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Cui M.,Nankai University | Xiao Z.,Nankai University | Wang Y.,Nankai University | Zheng M.,Nankai University | And 6 more authors.
Cancer Research | Year: 2015

HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARAmRNAby eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the retinoid receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling. © 2015 American Association for Cancer Research.

Sun L.,Tianjin Medical University | Zhang Q.,Tianjin Medical University | Luan H.,Tianjin Medical University | Zhan Z.,Tianjin Medical University | And 3 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2011

Background. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of non-small cell lung cancer (NSCLC). KRAS and EGFR somatic mutations in NSCLC may predict resistance and responsiveness to TKI, respectively. Nevertheless, most research to date has been conducted on samples from primary tumors. For many patients with advanced disease, their samples can only be obtained from metastases for test. The molecular characteristics of metastasized tumors may be different from those of primary tumors. Materials and methods. Mutation status of KRAS and EGFR between primary tumors and local lymph node metastases of 80 Chinese patients with NSCLC were analyzed by direct sequencing. Five of them were given gefitinib as neoadjunvant treatment after the EGFR-TKI sensitive mutations were detected in their biopsies of mediastinal lymph nodes metastases. McNemar's test was used to compare the EGFR and KRAS mutation status between primary tumors and corresponding local lymph node metastases. Data evaluation was carried out with SPSS-13.0 statistical software. Results. Among the 160 samples, one primary tumor and seven metastases were identified with KRAS mutations and 21 primary tumors and 26 metastases were found to have EGFR mutations. KRAS and EGFR mutation status was different between primary tumors and corresponding metastases in 6 (7.5%) and 7 (8.75%) patients, respectively. One patient with no TKI sensitive mutations detected in the primary tumor showed disease progression. Conclusion. Our results suggest that a considerable proportion of NSCLC in Chinese population showed discrepancy in KRAS and EGFR mutation status between primary tumors and corresponding metastases. This observation may have important implication for the use of targeted TKI therapy in the treatment of NSCLC patients. © 2011 Sun et al; licensee BioMed Central Ltd.

Zhang Y.H.,Key Laboratory of Cancer Prevention and Therapy
Zhonghua zhong liu za zhi [Chinese journal of oncology] | Year: 2010

To detect the expression of VEGF receptors in papillary renal cell carcinoma and to explore the correlation between their expression and clinical prognosis. Expression of VEGF receptors and PCNA (proliferating cell nuclear antigen) were evaluated in 82 patients with papillary renal cell carcinoma using tissue microarray and SP immunohistochemical staining. The expression of VEGFR-1 in papillary renal cell carcinoma was 82.93%, VEGFR-2 63.41%, VEGFR-3 34.15% and PCNA 67.07%, respectively. Increased VEGFR-2 expression was significantly correlated with tumor size (P = 0.016), histological grade (P = 0.034) and distant metastasis (P = 0.002). VEGFR-3 expression was correlated with histological grade (P = 0.028), lymph node status (P = 0.010) and distant metastasis (P = 0.018), but not correlated with gender, age, location, tumor size and TNM staging. VEGFR-1 expression had no correlation with any clinic and pathologic factors. PCNA expression was correlated with histological grade (P = 0.011), but not correlated with other factors. The expression of VEGFR-2 and VEGFR-3 in death cases were higher than that in surviving patients. Both VEGFR-2 and VEGFR-3 can serve as markers for prognosis of papillary renal cell carcinoma. Differently, VEGFR-3 is a predictor of lymph node metastasis, increased VEGFR-2 expression could be used to predict a potential blood dissemination.

Liu Y.,Tianjin Medical University | Liu Y.,Key Laboratory of Cancer Prevention and Therapy | Liu H.,Tianjin Central Hospital of Gynecology and Obstetrics | Bai X.,Tianjin Huanhu Hospital | And 4 more authors.
Gynecologic Oncology | Year: 2011

Objective: This study aims to determine the diagnostic value of diffusion-weighted imaging (DWI) in the differentiation of metastatic lymph nodes from non-metastatic lymph nodes in uterine cervical cancer. Methods: In 42 patients who underwent lymph node dissection for uterine cervical cancer, conventional MRI and DWI examinations were performed before surgery. Of the 1109 total dissected pelvic lymph nodes, 188 enlarged nodes with a short-axis diameter of 5 mm or greater were included for further analysis. Each of the size-based criteria (i.e., short-axis diameter and long-axis diameter) and ADC-based criteria (i.e., mean ADC, minimum ADC, mean rADC (relative ADC) and minimum rADC) were compared between metastatic lymph nodes and non-metastatic lymph nodes. Results: There were statistically significant differences between metastatic and non-metastatic lymph nodes in the short-axis diameter, long-axis diameter, mean ADC, minimum ADC, mean rADC and minimum rADC (P < 0.001). The Az of the minimum ADC (0.990) was greater than that of the other ADC-based criteria (0.974, 0.939, 0.976 for mean ADC, mean rADC and minimum rADC, respectively) and all size-based criteria (0.878 for short-axis diameter and 0.858 for long-axis diameter) (P < 0.05). Using the minimum ADC criteria (≤ 0.881 × 10- 3mm2/s), the sensitivity and specificity for differentiating metastatic from non-metastatic lymph nodes were 95.7% and 96.5%, respectively. Conclusions: DWI is feasible for differentiating metastatic from non-metastatic pelvic lymph nodes in patients with uterine cervical cancer and minimum ADC could be served as a representative marker. © 2011 Elsevier Inc. All rights reserved.

Lu S.,Tianjin Medical University | Lu S.,Key Laboratory of Cancer Prevention and Therapy | Wang Z.,Nanjing Medical University | Cui D.,Zhengzhou University | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2011

Glutathione S-transferase P1 (GSTP1) is involved in a wide range of detoxifying reactions. Any alteration in the structure, function, or expression of GSTP1 gene may alter the ability of a cell to inactivate carcinogens or mutagens, and thus modify an individual's risk to cancer. Previous epidemiological studies on the potential association between GSTP1 Ile105Val polymorphism and breast cancer risk have produced inconsistent results. In order to drive a more precise estimation of this association, we performed a meta-analysis of 30 published case-control studies including 15,901 cases and 18,757 controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results of this meta-analysis showed that GSTP1 Ile105Val polymorphism was not associated with breast cancer susceptibility in overall population. However, in subgroup analysis by ethnicity, we found a significant association among Asian population (for Val/Val vs. Ile/Ile: OR 1.27, 95% CI 1.02-1.83; for the recessive model Val/Val vs. Ile/Ile + Ile/Val: OR 1.42, 95% CI 1.20-1.69). When stratified by study design, significantly elevated susceptibility to breast cancer was found among hospital-based studies (for Val/Val vs. Ile/Ile: OR 1.38, 95% CI 1.16-1.63; for recessive model Val/Val vs. Ile/Val + Ile/Ile: OR 1.31, 95% CI 1.12-1.55; for dominant model: Val/Val + Ile/Val vs. Ile/Ile: OR 1.10, 95% CI 1.02-1.19). In conclusion, our meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase susceptibility to breast cancer in Asian population. © 2010 Springer Science+Business Media, LLC.

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