Galangin Inhibits Cholangiocarcinoma Cell Growth and Metastasis through Downregulation of MicroRNA-21 Expression

Abstract

Galangin, a natural flavonoid product derived from the root of galangal, is emerging as a promising anticancer agent against multiple cancers. Yet, whether it also has antitumor effects on cholangiocarcinoma (CCA) and the underlying mechanism is still unknown. Herein, we demonstrate that galangin exhibits multiple antitumor effects on CCA cells including decreases cell viability; inhibits proliferation, migration, and invasion; and induces apoptosis. Moreover, those phenotypic changes are associated with downregulated microRNA-21 (miR-21) expression. To support, overexpression of miR-21 blocks galangin-mediated antisurvival and metastasis effects on CCA cells. Mechanically, galangin increases the expression of phosphatase and tensin homolog (PTEN), a direct target of miR-21, resulting in decreased phosphorylation of AKT, a protein kinase which plays a critical role in controlling survival and apoptosis. In contrast, overexpression of miR-21 abrogates galangin-regulated PTEN expression and AKT phosphorylation. Taken together, these findings indicate that galangin inhibits CCA cell proliferation and metastasis and induces cell apoptosis through a miR-21-dependent manner, and galangin may provide a novel potential therapeutic adjuvant to treat CCA.

A High-Accuracy Model Based on Plasma miRNAs Diagnoses Intrahepatic Cholangiocarcinoma: A Single Center with 1001 Samples

“…MiR-21 is well recognized as an oncomir, which is highly expressed in cholangiocarcinoma tissue compared with the noncancerous biliary epithelium [ 24 , 25 , 26 , 27 ]. It plays important roles in the progress of cholangiocarcinoma through targeting PTEN/AKT pathway [ 27 , 28 ], TIMP3 (tissue inhibitor of metalloproteinases 3) [ 29 ], 15-PGDH (15-hydroxyprostaglandin dehydrogenase) [ 24 ], or EMT (epithelial–mesenchymal transition) [ 30 ]. We found that higher plasma miR-21 level was significantly associated with larger tumor size, implying a close correlation between miR-21 and tumor proliferation.…”

Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials

“…Also, galangin has a protective effect on ulcerative colitis induced by dextran sulfate sodium in mice and rats (Sangaraju et al 2019 ; Fan et al 2021 ). Galangin inhibits cell growth and metastasis of cholangiocarcinoma by downregulating the expression of microRNA-21 (Zou et al 2020 ). Besides, galangin inhibits epithelial-mesenchymal transition and angiogenesis of glioma by downregulating CD44 (Chen et al 2019a ).…”

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals

“…As stated in Section 2.1.8 , miR-21 directly modulates PTEN, whose function is to inactivate PI3K/Akt signaling in cancer. As a consequence of the miR-21 inhibition, formononetin and galangin upregulate PTEN levels in bladder and cholangiocarcinoma, respectively, thereby inhibiting cancer aggressiveness [ 42 , 43 ]. In colorectal cancer, gambogic acid induces apoptosis by suppressing miR-21 expression, and the cytotoxicity of gambogic acid is reversed by overexpressing miR-21 [ 44 ].…”

“…Matrine can facilitate cell cycle arrest and prohibit cell survival by enhancing miR-22 levels in colorectal cancer ( Figure 1 and Table 4 ). Indeed, it was also noticed that miR-22 targets Erb-B2 receptor tyrosine kinase 3 (ERBB3) and MDS1 and EVI1 complex locus (MECOM) in colorectal cancer [ 43 ]. However, given that miR-22 can target various transcripts with different functions, it is unsurprising that miR-22 acts as either an oncogene or tumor suppressor in a cellular context-dependent manner [ 222 ].…”