Hinokitiol up-regulates miR-494-3p to suppress BMI1 expression and inhibits self-renewal of breast cancer stem/progenitor cells

Abstract

Hinokitiol (β-thujaplicin) is a tropolone-related compound that has anti-microbe, anti-inflammation, and anti-tumor effects. Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells with tumor initiation, chemoresistant, and metastatic properties and have been considered the important therapeutic target in future cancer therapy. Previous studies reported that hinokitiol exhibits an anti-cancer activity against murine tumor cells through the induction of autophagy. The current research revealed that hinokitiol suppressed the self-renewal capabilities of human breast CSCs (BCSCs) and inhibited the expression of BMI1 at protein level without suppressing its mRNA. Treatment of hinokitiol in mammospheres induced the expression of miR-494-3p and inhibition of miR-494-3p expression in BCSCs. This treatment abolished the suppressive effects of hinokitiol in mammosphere formation and BMI1 expression. BMI1 is a target of miR-494-3p by luciferase-based 3′UTR reporter assay. Overexpression of miR-494-3p in BCSCs caused the down-regulation of BMI1 protein, inhibition of mammosphere forming capability, and suppression of their tumorigenicity. Moreover, miR-494-3p expression was significantly and inversely correlated with patient survival in two independent public database sets. Furthermore, treatment of hinokitiol in vivo suppressed the growth of xenograft human breast tumors as well as the expression of BMI1 and ALDH1A1 in xenograft tumors. In conclusion, these data suggest that hinokitiol targets BCSCs through the miR-494-3p-mediated down-modulation of BMI1 expression.

DNMT1 facilitates proliferation and metastasis of breast cancer cells by promoting MEG3 promoter methylation in MEG3/miR-494-3p/OTUD4 regulatory axis

“…The results implied that MEG3 could regulate the expression of miR-494-3p as a ceRNA. Zhou et al have previously reported that miR-494-3p can promote cell proliferation and tumor growth in breast cancer through targeted inhibiting TRIM21 expression 26 , and miR-494-3p has been found to inhibit self-renewal of breast cancer stem/progenitor cells 27 , indicating the important regulatory role of miR-494-3p in breast cancer. In the study, we inhibited the cell activity, migration and invasion abilities of breast cancer cells by overexpression of MEG3.…”

Gene Expression Patterns Associated with Tumor-Infiltrating CD4+ and CD8+ T Cells in Invasive Breast Carcinomas

“…The abnormal expression of miR-494 has been reported in various cancers. However, the role of miR-494 in carcinogenesis is contradictory, including a tumor suppressor role [45,46] and an oncogenic role [47,48]. Zhan et al revealed that miR-494 can inhibit the progression and metastasis of breast carcinomas by targeting P21 (RAC1) activated kinase 1 [49].…”

MicroRNAs as Theranostics Targets in Oral Carcinoma Stem Cells

“…As for cancer stemness, miR-494-3p was proven to target BMI1 and inhibit various features of cancer stemness in breast cancer. In addition, miR-494-3p expression was inversely correlated with patient survival [98]. MiR-494 also has been shown to influence the stemness properties of HCC by increasing various stemness genes, such as PROM1, Oct4 and Sox2, as well as ABCG2 transporter levels [99].…”