Downregulation of hepatoma-derived growth factor suppresses the malignant phenotype of U87 human glioma cells

School of Pharmacy, Nanjing Medical University, Nanjing, PR China.
Oncology Reports (Impact Factor: 2.3). 07/2012; 28(1):62-8. DOI: 10.3892/or.2012.1768
Source: PubMed


Hepatoma-derived growth factor (HDGF) has been shown to correlate with increased malignancy of different types of tumors and could be an independent prognostic index for human cancers. We previously found that HDGF is overexpressed in glioma tissues and that its expression level may correlate with the clinical pathological grade. In the present study, we investigated the effects of HDGF downregulation on the biological behaviors of U87 glioma cells. Our results showed that HDGF knockdown significantly inhibited the malignant phenotype of U87 cells, including the colony formation, migration and invasion in vitro, as well as tumorigenesis in vivo. Our data also suggest that hepatocyte growth factor/scatter factor (HGF/SF) may contribute to the HDGF-associated aggressive behavior of glioma cells.

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    ABSTRACT: Hepatoma-derived growth factor (HDGF) has been verified to serve as a credible prognostic marker for several types of cancers, but its role in urologic carcinomas remains undetermined. In this study, we analyzed the significance of HDGF, as well as its relative factors such as vascular endothelial growth factor-A (VEGF-A) and Ki-67, in penile squamous cell carcinoma (PSCC). Formalin-fixed paraffin-embedded PSCC samples from 54 patients receiving surgery at Qilu Hospital of Shandong University were included in the retrospective study. The expressions of HDGF, VEGF-A, and Ki-67 were detected by immunohistochemistry of a non-biotin polymerized horseradish peroxidase method. The relationships between the expressions of HDGF and VEGF-A, Ki-67 were assessed. Moreover, their correlations with clinical pathologic characteristics and disease prognosis were, respectively, evaluated. HDGF, VEGF-A, and Ki-67 were positively expressed in 28 (51.9 %), 29 (53.7 %), and 26 (48.1 %) patients, respectively. The expressions of VEGF-A and Ki-67 were closely correlated with PSCC type (P < 0.05). A statistically significant relationship between the expressions of HDGF and VEGF-A in PSCC was observed (P = 0.03). Patients with symptom interval of more than 6 months had a significantly poorer survival rate than those with symptom interval less than 6 months (43.3 vs. 70.8 %, P = 0.043). Patients with positive HDGF expression also showed a significantly poorer survival rate than those with negative HDGF expression (39.3 vs. 73.1 %, P = 0.013). Logistic regression demonstrated that the expression level of HDGF was an independent predictor for the prognosis of postoperative patients. The expression of HDGF significantly correlated with VEGF-A, but not Ki-67 expression. Overexpression of HDGF, rather than VEGF-A or Ki-67, was confirmed to be an independent prognosticator of poor outcome for PSCC patients.
    No preview · Article · Dec 2013 · Medical Oncology
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    ABSTRACT: HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.
    No preview · Article · Jul 2014 · Journal of Neuro-Oncology
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    ABSTRACT: Aim: To assess the expression of nuclear hepatoma-derived growth factor (HDGF) in benign and malignant gallbladder lesions and to determine its clinicopathological significance. Methods: We studied 40 patients with gallbladder cancer (GBC) and a control group of 40 patients with cholelithiasis. All diagnoses of GBC and cholelithiasis were confirmed by histopathological examination after surgery. None of the patients received chemotherapy or radiotherapy before surgery. All tissue samples were fixed in 4% formalin immediately after removal and embedded in paraffin for immunohistochemical staining. The HDGF expression in the GBC and cholelithiasis specimens was examined by immunohistochemical staining. The relationship between the HDGF expression and the clinicopathological parameters of GBC was analyzed. Results: Nuclear HDGF expression was significantly higher (77.5%) in GBC than in chronic cholelithiasis (21.5%, P < 0.001). High nuclear HDGF levels were associated with histopathological subtype (P < 0.05), clinical stage (P < 0.01), and perineural invasion (P < 0.01) but not with sex, age, history of gallstones, or lymph node metastasis. A univariate Kaplan-Meier analysis showed that positive nuclear HDGF expression was associated with decreased overall survival (P < 0.01). Multivariate Cox regression analysis showed that nuclear HDGF expression and lymph node metastasis were independent risk factors for disease-free survival. Conclusion: The expression of nuclear HDGF might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.
    No preview · Article · Jul 2014
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