Le Xu

Fudan University, Shanghai, Shanghai Shi, China

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Publications (15)45.48 Total impact

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    ABSTRACT: Interleukin-1β (IL-1β) and IL-18 are products of activated inflammasomes that play central roles in innate immunity and inflammation. This study was aimed to determine the effect of tumor-derived IL-1β and IL-18 on recurrence and survival of patients with localized clear cell renal cell carcinoma (ccRCC) following surgery.
    Urologic oncology. 09/2014;
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    ABSTRACT: Our present study aims to evaluate the impact of tumor microRNA-125b (miR-125b) on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery. We retrospectively enrolled 276 patients (200 in the training cohort and 76 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, cancer-specific survival (CSS) and recurrence-free survival (RFS) were recorded. Tumor miR-125b levels were assessed by in situ hybridization (ISH) in specimens of patients. Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on CSS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy. In both cohorts, tumor miR-125b positively correlated with Fuhrman grade. High tumor miR-125b indicated poor survival and early recurrence of patients with ccRCC, especially with advanced stage disease. After multivariable adjustment, tumor miR-125b was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of traditional TNM and UISS prognostic models was improved when tumor miR-125b was added. The results showed that tumor miR-125b is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy.
    Cancer Science 08/2014; · 3.48 Impact Factor
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    ABSTRACT: To investigate the clinical significance of N-acetylgalactosaminyltransferase 4 (GALNT4) expression in patients with clear-cell renal cell carcinoma (ccRCC). 104 patients who had undergone curative nephrectomy at Zhongshan Hospital during 2004 were enrolled in this study. In the cohort, 23 patients died from disease, 33 patients suffered recurrence, 3 patients died from other causes. GALNT4 densities were assessed by immunohistochemistry in specimens of patients. Univariate and multivariate Cox models and Receiver operating characteristic (ROC) analysis were used to analyze the impact of prognostic factors on overall survival (OS) and relapse-free survival (RFS). Kaplan-Meier analysis with log-rank test was used to compare the clinical outcomes between subgroups. Intratumoral GALNT4 expression was significantly lower than peritumoral tissues. Moreover, low GALNT4 expression was associated with poor OS (P = 0.001) and RFS (P = 0.004). Furthermore, intratumoral GALNT4 expression, which was negatively correlated with tumor size (P = 0.032), necrosis (P = 0.013), and TNM stage (P = 0.017), was determined to be an independent prognostic indicator for OS (hazard ratio [HR], 3.088; P = 0.020) and RFS (HR, 2.173; P = 0.047). Extension the TNM staging system by GALNT4 expression showed a better prognostic value for OS (AUC 0.786, P = 0.029) and RFS (AUC 0.761, P = 0.040). Intratumoral GALNT4 expression is a potential independent prognostic factor for OS and RFS in patients with ccRCC. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for patients with ccRCC.
    The Journal of urology 04/2014; · 3.75 Impact Factor
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    ABSTRACT: To investigate prognostic values of intratumoral p21-activated kinase 6 (PAK6) expression in patients with clear cell renal cell carcinoma (ccRCC). Immunohistochemistry in tissue microarray was used to evaluate the expression of PAK6 in 104 patients who had undergone nephrectomy at Zhongshan Hospital of Fudan University. Prognostic value and clinical outcomes were evaluated. Intratumoral PAK6 expression was significantly lower than nontumoral tissues (P < 0.001). Moreover, low expression of PAK6 was associated with unfavorable overall survival (OS) (P = 0.001) and recurrence-free survival (RFS) (P = 0.001). In the subgroup of patients with tumor, node, metastasis classification system (TNM) stage I + II disease, those with low expression of PAK6 were prone to have poor OS (P = 0.014) and RFS (P = 0.037). Intratumoral PAK6 low expression was correlated with tumor size (P = 0.001) and TNM stage (P = 0.006), and was identified as an independent prognostic factor for OS (hazard ratio 4.109, P = 0.002) and RFS (hazard ratio 3.175, P = 0.002). Use of an extended TNM staging system with intratumoral PAK6 expression showed a better prognostic value for OS [area under the receiver operating characteristic curve (AUC) 0.790, P = 0.022] and RFS (AUC 0.769, P = 0.040). The c-index of a Cox-based model combined with Eastern Cooperative Oncology Group performance status, TNM stage, Fuhrman grade, and PAK6 was 0.83 for OS and 0.80 for RFS. Intratumoral PAK6 could be a potential prognosticator for OS and RFS in ccRCC patients after nephrectomy. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for ccRCC patients.
