blot were performed for the measurement of RNAs and proteins. Function and mechanism assays were respectively conducted for the evaluation of bc biological behaviors and exploration of potential correlation of genes. According to bioinformatics analyses and experimental results, THBS2, up-regulated in bc tissues and cell lines, could facilitate cell migration, invasion and EMT in bc. CEBPB was validated to facilitate miR-29a-3p transcription, thus negatively modulating THBS2 expression. The results of rescue experiments reflected that CEBPB could regulate the malignant behaviors of bc cells via THBS2. Furthermore, CEBPB was ascertained to inhibit the transcription of B3GALTL to affect THBS2 protein O-fucosylation and secretion. The interaction between THBS2 and ITGB1 was confirmed and THBS2 was found to activate the PI3K/AKT signaling pathway. To conclude, CEBPB could restrain bc cell migration, invasion and EMT via inhibition on THBS2 expression and O-fucosylation.

CEBP-β and PLK1 as Potential Mediators of the Breast Cancer/Obesity Crosstalk: In Vitro and In Silico Analyses

“…In vitro and in vivo studies proved that the serine/threonine protein kinase PLK1, whose phosphorylation is directly related to the kinase activity [ 41 ] is significantly correlated with metastasis, drug resistance, p53 mutation and stemness in BC cells [ 30 , 42 , 43 , 44 , 45 , 46 ]. To confirm RNA-sequencing results, we evaluated the effects of CM on the expression and phosphorylation levels of PLK1 in immunoblotting analysis.…”

“…The DIN central hub pool-like kinase 1 (PLK-1) plays key functions in multiple stages of the cell cycle, including the control of the G2/S checkpoint, centrosome maturation, spindle formation, chromosome segregation, DNA replication, cytokinesis, and meiosis [ 97 , 98 ], and its expression has been positively correlated with several cancers, including glioma [ 99 ], thyroid carcinoma [ 100 ], head and neck squamous cell carcinoma [ 101 ], melanoma [ 102 ], colorectal cancers [ 103 ], esophageal carcinoma [ 104 ], ovarian carcinoma [ 105 ], prostate cancer [ 106 ], and BC [ 107 ]. In vitro and in vivo studies proved that PLK1 is significantly correlated with metastasis, drug resistance, p53 mutation and stemness in BC cells [ 30 , 42 , 43 , 44 , 45 , 46 , 108 ]. In addition, PLK1 is a regulator of the cancer stem cell (CSC) phenotype whose inhibition prevents the stemness phenotype in cancer cells [ 42 , 46 ].…”

“…Interestingly, PLK1 correlates with the hormone-independent growth of ERα-positive BC cells, and its inhibition leads to a decrease in growth of long-term estrogen-deprived (LTED) BC cells [ 108 ]. Moreover, Jeon et al found a high expression of PLK1 in Tamoxifen-resistant BC cells and demonstrated that PLK1 knockdown significantly decreases their proliferation, migration, and tumor growth [ 43 ]. In addition, Akdeli and colleagues identified rs27770 as a functional polymorphism that might affect cancer risk, progression and pharmacological resistance by modulating the secondary structure and stability of PLK1 mRNA [ 109 ].…”

“…Unsurprisingly, PLK1 is expressed in various types of malignancy and, despite some of them being described as a tumor suppressor (reviewed in [ 155 , 156 ]), its overexpression was widely correlated to poor prognosis in cancer, including BC [ 30 , 107 , 150 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ]. In vitro and in vivo studies proved that PLK1 is significantly correlated with metastasis, drug resistance, p53 mutation and stemness in BC cells [ 30 , 42 , 43 , 44 , 45 , 46 ]. In addition, PLK1 is a regulator of the cancer stem cell (CSC) phenotype whose inhibition prevents the stemness phenotype in cancer cells [ 42 , 46 ].…”

“…Interestingly, PLK1 correlates with the hormone-independent growth of ERα-positive BC cells, and its inhibition leads to a decrease in growth of long-term estrogen-deprived (LTED) BC cells [ 108 ]. Moreover, Jeon et al found a high expression of PLK1 in Tamoxifen-resistant BC cells and demonstrated that PLK1 knockdown significantly decreases their proliferation, migration, and tumor growth [ 43 ]. High PLK1 expression was also described in patient-derived xenografts (PDX) from bone metastasis compared to matched primary breast tumors [ 165 ].…”