Xingbo Zhao

Shandong University, Chi-nan-shih, Shandong Sheng, China

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Publications (14)37.25 Total impact

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    ABSTRACT: Abstract Objective: Basic fibroblast growth factor (FGF2)-mediated Extracellular signal-regulated kinases1/2 (ERK1/2) signaling is a critical modulator in angiogenesis. SPRY4 has been reported to be a feedback negative regulator of FGFs-induced ERK1/2 signaling. The aim of this study was to explore the role of SPRY4 in endometrial adenocarcinoma cell. Materials and methods: The effect of SPRY4 expression on FGF2-mediated ERK1/2 signaling was detected by luciferase assay and Western blot analysis. The growth of Ishikawa cells was detected using colony formation assay and cell number counting experiment. Results: We found that plasmid-driven SPRY4 expression efficiently blocked the activity of FGF2-induced ERK1/2 signaling in Ishikawa cells. SPRY4 expression significantly reduced the proliferation and 17β-estradiol-induced proliferation of Ishikawa cells. Conclusion: SPRY4 may function as a tumor suppressor in endometrial adenocarcinoma.
    Gynecological Endocrinology 05/2014; · 1.30 Impact Factor
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    ABSTRACT: Dual-specificity phosphatase 6 (Dusp6), Sprouty4, and similar expression to FGF (Sef) are negative modulators of FGF2/ERK1/2 signaling. The objective of the study was to evaluate the expressions of Dusp6, Sprouty4, and Sef in eutopic endometria of patients with adenomyosis. Endometria from 30 women with adenomyosis and 29 women without adenomyosis were used in this study. The expressions of Dusp6, Sprouty4, and Sef were investigated by immunohistochemical analysis. We found that Dusp6, Sprouty4, and Sef expressions were present in endometrial epithelial cells of normal endometria and eutopic endometria of adenomyosis. Weak immunostainings were noted in stromal cells in both endometria. No cyclical change was noted either in normal endometria or in eutopic endometria of adenomyosis during menstrual cycle. By immunohistochemical analysis, we found that eutopic endometria of adenomyosis showed significantly decreased Dusp6, Sprouty4, and Sef expressions compared with normal endometria. By in situ hybridization analysis, we found that the mRNA expressions of Dusp6, Sprouty4, and Sef were downregulated in eutopic endometria of adenomyosis compared with normal endometria. We conclude that downregulation of Dusp6, Sprouty4, and Sef-negative modulators of FGF2/ERK1/2 signaling-was present in eutopic endometria of adenomyosis, which may play critical roles in the development of adenomyosis.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2014; · 2.07 Impact Factor
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    ABSTRACT: Phosphatase and tensin homolog (PTEN) and protein phosphatase type 2A (PP2A) are negative modulators of PI3K/AKT/survivin signaling. To evaluate immunoexpression of PTEN, PP2A and survivin in adenomyosis, ectopic lesions from 28 patients with adenomyosis and endometria from 30 controls without adenomyosis were employed in the study. The expression of PTEN, PP2A and survivin was examined with the use of immunohistochemistry. We found a decreased expression of PP2A and PTEN in adenomyosis. The expression of PTEN showed great individual differences in adenomyosis, although expression of both PP2A and PTEN was lower in adenomyosis than in normal endometria. In contrast, the expression of survivin was higher in adenomyosis. Our results suggest the important role of the PI3K cascade in the pathogenesis and development of adenomyosis.
    Reproductive Biology. 01/2014;
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    ABSTRACT: Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17β-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell.