    Annals of Surgical Oncology 04/2014; · 4.12 Impact Factor
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    ABSTRACT: As the most abundant tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. CD68(+) TAMs display diversely polarized programs comprising CD11c(+) proinflammatory macrophages (M1) and CD206(+) immunosuppressive macrophages (M2). The aim of this study was to determine the survival impact of diametrically polarized TAMs in clear-cell renal cell carcinoma (ccRCC) and their application to stratification of patients according to their prognostic values. The study included 185 consecutive patients with ccRCC who underwent nephrectomy between 1999 and 2001. CD68(+) total and diametrically polarized (CD11c(+) M1 and CD206(+) M2) TAM densities were assessed by immunohistochemistry, and the relationships with clinicopathologic features and prognosis were evaluated. Low CD11c(+) TAM density and high CD206(+) TAM density were associated with reduced cancer-specific survival (P = 0.043 and P = 0.017, respectively), whereas CD68(+) TAM density only had borderline prognostic significance (P = 0.062). Furthermore, combined analysis of CD11c(+) and CD206(+) TAMs (CD11c/CD206 signature) had a better power to predict patients' outcome (P = 0.010). Together with TNM stage, tumor necrosis, and performance status, CD11c/CD206 signature was an independent prognostic factor (P = 0.010). When applied to the University of California Integrated Staging System intermediate-/high-risk group for localized ccRCC, CD11c/CD206 signature could further distinguish patients with dismal prognosis (P = 0.004). Intratumoral balance of diametrically polarized TAMs is a novel independent predictor for survival in patients with ccRCC. Tipping the balance toward an antitumoral phenotype might be a promising target of postoperative adjuvant therapy.
    Annals of Surgical Oncology 03/2014; · 4.12 Impact Factor
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    ABSTRACT: Purpose Interleukin-1β (IL-1β) and IL-18 are products of activated inflammasomes that play central roles in innate immunity and inflammation. This study was aimed to determine the effect of tumor-derived IL-1β and IL-18 on recurrence and survival of patients with localized clear cell renal cell carcinoma (ccRCC) following surgery. Methods We retrospectively enrolled 267 patients with localized ccRCC undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS), and overall survival (OS) were recorded. IL-1β and IL-18 levels were assessed by immunohistochemistry in tumor tissues. The Kaplan-Meier method was used to compare survival curves. Cox regression models were used to analyze the effect of prognostic factors on RFS and OS. Concordance index was calculated to assess predictive accuracy. Results Both high IL-1β and high IL-18 levels were associated with increased risk of recurrence (P<0.001 and P<0.001, respectively) and reduced survival (P<0.001 and P = 0.001, respectively). The combination of IL-1β and IL-18 expression (IL-1β/IL-18 signature) could further refine prognostic stratification. Multivariate analyses confirmed that IL-1β/IL-18 signature was an independent prognostic factor for RFS and OS (P = 0.005 and P = 0.044, respectively). The predictive accuracy of well-established prognostic models improved when the IL-1β/IL-18 signature was added. Notably, the improvement in prediction was mainly observed in patients with low-risk disease. Conclusions The combined high expression of IL-1β and IL-18 is an independent predictor for poor prognosis in patients with localized ccRCC, and the prognostic value is more pronounced in patients with low-risk disease.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
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    ABSTRACT: The transcription factor PROX1 (prospero homeobox 1) has a critical role in the development of various organs, and has been implicated in both oncogenic and tumor-suppressive functions in human cancers. However, the role of PROX1 in the development of renal cell carcinomas (RCCs) has not yet been studied. Here, we reported that PROX1 expression was decreased in human RCC tissues compared with adjacent normal tissues. In RCC tissues, however, poorly differentiated RCC expressed higher PROX1 levels compared with well-differentiated RCC. In addition, the PROX1 immunostaining levels were positively correlated with tumor nuclear grade and lymph node metastasis. Further, high PROX1 expression indicated poor survival for patients. These findings imply that in the different developmental stages of RCC, PROX1 may exert distinct functions according to the specific microenvironment of tumor. Moreover, in vitro experiments revealed that PROX1 overexpression enhanced the proliferation and migration of RCC cells; conversely, PROX1 depletion by siRNA attenuated the proliferation and migration of RCC cells. Collectively, these observations suggest that PROX1 plays an important role in RCC development and progression, and PROX1 may be a novel target for prevention and treatment of RCC.
    PLoS ONE 01/2014; 9(5):e95996. · 3.53 Impact Factor
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    ABSTRACT: Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2 through accelerating proteasome-mediated EZH2 degradation in hepatoma cells. Overexpression of EZH2 reversed sorafenib-induced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2 knockdown or EZH2 inhibition with 3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2 and H3K27 trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2 degradation. Genetic deletion or pharmacological ablation of EZH2 made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients.
