Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti‐inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM‐preconditioned MSCs. OSM‐preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM‐preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor‐β1‐ or OSM‐induced extracellular matrix production in MRC‐5 fibroblasts through paracrine effects. In bleomycin‐induced lung fibrotic mice, transplantation of OSM‐preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ‐tagged MSCs were detected in the lung tissues of the OSM‐preconditioned MSC‐treated mice 18 days after post‐transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM‐preconditioned MSCs in alleviating lung fibrosis in the mice. Stem Cells Translational Medicine 2017;6:1006–1017

Purpose: Human papillomavirus (HPV) 16/18 infection is reported to be associated with nonsmoking Taiwanese female lung cancer. In this study, we attempted to further reveal the association between HPV infection with Mcl-1 and interleukin (IL)-6 expressions and to elucidate the roles of HPV infection in lung tumorigenesis. Experimental Design: IL-6 and Mcl-1expressions were investigated in 79 tumor tissues from lung cancer patients by immunohitochemistry. Secreting IL-6 levels and Mcl-1expressions were examined by ELISA and Western blot, respectively, in HPV 16/18 E6-and E7-transfected A549 human lung cancer cells, as well as in the HPV16-infected TL-1lung cancer cells established from lung cancer patients. Results: Lung tumors (70.9% and 57.0%) had positive IL-6 and Mcl-1immunostainings, respectively. Significant correlation between IL-6 and Mcl-1 expression were observed (P < 0.0001).Both IL-6 and Mcl-1 expression were significantly associated with HPV 16/18 infection (P = 0.014 and P = 0.004, respectively). IL-6 and Mcl-1protein levels were not only elevated in HPV 16/18 E6-and E7-transfected A549 cells but also in TL-1 cells. Phosphatidylinositol-3-OH kinase pathway was the major pathway contributing to the up-regulation of Mcl-1 by IL-6 in HPV-infected lung cancer cells. Conclusions: The up-regulating effects of HPV 16/18 E6 and E7 to IL-6 and Mcl-1expressions were observed in E6-and E7-transfected A549 cells and in HPV16-infected TL-1 cells, mainly through the phosphatidylinositol-3-OH kinase pathway. The involvement of HPV infection in lung tumorigenesis may be partly through a concomitant increased expression of autocrine and/or paracrine IL-6 and the downstream Mcl-1.

Resveratrol, a naturally occurring dietary compound with chemopreventive properties has been reported to trigger a variety of cancer cell types to apoptosis. Whether resveratrol shows any activity on human nasopharyngeal carcinoma (NPC) cells remained to be determined. The aim of this study was to investigate the effect and mechanism of resveratrol on human NPC cells. Treatment of resveratrol resulted in significant decrease in cell viability of NPC cell lines in a dose- and time-dependent manner. A dose-dependent apoptotic cell death was also measured by flow cytometery analysis. Molecular mechanistic studies of apoptosis unraveled resveratrol treatment resulted in a significant loss of mitochondrial transmembrane potential, release of cytochrome c, enhanced expression of Fas ligand (FasL), and suppression of glucose-regulated protein 78 kDa (GRP78). These were followed by activation of caspases-9, -8, -4, and -3, subsequently leading to DNA fragmentation and cell apoptosis. Furthermore, up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria, and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment.

Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time-dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-9, -8, -4 and -3. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC.