Isoliquiritigenin Derivative Regulates miR-374a/BAX Axis to Suppress Triple-Negative Breast Cancer Tumorigenesis and Development

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the largest proportion of breast cancer-related deaths. Thus, it is imperative to search for novel drug candidates with potent anti-TNBC effects. Recent studies suggest that isoliquiritigenin (ISL) can significantly suppress the growth, migration, and invasion of breast cancer cells. We previously synthesized ISL derivatives and found that 3′,4′,5′,4″tetramethoxychalcone (TMC) inhibits TNBC cell proliferation to a greater degree than ISL. The present study aimed to investigate the mechanisms underlying the anti-TNBC effects of TMC in vitro and in vivo. We show that TMC significantly inhibits the proliferative, migratory, and invasive abilities of MDA-MB-231 and BT549 cells. TMC induces apoptosis through the upregulation of Bax and downregulation of Bcl-2. PCR arrays demonstrate a significant decrease in miR-374a expression in TNBC cells after 24-h TMC treatment. MiR-374a is overexpressed in TNBC cells and has oncogenic properties. Realtime PCR analysis confirmed that TMC inhibits miR-374a in a dose-dependent manner, and luciferase assays confirmed that BAX is targeted by miR-374a. Further, we show that TMC increases Bax protein and mRNA levels by inhibiting miR-374a. TMC also attenuates TNBC tumor volumes and weights in vivo. These results demonstrate that TMC inhibits TNBC cell proliferation, foci formation, migration, invasion, and tumorigenesis, suggesting its potential to serve as a novel drug for treating TNBC through miR-374a repression.

CENPL, ISG20L2, LSM4 and MRPL3 Are Four Novel Hub Genes Involved in Breast Cancer Development and Progression

“…The brown module contained 730 genes and the blue module contained 920 genes, of which 104 hub genes (38 genes in brown module and 64 genes in blue module) in above modules were identi ed according to the lter standard (MM 0.6, GS 0.3). Literature search in PubMed suggested that the majority of the hub genes such as UHRF1, HMMR, AXIN1 and BAX, have been involved in the occurrence, progression and distant metastasis of breast cancer [53][54][55][56]. Among those 104 hub genes, we chose four never reported genes in breast cancer, namely CENPL, ISG20L2, MRPL3, and LSM4, to further explore their correlations with clinicopathological variables as well as their diagnostic and prognostic values.…”

Perspectives on the Role of Isoliquiritigenin in Cancer

“…ISL-derived new compounds offer another solution to improve the bioavailability and water-soluble issues [ 31 , 32 , 33 , 34 , 35 , 36 ]. Considering the chalone structure, the α,β-unsaturated ketone is an important part of its biological activity by modifying on the phenol ring to improve the performance of ISL.…”

“… 2′,4′-dimethoxy-4-hydroxychalcone ( Figure 2 e): shows in vivo antidiabetic activity [ 35 ]. 3′,4′,5′,4″-tetramethoxychalcone (TMC; Figure 2 f): Introducing methylation of hydroxy groups significant increase cytotoxic activity in breast cancer [ 31 ], especially targeting on triple-negative breast cancer (TNBC) [ 33 ]. ISL-17 ( Figure 2 g): A fluorine atom was introduced to the structure of ISL named ISL-17 showed the anti-tumor activities in gastric cancer [ 32 ].…”

“…3′,4′,5′,4″-tetramethoxychalcone (TMC; Figure 2 f): Introducing methylation of hydroxy groups significant increase cytotoxic activity in breast cancer [ 31 ], especially targeting on triple-negative breast cancer (TNBC) [ 33 ].…”

“…Interestingly, ISL also can inhibit the PI3K/AKT pathway and thus suppresses EMT and increases the antiproliferative effect [ 40 , 66 , 67 , 69 ]. ISL or its derivatives show a greater influence by regulating the miR-374a/BAX axis, the -374a/PTEN/AKT axis, or the autophagy-mediated apoptosis (p62/caspase-8) pathway, especially in TNBC [ 33 , 67 , 69 ]. Recent studies have also demonstrated that ISL causes chemosensitization and induces autophagy following the degradation of the ABCG2 autophagy–lysosome pathway or the miR-25-mediating ULK1 (a kinase involved in autophagy) [ 40 , 56 ].…”