    Cancer Science 06/2013; 104(6). · 3.48 Impact Factor
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    ABSTRACT: Although multitargeted tyrosine kinase inhibitor sunitinib has been used as first-line therapeutic agent against metastatic renal cell carcinoma (mRCC), the molecular mechanism and functional role per se for its therapeutic performance remains obscure. Our present study revealed that sunitinib-treated RCC cells exhibit senescence characteristics including increased SA-β-gal activity, DcR2 and Dec1 expression, and senescence-associated secretary phenotype (SASP) such as proinflammatory cytokines IL-1α, IL-6 and IL-8 secretion. Moreover, sunitinib administration also led to cell growth inhibition, G1-S cell cycle arrest and DNA damage response in RCC cells, suggesting therapeutic significance of sunitinib-induced RCC cellular senescence. Mechanistic investigations indicated that therapy-induced senescence (TIS) following sunitinib treatment mainly attributed to p53/Dec1 signaling activation mediated by Raf-1/NF-κB inhibition in vitro. Importantly, in vivo study showed tumor growth inhibition and prolonged overall survival were associated with increased p53 and Dec1 expression, decreased Raf-1 and Ki67 staining, and upregulated SA-β-gal activity after sunitinib treatment. Immunohistochemistry analysis of tumor tissues from RCC patients receive sunitinib neoadjuvant therapy confirmed the similar treating phenotype. Taken together, our findings suggested that sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation via inhibited Raf-1/NF-κB activity. These data indicated potential insights into therapeutic improvement with reinforcing TIS-related performance or overcoming SASP-induced resistance.
    Cancer Science 04/2013; · 3.48 Impact Factor
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    ABSTRACT: Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho is recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remains obscure. In our present study, immunohistochemical staining in tissue microarray containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than those patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition (EMT) and cellular migration and invasion in RCC. Besides, no alteration of α-2,6 sialidase activity was found after Klotho overexpression in RCC. The molecular signals for abovementioned phenomenon involved Klotho-mediated inhibition of PI3K/Akt/GSK3β/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho as a tumor suppressor via inhibiting PI3K/Akt/GSK3β/Snail signaling, thus suppressing EMT and tumor migration and invasion during RCC progression, which might be used as a potential therapeutic approach for advanced RCC.
    Cancer Science 02/2013; · 3.48 Impact Factor
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    ABSTRACT: Klotho was originally characterized as an aging suppressor gene that predisposed Klotho-deficient mice to premature aging-like syndrome. Although Klotho was recently reported to exhibit tumor suppressive properties during various malignant transformations, the functional role and molecular mechanism of Klotho in hepatocarcinogenesis remains poorly understood. In our present study, immunohistochemical Klotho staining levels in a clinical follow-up of 52 hepatoma patients were significantly associated with liver cirrhosis, tumor multiplicity and venous invasion. The overall survival rate of hepatoma patients with high Klotho expression was significantly lower than those patients with low Klotho expression. Moreover, Klotho overexpression increased cellular migration, anchorage-independent growth, and anoikis resistance in hepatoma cells. Klotho overexpression elevated p21-activated kinase 1 (PAK1) expression and shRNA-mediated PAK1 knockdown and kinase activity inhibition with kinase dead mutant PAK1 K299R coexpression or allosteric inhibitor IPA3 treatment reversed anoikis resistance in Klotho-overexpressed hepatoma cells. More importantly, the pivotal significance of upregulated VEGFR2 protein levels mediated by Klotho expression was confirmed by VEGFR2 inhibitor Axitinib and blocking antibody treatment in hepatoma cells. Axitinib treatment sensitized anoikis was reversed by constitutive active mutant PAK1 T423E coexpression in Klotho-overexpressed hepatoma cells. Conversely, knockdown of Klotho reduced VEGFR2/PAK1 dependent anoikis resistance, which could be reversed by PAK1 T423E. These results revealed a novel oncogenic function of Klotho in promoting anoikis resistance via activating VEGFR2/PAK1 signaling, thus facilitating tumor migration and invasion during hepatoma progression, which could provide a putative molecular mechanism for tumor metastasis.
    PLoS ONE 01/2013; 8(3):e58413. · 3.53 Impact Factor
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    ABSTRACT: A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of hepatitis B virus X protein (HBx) in HBV-associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in hepatoma invasion and metastasis remains poorly understood. In the present study, we found that HBx expression could induce epithelial-mesenchymal transition in hepatoma and hepatic cells. This effect was shown due to stabilized Snail protein through activating the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3β (PI3K/AKT/GSK-3β) signal pathway by HBx expression. Functional studies revealed that HBx expression could enhance hepatoma cell migration and invasion in vitro. Moreover, stable HBx expression could also facilitate intrahepatic and distant lung metastasis of HCC in a nude mice tumor metastasis model in vivo. The correlation between increased PI3K/AKT/GSK-3β signaling with elevated Snail protein level was also observed in HCC tumor tissues with intrahepatic metastasis or chronic HBV infection. These results revealed a novel function of HBx in promoting epithelial-mesenchymal transition through Snail protein stabilization by activating PI3K/AKT/GSK-3β signaling, thus facilitating tumor invasion and metastasis during HCC progression. This could provide a putative molecular mechanism for tumor recurrence and metastasis in HBV-associated HCC patients.