    Molecular and Cellular Endocrinology 02/2013; · 4.04 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the role of microRNA-21 (miR-21) in the regulation of phosphatase and tensin homolog deleted from chromosome-10 (PTEN) expression and proliferation of endometrioid endometrial cancer (EEC) cells. We performed a qRT-PCR assay with miR-21 and PTEN in 16 paired EEC tumor tissues and adjacent non-tumor endometrium. To investigate the regulation of PTEN by miR-21, we designed gain- and loss-of-function of miR-21 experiments in the KLE cell line by transfection with a synthetic miR-21 mimic and inhibitor. To validate the putative binding site of miR-21 in the 3' untranslated region (3'-UTR) of PTEN messenger RNA (mRNA), a dual-luciferase reporter assay was carried out. To evaluate the potential effect of miR-21 on EEC proliferation, we performed both overexpression experiments, using an miR-21 mimic, and inhibition assays, using an miR-21 inhibitor. miR-21 was overexpressed in EEC and was inversely correlated with PTEN protein expression (P<0.001). miR-21 regulated PTEN protein expression and cell proliferation in the KLE cell line and the direct binding of miR-21 to the PTEN 3'-UTR was confirmed using a dual-luciferase reporter assay. The upregulation of miR-21 led to a significant decrease in the PTEN protein expression level (P=0.007). The downregulation of miR-21 led to a significant increase in PTEN protein (P=0.002). The expression of luciferase in the wt-PTEN-3'-UTR-pGL3 group was downregulated in the presence of the miR-21 mimic (P=0.001). miR-21 was overexpressed in EEC. In conclusion, we demonstrated that the expression of PTEN protein, but not mRNA, was negatively directly regulated by miR-21 in the KLE cell line. The overexpression of miR-21 modulated EEC cell proliferation through the downregulation of PTEN.
    Oncology letters 12/2012; 4(6):1290-1296. · 0.24 Impact Factor
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    ABSTRACT: To investigate the expression and humoral immune response of sperm-associated antigen 9 (SPAG9) in endometri al carcinoma. Sperm-associated antigen 9 gene expression levels were evaluated in endometrial carcinoma, endometrial hyperplasia, adjacent tissues, and normal endometrial tissues by reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blot. Sperm-associated antigen 9 concentration in serum samples from 10 healthy women, 20 women with benign diseases, and 50 women with endometrial carcinoma was detected by enzyme-linked immunosorbent assay. (1) Sperm-associated antigen 9 antibodies were detected in approximately 72% of patients with endometrial cancer but not in healthy controls. (2) A significant difference has been found among pathological types and degrees (P < 0.05), and it was also found to be expressed in transferred lymph nodes. (3) Sperm-associated antigen 9 serum concentration (ng/mL) of patients with endometrial carcinoma is significantly higher than those of the healthy group (P < 0.05). Patients harboring grade 3 endometrial carcinoma were found to have significantly higher SPAG9 concentrations than those of grade 1/grade 2 (P = 0.003). SPAG9 is positively expressed in endometrial cancer, and with a high humoral immune response in patients. It may serve as a new type of endometrial cancer markers for early detection, diagnosis and treatment.
    International Journal of Gynecological Cancer 12/2011; 22(1):87-93. · 1.94 Impact Factor
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    ABSTRACT: Stroma-tumor communication plays an important role in the genesis of neoplasia. In the current study, we investigated the effect of normal stromal cells on the survival and apoptosis signaling of endometrial cancer cells and further explored the possible mechanism implied in this communication. Using primarily cultured normal endometrial stromal cells and an endometrial adenocarcinoma cell line, Ishikawa cells, we established a 2D-coculture system to observe the stromal cell-tumor cell crosstalk in endometrial carcinomas. Using methyl thiazolyl tetrazolium (MTT) assays, cell counting and colony formation assays, we analyzed the effect of stomal cells on the growth and proliferation of Ishikawa cells under different conditions. Using western blot analysis, we determined the effect of stromal cells on the activity of PI3K/AKt/Survivin signaling in Ishikawa cells under different conditions. Using immunohistochemistry analysis, we determined the expression of Survivin in normal endometria and endometrial adenocarcinomas. We found that the paracrine factors from normal endometrial stromal cells grown on Matrigel repeatedly and significantly decreased hormone-stimulated activity of PI3K/AKt/Survivin signaling in Ishikawa cells, which were proved to be increased in endometrial adenocarcinoma and essential in hormone-induced cell growth in Ishikawa cells. Paracrine factors from normal endometrial stromal cells can inhibit hormone-stimulated cell proliferation in Ishikawa cells by regulating cell survival and apoptosis through PI3K/AKt/Survivin signaling.
