Vitamin C counteracts miR-302/367-induced reprogramming of human breast cancer cells and restores their invasive and proliferative capacity

Epigenetic reprogramming by embryonic stem cell-specific miR-302/367 cluster has shown some tumor suppressive effects in cancer cells of different tissues such as skin, colon, and cervix. Vitamin C has been known as a reprogramming enhancer of human and mouse somatic cells. In this study, first we aimed to investigate whether exogenous induction of miR-302/367 in breast cancer cells shows the same tumor suppressive effects previously observed in other cancer cells lines, and whether vitamin C can enhance reprogramming of breast cancer cells and also improve the tumor suppressive function of miR-302/367 cluster. Overexpression of miR-302/367 cluster in MDA-MB-231 and SK-BR-3 breast cancer cells upregulated expression of miR-302/367 members and also some core pluripotency factors including OCT4A, SOX2 and NANOG, induced mesenchymal to epithelial transition, suppressed invasion, proliferation, and induced apoptosis in the both cell lines. However, treatment of the miR-302/367 transfected cells with vitamin C suppressed the expression of pluripotency factors and augmented the tumorigenicity of the breast cancer cells by restoring their proliferative and invasive capacity and compromising the apoptotic effect of miR-302/367. Supplementing the culture medium with vitamin C downregulated expression of TET1 gene which seems to be the reason behind the negative impact of vitamin C on the reprogramming efficiency of miR-302/367 cluster and its anti-tumor effects. Therefore application of vitamin C may not always serve as a reprogramming enhancer depending on its switching function on TET1. This phenomenon should be carefully considered when considering a reprogramming strategy for tumor suppression.     

Delivery of BR2‐SOX17 fusion protein can inhibit cell survival,proliferation, and invasion in gastric cancer cells through regulating Klotho gene expression

The prognosis of advanced gastric cancer is poor and understanding the biology and subsequent development of new targeting therapy is still an urgent need. This study was conducted to explore the effect of BR2 (a 17‐amino acid peptide)‐SOX17 (human sex determining region Y (SRY)‐related high‐mobility group (HMG) box protein family member 17) fusion protein on Klotho gene expression in gastric cancer cells. The regulatory effects of SOX17 on Klotho gene in gastric cancer cells were tested using dual‐luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. The therapeutic effects of BR2‐SOX17 were evaluated by proliferation, colony formation, invasion assay, and cell apoptosis analysis. Results showed that SOX17 enhanced Klotho gene expression in gastric adenocarcinoma cells through binding to the promoter of Klotho gene. BR2‐SOX17 fusion protein was effective in delivering SOX17 into gastric cancer cells and subsequently inhibited the cell proliferation, colony formation, and invasion, increased E‐cadherin protein expression, decreased vimentin protein expression, as well as induced apoptosis. Our findings suggested SOX17 can bind to the promoter of Klotho gene to enhance Klotho gene expression in gastric cancer cells. The fused BR2‐SOX17 protein is an effective agent for targeting therapy of gastric cancer.     

E-Cadherin repression increases amount of cancer stem cells in human A549 lung adenocarcinoma and stimulates tumor growth

Here we show that cancer stem cells amount in human lung adenocarcinoma cell line A549 depends on E-cadherin expression. In fact, downregulation of E-cadherin expression enhanced expression of pluripotent genes (c-MYC, NESTIN, OCT3/4 and SOX2) and enriched cell population with the cells possessing the properties of so-called ‘cancer stem cells’ via activation of Wnt/β-catenin signaling. Repression of E-cadherin also stimulated cell proliferation and migration in vitro, decreased cell amount essential for xenografts formation in nude mice, increased tumors vascularization and growth. On the other hand, E-cadherin upregulation caused opposite effects i.e. diminished the number of cancer stem cells, decreased xenograft vascularization and decelerated tumor growth. Therefore, agents restoring E-cadherin expression may be useful in anticancer therapy.