Muyan Cai

Sun Yat-Sen University Cancer Center, Shengcheng, Guangdong, China

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Publications (14)45.49 Total impact

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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which NF-κB pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and NF-κB pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-κB induced activation, Golgi phosphoprotein 3 (GOLPH3). The mRNA and protein expression levels of GOLPH3 were frequently upregulated in HCC and GOLPH3 expression correlated closely with clinical stage and survival in both of testing and validation cohorts. Ectopic overexpression of GOLPH3 in PLC/PRF/5 (PLC) and Huh7 HCC cells protected against cisplatin-induced apoptosis, promoted angiogenesis and proliferation, and increased the aggressiveness of HCC cells in vitro and in vivo, whereas inhibition of GOLPH3 led to decreased aggressiveness. Through analysis of two published HCC patient profiles, GOLPH3 expression significantly correlated with NF-κB signaling. Furthermore, we demonstrated that GOLPH3 promoted K63-linked polyubiquitination of tumor necrosis factor receptor associated factor 2(TRAF2), receptor interacting protein (RIP) and NF-κB essential modulator (NEMO) and substantially sustained the activation of NF-κB in HCC cells. Taken together, our findings provided evidences that GOLPH3 is a prognostic and/or potential therapeutic biomarker for HCC patients and plays an important role in activation of the NF-κB pathway during HCC progression.
    The Journal of Pathology 11/2014; · 7.33 Impact Factor
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    ABSTRACT: To investigate the frequency of different types of mature T- and NK-cell lymphomas diagnosed in a 4-year period at Sun Yat-sen University Cancer Center, and to study baseline CD30 for potential anti-CD30 targeted therapy in mature T- and NK-cell lymphoma.
    Zhonghua bing li xue za zhi Chinese journal of pathology 08/2014; 43(8):508-11.
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    ABSTRACT: MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.
    Oncotarget 07/2014; · 6.63 Impact Factor
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    ABSTRACT: α4 is upregulated in several types of human cancer and possesses an oncogenic role. However, the abnormalities of α4 and its underlying mechanisms in the pathogenesis of bladder urothelial carcinoma (BUC) remain unknown. α4 expression profile was examined by reverse transcription polymerase chain reaction, western blotting and immunohistochemistry (IHC) in BUC tissues and normal urothelial bladder epithelial tissues. Short hairpin RNA (ShRNA) interfering approach was employed to suppress endogenous α4 expression in BUC cells to determine its role in tumourigenesis, invasion/metastasis and the potential mechanism. α4 expression in BUC was significantly up-regulated at both mRNA and protein levels compared with that in normal urothelial bladder epithelial tissues. High expression of α4 was inversely correlated with poor survival of the BUC patients (P<0.05). Down-regulation of α4 in BUC EJ and T24 cells led to a G1 phase cell cycle arrest, suppressed cell growth, markedly inhibited invasive motility in vitro and metastatic potential in vivo. Moreover, down-regulation of α4 was found to increase E-cadherin expression and reduce metastasis-associated protein 1 (MTA1) expression either in transcript or protein levels. Importantly, a significant correlation between high expression of α4 and negative expression of E-cadherin in BUC cohorts was observed (P<0.001). These findings suggest a potential important role of α4 in control of cell migration and/or invasion via the regulation of E-cadherin expression, and the high α4 expression, as examined by IHC, is an independent molecular marker for shortened survival time of patients with BUC.
    European journal of cancer (Oxford, England: 1990) 01/2014; · 4.12 Impact Factor
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    ABSTRACT: Krüppel-like factor 17 (KLF17), a member of the KLF transcription factor family, has been shown to inhibit the epithelial-mesenchymal transition (EMT) and tumor growth. However, the expression, cellular function and mechanism of KLF17 in endometrioid endometrial cancer (EEC; a dominant type of endometrial cancer) remains elusive. Here, we report that among the KLF family members, KLF17 was consistently upregulated in EEC cell lines compared with immortalized endometrial epithelial cells. Overexpression of KLF17 in EEC cell lines induced EMT and promoted cell invasion and drug resistance, resulting in increased expression of TWIST1. In contrast, KLF17 suppression reversed EMT, diminished cell invasion, restored drug sensitivity and suppressed TWIST1 expression. Luciferase assays, site-directed mutagenesis and transcription factor DNA binding analysis demonstrated that KLF17 transactivates TWIST1 expression by directly binding to the TWIST1 promoter. Knockdown of TWIST1 prevented KLF17-induced EMT. Consistent with these results, both KLF17 and TWIST1 levels were found to be elevated in EECs compared to normal tissues. KLF17 expression positively correlated with tumor grade, but inversely correlated with estrogen and progesterone receptor expression. Thus, KLF17 may have an oncogenic role during EEC progression via initiating EMT through the regulation of TWIST1.
    Carcinogenesis 11/2013; · 5.27 Impact Factor