    Gynecologic Oncology 07/2011; 123(2):387-92. · 3.93 Impact Factor
  • Lei Yan, Xingbo Zhao, Xiaoyan Qin
    European journal of obstetrics, gynecology, and reproductive biology 07/2011; 159(1):231-2. · 1.97 Impact Factor
  • Hui Zhang, Xingbo Zhao, Lei Yan, Mingjiang Li
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    ABSTRACT: Fibroblast growth factors (FGF) axis, and in particular FGF2 axis, is an important mitogenic stimulus in endometrial carcinogenesis. hSef is a key inhibitory regulator of FGF signaling and aberrant hSef expression is reported to be present in various human carcinomas. The objective of this study was to investigate the role of hSef in the growth and proliferation of endometrial adenocarcinoma cells and to explore the mechanism that may be involved. Using western blot analysis, we determined the expression of hSef in Ishikawa cells under different conditions. Using luciferase reporter assays and western blot analysis, we detected the effect of hSef on MAPK/ERK-mediated FGF2 signaling. Using MTT, cell counting and colony formation assays, we analyzed the growth and proliferation of Ishikawa cells under different conditions. We found that the hSef expression was positively regulated by FGF2-induced MAPK/ERK signaling and inversely, hSef expression efficiently inhibited the activity of FGF2-induced MAPK/ERK signaling, indicating the presence of hSef-mediated negative feedback mechanism for FGF signaling in endometrial cancer cells. In addition, we found that MAPK/ERK signaling was essential for the growth and proliferation of endometrial cancer cells in vitro, and hSef expression significantly reduced the cell proliferation. hSef expression can inhibit the growth and proliferation of endometrial cancer cells via acting on the FGF2/MAPK/ERK signaling.
    Gynecologic Oncology 06/2011; 122(3):669-74. · 3.93 Impact Factor
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    ABSTRACT: To explore the stroma-epithelium interactions in endometriosis and to identify the possible signalling pathways involved in this cross-talk. Laboratory study via primary cultured endometrial stromal and epithelial cells. University Hospital. Fifteen patients with endometriosis confirmed by histopathology were recruited in the study, and 12 women free of endometriosis were used as control group. Specific NFkappaB inhibitor 1-Pyrrolidinecarbodithioic acid ammonium salt (PDTC) was used in cell cultures. The expression and secretion of MMP-2, MMP-9, TIMP-1, TIMP-2 and the DNA-binding activity of NFkappaB in normal endometrial stromal cells or in co-cultures with normal or endometriotic epithelial cells from patients with endometriosis. Endometrial epithelial cells induced MMP-9 and MMP-2 expression in normal stromal cells in vitro. In co-cultures with endometriotic epithelial cells, normal endometrial stromal cells expressed and secreted higher MMP-2 (p < 0.05) and MMP-9 (p < 0.05). Specific inhibition of NFkappaB pathway in stromal cells abolished this induction effect by epithelial cells. Endometriotic epithelial cells induce MMPs expression and secretion in normal endometrial stromal cells via an NFkappaB-dependent pathway in vitro. This cross-talk between epithelial cells and stromal cells may facilitate the implantation and extension of the ectopic foci and favour the development of the disease.
    Gynecological Endocrinology 11/2009; 26(6):456-67. · 1.30 Impact Factor
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    ABSTRACT: The objective of this study was to explore the mechanism of phosphatase and tensin homolog (PTEN) loss in endometriosis. We found that aberrant PTEN expression and mitogen-activated protein kinases (MAPK)/ERK, phosphoinositide 3-kinase (PI3K)/AKt, and nuclear factor-kappaB (NFkappaB) signaling overactivities coexisted in endometriosis. In vitro, 17beta-estradiol rapidly activated the 3 pathways in endometriotic cells and specific inhibitions on the 3 pathways respectively blocked 17beta-estradiol-induced cell proliferation. 17beta-estradiol suppressed PTEN transcription and expression in endometriotic cells which was abolished by specific NFkappaB inhibition. CONCLUSION(S): Total/nuclear PTEN-loss and MAPK/ERK, PI3K/AKt, and NFkappaB signal overactivities coexist in endometriosis. In vitro, 17beta-estradiol can promotes cell proliferation in endometriosis by activating PI3K/AKt pathway via an NFkappaB/PTEN-dependent pathway. For the first time we propose the possibility of the presence of a positive feedback-loop: 17beta-estradiol-->high NFkappaB-->low PTEN-->high PI3K-->high NFkappaB, in endometriosis, which may finally promote the proliferation of ectopic endometrial epithelial cells and in turn contributes to the progression of the disease.