    Cancer Science 09/2012; · 3.48 Impact Factor
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    ABSTRACT: Both the Notch1 and PI3K/Akt pathways are aberrantly activated in clear cell renal cell carcinoma (CCRCC) and involved in the tumorigenesis. The aim of this study was to test our hypothesis that elevated Notch1 signaling activity exerts its growth-promoting effects via the PI3K/Akt pathway in CCRCC. To investigate the relationship between the two pathways, we enhanced and suppressed the Notch1 activity respectively in a CCRCC cell line through diverse means, and then evaluated ensuing phosphorylated Akt (pAkt) levels. To further study their collaboration in promoting tumor growth, cell proliferation assay, colony formation assay and cell cycle analysis were conducted under several different conditions. Immunostaining of the tissue microarrays was used to determine whether the phenomena we observed also existed in vivo. The results showed that Notch1 signaling was activated in CCRCC tissue samples and cell lines. Notch1 activation increased CCRCC cell proliferation, enhanced anchorage-independent growth, and accelerated G1/S cell cycle progression. Such effects of the Notch1 signaling were, at least in part, mediated by the PI3K/Akt pathway. Correlations between Notch1, pAkt and Ki-67 protein levels in tissue microarrays reinforced our in vitro findings. Taken together, the current study established a functional link between the Notch1 and PI3K/Akt pathways in CCRCC. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02291.x, 2012).
    Cancer Science 03/2012; · 3.48 Impact Factor
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    ABSTRACT: The pathological roles of Notch pathway in renal cell carcinoma are still unclear, although Notch signaling has been shown to have an effect on many malignant tumors. In this study, Jagged1 was detected to examine its expression pattern and clinical significance in renal cell carcinoma. Normal and cancerous kidney tissues from three renal cell carcinoma patients were analyzed using western blot and reverse transcriptase-polymerase chain reaction for Jagged1 expression. Subsequently, extensive immunohistochemistry was performed to detect Jagged1 expression in 129 renal cell carcinoma cases. Clinicopathological data for these patients were evaluated. The prognostic significance was assessed using the Kaplan-Meier survival estimates and log-rank tests. A multivariate study with the Cox proportional hazard model was used to evaluate the prognosis-related aspects. Western blot and polymerase chain reaction results showed markedly increased Jagged1 protein and mRNA levels in renal cell carcinoma tissues compared with normal kidney tissues, which was further verified by immunohistochemical analysis. The expression level of Jagged1 was strongly associated with tumor size, nuclear grade and TNM stage. In addition, high Jagged1 expression was statistically linked to reduced overall and disease-free survival, especially at the early stage (P < 0.001 and <0.001, respectively). Jagged1 expression was found to be an independent prognostic factor for both overall survival and disease-free survival in multivariate analysis (P = 0.035 and 0.028, respectively). Notch signaling may play an important role in the progress of renal cell carcinoma. Jagged1 expression may be useful for predicting prognosis in patients with renal cell carcinoma, especially at the early stage.
    Japanese Journal of Clinical Oncology 11/2010; 41(3):411-6. · 1.90 Impact Factor
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    ABSTRACT: To investigate resting energy expenditure (REE) and body composition and the relationship between substrate utilization and energy expenditure in urologic cancer patients. Measured resting energy expenditure (mREE) was detected by indirect calorimetry in 122 urologic cancer patients and 131 control subjects. Extracellular fluid (ECF), intracellular fluid (ICF), and total water (TW) were measured by bioelectrical impedance appliance. Fat oxidation rate (F-O), carbohydrate oxidation rate, fat mass (FM), and fat free mass (FFM) were further determined. Compared with the controls, cancer patients showed significantly elevated mREE and mREE/FFM (P = 0.049; P < 0.001). Of all the cancer patients, 50% (n = 61) were hypermetabolic, 43.4% (n = 53) normometabolic, and 6.6% (n = 8) hypometabolic, whereas 35.1% (n = 46) of the controls were hypermetabolic, 56.5% (n = 74) normometabolic, and 8.4% (n = 11) hypometabolic. REE was correlated to substrate oxidation rate (R(2) = 0.710). Cancer patients exhibited no significant difference in FM, FM/body weight (BW) and FFM, compared with controls. Cancer patients presented no significant difference in TW compared with controls (P = 0.791), but they had increased ECF (P < 0.001) and decreased ICF (P < 0.001). Aberrations in substrate utilization may contribute to the elevated energy expenditure in urologic cancer patients. Cancer type and pathologic stage are influential factors of REE.
    Urologic Oncology 09/2010; 30(5):711-8. · 3.65 Impact Factor