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Gao H.,Qingdao University | Teng C.,Qingdao Hiser Medical Center | Huang W.,Qingdao University | Peng J.,Chongqing Normal University | Wang C.,Qingdao University
International Journal of Molecular Sciences | Year: 2015

The transcription factor sex determining region (Y SRY)-box 2 (SOX2) is known to play a crucial role in the maintenance of self renewal or pluripotency of undifferentiated embryonic and neuronal stem cells. An elevated expression of SOX2 has been correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). We sought to investigate the mechanism(s) by which SOX2 modulates the ESCC metastasis. The SOX2 coding DNA sequence was inserted into pCMV vector and stably transfected in ESCC cells (Eca-109). The effect of SOX2 over expression was evaluated on cell migration, invasion and epithelial to mesenchymal transition (EMT). We also measured the expression of Slug to explore if this transcription factor is involved in SOX2-mediated regulation of cell migration/invasion and EMT. In addition, we determined the role of STAT3/HIF-1α to further probe the mechanism of SOX2-mediated metastasis via Slug. Our results demonstrated that SOX2 over expressing Eca-109 cells showed an enhanced cell migration/invasion. Moreover, these cells exhibited the EMT characteristics, that is, a significantly suppressed expression of the epithelial cells marker with a concomitant enhancement of those of the mesenchymal markers. An increased expression of Slug in SOX2 over expressing cells suggested the involvement of this transcription factor in SOX2-regulated metastasis. Whereas the expressions of STAT3/HIF-1α were found to be up-regulated in SOX2 expressing cells, blockade of these transcription factors resulted in the inhibition of Slug expression at both protein and mRNA levels. Conclusion: These results suggest that SOX2 promoted the metastasis of ESCC, at least in part, by modulating Slug expression through the activation of STAT3/HIF-1α signaling. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Jiang W.-J.,Qingdao Hiser Medical Center
Zhonghua Shiyan Yanke Zazhi/Chinese Journal of Experimental Ophthalmology | Year: 2012

Background: Increase in ophthalmic optical medical instruments and microsurgical applications leads to retinal photochemical damage and other problems delivery of a variety of devices, so the in-depth study and understanding of its pathogenesis after retina light damage can provide a reference for the clinical treatment of related diseases. Objective: This study was to investigate the therapeutic effect and relative mechanism of erythropoietin (EPO) on mouse retina photic injury by studying the expression of matrix metalloproteinases-2(MMP-2) and MMP-9. Methods: Fifty-two SPF BALB/c mice were randomized into normal control group, simple light-induced group and EPO pretreatment group by balloting method. The mice of simple light-induced group and EPO pretreatment group were continuously irradiated with 6000 lx diffuse light for 4 hours in a home-made box to establish the models of light-induced damage; while recombinant human EPO(rhEPO) of 5000 U/kg was intraperitoneally injected prior to the light exposure in the EPO pretreatment group. The expressions of MMP-2 and MMP-9 were examined at 6, 12, 36, 72, 96 hours and 7 days following light-exposure by immunohistochemistry. Results: Edema and structural disorder of RPE cells appeared in the simple light-induced group after light-exposure and aggravated with lapse of light-exposure time, but no similar change was seen until 7 days in the EPO pretreatment group. The immunohistochemistry findings showed that the expression of MMP-2(A value) in RPE cells was less in the normal mice. However, a large quantity of positive cells appeared in RPE layer 36 hours after light-exposure. Compared with the simple light-induced group, the positive expression of MMP-2 protein in EPO pretreatment group was significantly decreased, showing statistically significant differences among these three groups and different time points (Fgroup= 3.68, P = 0.04; Ftime = 9.13, P = 0.00). There was hardly any MMP-9 expression in the retina of the normal mice. In simple light-induced group, a few of positive cells appeared in RPE layer 6 hours after light-exposure and reached its peak 12 hours following light-exposure. The gradually down-regulation of MMP-9 expression happened 96 hours later following light-irradiation. The expression tendency of MMP-9 in EPO pretreatment group was similar to the simple light-induced group. Significant differences in expressions of MMP-9 were found among different groups and time points (Fgroup = 3.61, P = 0.04; Ftime= 16.91, P = 0.00). Conclusions: MMP-2 and MMP-9 may be involved in the mechanism of retina photic injury by down-regulating the expression of MMP-2 and MMP-9 in RPE cells. Copyright © 2012 by the Chinese Medical Association.

