Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of cancer stem cells (CSCs)-mediated post-surgical recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become a new approach for the treatment of HCC. GLA exhibits anti-tumor effects in that it attenuates the proliferation, migration, invasion, and angiogenesis of human cancer cells. However, the functions of GLA in the regulation of CSCs-like properties in HCC cells, and the molecular mechanisms underlying in remain obscure. Here we found that GLA attenuated the CSCs-like properties by the microRNA-148a (miR-148a)-mediated inhibition of transforming growth factor beta (TGF-β)/SMAD2 signal pathway in HCC cell lines (HepG2, Huh-7, and MHCC97H). Indeed, GLA inhibited the activations/expressions of both TGFβ-induced and the endogenous SMAD2. Further, GLA improved the expression of miR-148a in a dose/time-dependent manner. MiR-148a, which targeted the SMAD2-3′UTR, decreased the expression and function of SMAD2. Knockdown of miR-148a abolished the GLA-induced inhibition of TGF-β/SMAD2 signal pathway and the CSCs-like properties in HCC cells. Our study found a novel mechanism that GLA inhibits the CSCs-like properties of HCC cells by miR-148a-mediated inhibition of TGF-β/SMAD2 signal pathway, which may help to identify potential targets for the therapies of HCC.

In breast cancer, the cancer stem cells (CSCs) are thought to be the main cause of metastasis and recurrence. Targeting of CSCs or cancer cells with stem cell-like properties has become a new approach for the treatment of breast cancer. Glabridin (GLA), a phytochemical from the root of Glycyrrhiza glabra, exhibited effective antitumor properties in various human cancer cells. However, the roles of GLA in the regulation of CSC-like properties and the underlying molecular mechanisms remain unclear. Here, we reported that GLA attenuated the CSC-like properties through microRNA-148a (miR-148a)/transforming growth factor beta (TGFβ)-SMAD2 signal pathway in vitro and in vivo. In MDA-MB-231 and Hs-578T breast cancer cell lines, GLA enhanced the expression of miR-148a through DNA demethylation. By targeting of the SMAD2-3'-UTR, miR-148a blocked the expression/activation of SMAD2, and in turn, restored the epithelial characteristics, adhesive abilities, and CSC-like properties. Furthermore, in mouse xenograft models, we also confirmed that GLA attenuated the tumor growth, mesenchymal characteristics, and CSCs-like properties via demethylation-activated miR-148a. Our findings suggested a potential treatment strategy to reduce the CSCs-like properties, and therefore enhance the effectiveness of breast cancer therapy.

Gastric carcinoma (GC) is the second leading cause of cancer-related mortality worldwide. The efficacy of standard chemotherapy for GC, such as cisplatin (CDDP), is dissatisfactory partly due to the toxic/side-effects. Sulforaphane (SFN), which exhibits effective anti-cancer functions, is a phytochemical converted from cruciferous plants. Our present study aimed to identify whether SFN could enhance the anti-cancer effects of low-dose CDDP and to determine the underlying mechanisms. Herein, co-exposure of SFN and CDDP significantly inhibited the viabilities of gastric cancer cells. For the molecular mechanisms, CDDP alone increased the cancer stem cell (CSC)-like properties in gastric cancer cells via activating the interleukin-6 (IL-6)/IL-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signaling. However, SFN could activate the microRNA-124 (miR-124), which directly targets the 3′-untranslated regions (UTR) of the IL-6R and STAT3. Moreover, knockdown of miR-124 eliminated the effects of SFN on CSC-like properties in GC cells, and in turn enhanced the anti-cancer effects of low-dose CDDP. These findings not only suggested a mechanism whereby SFN enhanced the anti-cancer functions of CDDP, but also helped to regard SFN as a potential chemotherapeutic factor in gastric cancer.

Angiogenesis plays a pivotal role in breast cancer progression. Cyanidin-3-glucoside (C3G), one of the most widely distributed anthocyanins in edible fruits, shows antioxidative and anti-inflammatory property as well as induction of breast cancer cells apoptosis. However, the effect of C3G on breast cancer-induced angiogenesis remains unknown. In the present study, we found that C3G could attenuate breast cancerinduced angiogenesis via inhibiting VEGF, a key cytokine for angiogenesis, expression and secretion. Furthermore, signal transducer and activator of transcription 3 (STAT3) could transcriptionally activate VEGF, and C3G reduced STAT3 expression at both mRNA and protein level. Subsequently, our data showed that C3G induced miR-124 expression. Moreover, miR-124 could directly repress STAT3 expression, and miR-124-mediated STAT3 down-regulation was responsible for the inhibition of C3G on VEGF and angiogenesis. Taken together, we supplied more evidence to the antibreast cancer property of C3G.

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