    Molecular and Cellular Endocrinology 11/2009; 317(1-2):31-43. · 4.04 Impact Factor
  • Lei Yan, Yongjie Tian, Yibing Fu, Xingbo Zhao
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    ABSTRACT: To report a case of successful pregnancy after treatment for endometrial stromal sarcoma. Case report. Gynecology department at a provincial hospital affiliated with a university. A 25-year-old woman (gravida 0, para 0) with a misdiagnosis of myoma who received a pathologic diagnosis of endometrial stromal sarcoma after the first surgery. Second fertility-preserving surgery and chemotherapy. Successful pregnancy and follow-up visit. After the conservative treatment, the patient entered complete remission. She conceived naturally and delivered at 39 weeks' gestation by caesarean section approximately 40 months after the surgery. Endometrial stromal sarcoma is a rare uterine tumor with a poor prognosis. This case shows that successful pregnancy is possible after effective conservative treatment by local surgical resection and adjunct chemotherapy.
    Fertility and sterility 10/2009; 93(1):269.e1-3. · 3.97 Impact Factor
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    ABSTRACT: In normal endometrium, stromal factors regulate the growth of epithelial cells. However, epithelial cells in endometriotic lesions display increased proliferation and decreased apoptosis. This work tested the hypothesis that in endometriosis stromal cells lose the ability to regulate survival signaling and cell growth in epithelial cells. Primary normal, endometriotic eutopic and ectopic epithelial cells were cultured in the presence of medium conditioned by normal, eutopic and ectopic endometriotic endometrial stromal cells. Endometriotic epithelial cells showed higher Survivin expression than normal epithelial cells. Conditioned medium (CM) from normal or eutopic endometriotic stromal cells significantly inhibited the Survivin expression and AKt phosphorylation in normal or eutopic endometriotic epithelial cells. However, CM from ectopic endometriotic stromal cells did not have an inhibitory effect on normal or ectopic endometriotic epithelial cells. Inhibition of AKt phosphorylation and Survivin expression in normal or eutopic endometriotic epithelial cells in the presence of stromal factors from normal or eutopic endometriotic stromal cells was enhanced by progesterone, whereas progesterone had little effect in the presence of stromal factors from ectopic endometriotic stromal cells. The inability of ectopic endometriotic stromal cells to regulated PI3K/AKt/Survivin signaling and mediate the progesterone response in endometriotic epithelial cells may facilitate epithelial cell proliferation in endometriosis and promote the survival of endometriotic lesions.
    Molecular Human Reproduction 09/2009; 15(10):653-63. · 4.54 Impact Factor
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    ABSTRACT: To compare the expression of human leukocyte antigen-G (HLA-G) in endometrial samples from patients with and without adenomyosis. Laboratory study using human tissue. University hospital. Thirty-four patients with adenomyosis and 11 with myoma of the uterus. Human leukocyte antigen-G protein expression and localization with immunohistochemistry. Quantitative analysis of HLA-G protein expression, according to H-score. A statistically significant difference was noted in HLA-G expression between the glandular cells of eutopic and ectopic endometrium (Mann-Whitney test, 412). The H-score of the negative control was 0.05 +/- 0.03 (mean +/- SD). In stromal cells, we observed a statistically significantly higher expression of HLA-G in eutopic endometrium than in ectopic endometrium (Mann-Whitney test, 169), whereas the H-score of the negative control was 0.05 +/- 0.02. A statistically significant correlation was found between HLA-G expression in ectopic and eutopic endometrium in patients with adenomyosis, both in glands (r = 0.89) and in stroma (r = 0.78). Patients with adenomyosis had HLA-G expression in eutopic and ectopic endometrial cells. This could be an explanation for the cells' ability to escape from the hosts' immunosurveillance and to survive without being eliminated by the immune system.
    Fertility and sterility 11/2007; 90(5):1599-604. · 3.97 Impact Factor