Li T.,Colorectal Center | Gao F.,Qingdao Hiser Medical Center | Zhang X.-P.,Colorectal Center
Oncology Reports | Year: 2015

MicroRNAs (miRNAs) are a conserved class of small non-coding RNAs that play important roles in diverse biological processes, including chemoresistance. However, the molecular mechanism as to how miR-203 modulates the chemosensitivity to 5-fluorouracil (5-FU) in colorectal cancer is poorly known. In the present study, we found that miR-203 was downregulated in the 5-FU-resistant cell line LoVo/5-Fu, and was inversely correlated with the extent of 5-FU chemoresistance. Cytotoxicity assay showed that the inhibition of miR-203 expression enhanced 5-FU chemoresistance in colorectal cancer cells, while miR-203 overexpression increased 5-FU chemosensitivity. We then validated that thymidylate synthase (TYMS) was a direct target of miR-203 and miR-203 suppressed TYMS protein levels. Silencing of TYMS enhanced 5-FU chemosensitivity, similar to the roles of miR-203. Finally, we discovered that miR-203 increased the inhibitory effects of 5-FU on tumor growth in vivo. Overall, our data indicate that miR-203 enhances 5-FU chemosensitivity via the downregulation of TYMS in colorectal cancer and provide important insight into the mechanism of 5-FU resistance in colorectal cancer patients. More important, the present study suggests that miR-203 has the potential as a therapeutic strategy for 5-FU-resistant colorectal cancer.

Hu K.-X.,Academy of Military Medicine Science | Wang M.-H.,Academy of Military Medicine Science | Fan C.,Qingdao Hiser Medical Center | Wang L.,Academy of Military Medicine Science | And 2 more authors.
International Immunopharmacology | Year: 2011

The results of haploidentical hematopoietic stem cell transplantation (HSCT) have been disappointing due to the high incidence of severe graft-versus-host disease (GVHD) and infectious complications. It is well known that mesenchymal stem cells (MSCs) can prevent severe acute GVHD in HSCT. However, there is a controversy concerning whether MSC-mediated suppression of T cell functions is accompanied by inducing T cells maturation effects after HSCT. The CB6F1 (H-2bd) female mice irradiated with 8 Gy 60Co γ-rays were divided into two groups: mice in the MSCs group were infused with MSCs labeled with cm-DiI and mononuclear cells from the bone marrow and spleen of BALB/c (H-2d) mice; the control group was infused with only the mononuclear cells of BALB/c (H-2d) mice. After transplantation, chimerisms of donor MSCs were observed in the recipients. The recovery of the T-lymphocyte subpopulation, the proliferative activity of T-cells after stimulation with ConA, the mixed lymphocytes' reaction between donor and recipient and three parts, and the number of apoptosis thymus cells were compared in two groups. The results showed that MSCs preferentially homed to the thymus and grew there, a more rapid recovery of T-cells in the peripheral blood, and decreased the apoptosis of the thymocytes. Thus MSCs may affect the thymus in order to improve T-cells maturation and immune system recovery. © 2011 Elsevier B.V.

Gao H.,Qingdao University | Liu Y.,Qingdao Hiser Medical Center | Li K.,Shandong Provincial Hospital Affiliated to Shandong UniversityShandong | Wu T.,Qingdao 5th Peoples Hospital | And 2 more authors.
American Journal of Translational Research | Year: 2016

Acute myeloid leukemia (AML) represents a heterogeneous group of hematological neoplasms with marked heterogeneity in response to both standard therapy and survival. Hispidulin, a flavonoid compound that is anactive ingredient in the traditional Chinese medicinal herb Salvia plebeia R. Br, has recently been reported to have anantitumor effect against solid tumors in vitro and in vivo. The aim of the present study was to investigate the effects of hispidulin on the human leukemia cell line in vitro and the underlying mechanisms of its actions on these cells. Our results showed that hispidulin inhibits AML cell proliferation in a dose- and time-dependent manner, and induces cell apoptosis throughan intrinsic mitochondrial pathway. Our results also revealed that hispidulin treatment significantly inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) expression in both tested AML cell lines in a dose-dependent manner, and that the overexpression of EMMPRIN protein markedly attenuates hispidulin-induced cell apoptosis. Furthermore, our results strongly indicated that the modulating effect of hispidulin on EMMPRIN is correlated with its inhibitory effect on both the Akt and STAT3 signaling pathways. © 2016, E-Century Publishing Corporation. All rights reserved.

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