DLC1 (deleted in liver cancer-1) is a new candidate tumor suppressor gene, which is inactive in various types of human cancers including colon cancer. To study the function of DLC1, we constructed a pcDNA3.1 vector containing the DLC1 gene and transfected it into HT29 colon cancer cells that were deficient in DLC1 expression. The restoration of DLC1 expression in HT29 cells significantly inhibited cell proliferation and migration. Flow cytometry showed that DLC1 transfection into HT29 cells induced apoptosis and that the cell cycle was arrested at S-phase. Additionally, cyclinD1 mRNA and protein expression were down-regulated while p21 expression was increased in pcDNA3.1-DLC1-HT29 cells compared to wild HT29 cells. These results confirm the role of DLC1 gene as a tumor suppressor, which may be manifested by regulation of p21 and cyclinDl. The DLC1 gene has a potential therapeutic role in inhibiting the development of colon cancer.
Breast cancer is the most prevalent malignancy among women worldwide. Paclitaxel (Taxol) is a widely applied chemotherapeutic agent against breast cancer. Although Taxol therapy has achieved improvements recently, development of chemoresistance of breast cancer patients is a major obstacle, leading to therapeutic failure. Long non-coding RNAs (lncRNAs) play pivotal roles in tumorigenesis and progresses of breast cancer. However, the biological roles and molecular targets of lncRNA NEAT1 in Taxol-resistant breast cancer remain unclear. Here, we report that NEAT1 is significantly upregulated in breast tumors and cell lines. In addition, silencing NEAT1 effectively sensitizes breast cancer cells to Taxol. Bioinformatical analysis and luciferase assay demonstrated that miR-23a-3p could be sponged and downregulated by NEAT1. We demonstrated that miR-23a-3p was downregulated and functioned as a tumor suppressor in breast cancer. Furthermore, in the established Taxol-resistant MDA-MB-231 breast cancer cell line, we detected significantly increased NEAT1 expression and downregulated miR-23a-3p expression. Importantly, FOXA1 was identified and validated as a direct target of miR-23a-3p in breast cancer cells. Rescue experiments demonstrated that the restoration of miR-23a-3p in NEAT1-overexpressing Taxol-resistant breast cancer cells successfully overcame the NEAT1-promoted Taxol resistance. Taken together, our results revealed the clinical roles and molecular mechanisms for the NEAT1-mediated chemoresistance, providing new insights into the development of non-coding RNA-based therapeutic strategies for enhancing the anti-cancer effects of traditional chemotherapeutic drugs.
The dedifferentiation of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of vascular remodeling-related disease. The present study aimed to investigate the effects of shexiangbaoxin (SXBX) pill, a traditional Chinese medicinal formula on VSMCs dedifferentiation and its potential mechanisms. High-fat diet (HFD) was introduced to lipoprotein receptor-deficient (LDLR-/-) mice to generate hyperhomocysteinemia (HHcy), and plasma Hcy and lipid levels were analyzed. The phenotype of VSMCs was assessed in mice with the treatment of low (45 mg/kg/d) or high (90 mg/kg/d) SXBX pill by measuring the contractile protein α-SMA, SM22α and synthetic proteins OPN using RT-qPCR, western blotting and immunofluorescence assay. In vitro, the proliferation, migration and dedifferentiation of VSMCs were measured by MTT, Edu incorporation, wound healing and western blotting assay. Small interfering RNA technology was used to examine the role of NLRP3 in the effects of SXBX pill on dedifferentiation. The results indicated that although SXBX pill had no influence on HFD-induced HHcy and hyperlipidaemia, it reversed HHcy-induced dedifferentiation of VSMCs in vivo. SXBX pill significantly inhibited proliferation, migration and dedifferentiation of Hcy-treated VSMCs. In addition, we found that Hcy activated NLRP3 inflammasomes in VSMCs and SXBX pill could attenuate NLRP3 inflammasomes activation. Moreover, subsequent analysis suggested that SXBX pill inhibited NLRP3 inflammasomes activation through regulation of ERK1/2 and p38 MAPK pathway. Knockdown of NLRP3 reversed the inhibitory effects of SXBX pill in VSMCs. In conclusion, SXBX pill inhibited Hcy-induced proliferation, migration and dedifferentiation of VSMCs by suppressing NLRP3 inflammasomes activation via of ERK/p38 MAPK pathway.
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