Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, antiinflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer.
Abstract. Lung cancer is one of the leading causes of cancerrelated death worldwide. Curcumin has been reported to have an antitumor effect by inducing apoptosis and suppressing growth of tumor cells. However, the mechanism by which curcumin exerts its anti-cancer effect needs further research. The purpose of the present study was to identify a miRNAmediated mechanism which plays a role in the anti-cancer effects of curcumin. Alterations in miRNA expression were seen in curcumin-treated A549 cells, including significant downregulation of miRNA-186 * expression by microarray analysis and real-time PCR. The miRNA-186 * functions by overexpression or inhibition were investigated using biological assays in A549 cells. Additionally, caspase-10 was identified as a target of miRNA-186 * using dual luciferase reporter assays and Western blot analysis. These results demonstrate that curcumin induces A549 cell apoptosis through a miRNA pathway. Also, miRNA-186 * could serve as a potential gene therapy target in curcumin treatment. Furthermore, caspase-10 was shown to be a target of miR-186 * regulation.
Purpose
To examine effects and mechanisms of transient activation of Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in head and neck cancer survivors.
Experimental Design
Mouse salivary glands and cultured human salivary epithelial cells were irradiated by single 15Gy dose. Hedgehog pathway was transiently activated in mouse salivary glands by shortly over-expressing Sonic hedgehog (Shh) transgene or administrating Smoothened Agonist and in human salivary epithelial cells by infecting with adenovirus encoding Gli1. Activity of Hedgehog signaling was examined by expression of Ptch1-lacZ reporter and endogenous Hedgehog target genes. Salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPCs), parasympathetic innervation and expression of related genes were examined by flow cytometry, salisphere assay, IHC, quantitative RT-PCR, Western blot and ELISA.
Results
Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh over-expression activated Hedgehog pathway in ductal epithelia and that after irradiation rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by rescue of signaling activities of Bmi1 and Chrm1/HB-EGF pathways. The preservation of parasympathetic innervation was related with rescue of expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of salivary stem/progenitor cells and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation.
Conclusions
These findings suggest that transient activation of Hedgehog pathway has the potential to restore irradiation-induced salivary gland dysfunction.
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