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    ABSTRACT: Renal impairment is a frequent accompaniment post-myocardial infarction (MI) heart failure. However, the mechanisms and predictors are yet poorly understood. The present study aimed to explore early markers for renal impairment and to test the hypothesis that angiotensin II type 1 receptor (AT1R) blocker exerted renoprotection by regulating local angiotensin II receptors post-MI heart failure. Sprague-Dawley rats underwent ligation of the left descending coronary artery and were treated with losartan (20 mg/kg/day) or vehicle for 3 or 9 weeks. Samples of urine, blood, and kidney were collected for assessment of renal function, histology, and protein changes. The current study revealed that blood cystatin C, rather than serum creatinine and blood urea nitrogen, as well as urine proteins, increased post-MI heart failure significantly. These changes were associated with increased immunohistochemical staining of AT1R and AT2R proteins, accompanied by increased renal fibrosis, tubular necrosis, and inflammatory cell infiltration. Treatment with losartan for MI rats significantly attenuated upregulated AT1R but not AT2R. Losartan also decreased blood cystatin C levels and attenuated renal fibrosis, tubular necrosis, and inflammatory cell infiltration. In conclusion, blood cystatin C may be a better marker for early renal impairment. AT1R blockers modulated local angiotensin II receptors, as well as inflammatory reaction and profibrotic effects, providing potential clinical application in the setting of cardiorenal syndrome post-MI.
    Renal Failure 04/2013; · 0.94 Impact Factor
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    ABSTRACT: Cyclin F, capable of forming SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, is implicated in controlling centrosome duplication and preventing genome instability. Cyclin F oscillates during cell cycle with a similar pattern of cyclin A. However, its expression and the relevant significance in cancer remain totally obscure. In this study, we showed that cyclin F was noticeably decreased in 16 pairs of tissue samples of hepatocellular carcinoma (HCC), compared to paracarcinoma tissues, at both mRNA and protein levels. Immunohistochemical staining data revealed that in 71.8% (176/245) of HCC cases, cyclin F expression in tumor tissue was much lower than that in nontumorous tissue. Low cyclin F expression, defined by receiver operating characteristic curve (ROC) analysis, was present in 69.0% of HCC patients. Low expression of cyclin F significantly correlated with tumor size, clinical stage, serum AFP level and tumor multiplicity. Further study showed that cyclin F expression was reversely associated with tumor differentiation in HCC. Kaplan-Meier analysis indicated that low cyclin F expression was related to poor overall survival and recurrence-free survival. The prognostic impact of cyclin F was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low cyclin F expression was an independent poor prognostic marker for overall survival. Collectively, we conclude that cyclin F is downregulated in HCC and could be served as a promising prognostic marker for patients suffering from this deadly disease.
    Cancer Science 01/2013; · 3.53 Impact Factor
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    ABSTRACT: Age at diagnosis has been shown to be an independent prognostic factor of localized renal cell carcinoma (RCC) in several studies. We used contemporary statistical methods to reevaluate the effect of age on the cancer-specific survival (CSS) of localized RCC. 1,147 patients with localized RCC who underwent radical nephrectomy between 1993 and 2009 were identified in our four institutions. The association between age and CSS was estimated, and the potential threshold was identified by a univariate Cox model and by martingale residual analysis. Competing risks regression was used to identify the independent impact of age on CSS. The median age was 52 years (range, 19-84 years). The median follow-up was 61 months (range, 6-144 months) for survivors. A steep increasing smoothed martingale residual plot indicated an adverse prognostic effect of age on CSS. The age cut-off of 45 years was most predictive of CSS on univariate Cox analysis and martingale residual analysis (p = 0.005). Age ≤45 years was independently associated with a higher CSS rate in the multivariate Cox regression model (HR = 1.59, 95% CI = 1.05-2.40, p = 0.027) as well as in competing risks regression (HR = 3.60, 95% CI = 1.93-6.71, p = 0.001). Increasing age was associated with a higher incidence of cancer-specific mortality of localized RCC. Age dichotomized at 45 years would maximize the predictive value of age on CSS, and independently predict the CSS of patients with localized RCC.
    PLoS ONE 10/2012; 7(10):e48489. · 3.53 Impact Factor
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    ABSTRACT: Objectives: We aimed to investigate the nature of endometrial stromal sarcoma (ESS) arising from endometriosis. Methods: The clinical data of 5 patients with ESS arising from endometriosis were reviewed retrospectively. The expression of CD117, HER2/neu, EGFR, VEGF, and PDGFR was analyzed by immunohistochemical staining. Results: The median age of the 5 patients was 45 years. The primary tumor sites were the ovary in 2, the pelvis in 2, and the cervical canal in 1 patient. Three patients had disseminated disease at diagnosis. Four patients underwent complete tumor resection. All of the 5 cases received adjuvant chemotherapy and 2 received progesterone therapy, while none were treated with radiotherapy. No recurrence occurred in the 4 cases who had complete tumor resection, and the only patient who progressed was the patient in whom the tumor was unresectable. Tumor cells in all cases exhibited positive staining for PDGFR and were negative for CD117 and HER2/neu. The expression of EGFR and VEGF was observed in 2 and 4 cases, respectively. Conclusion: ESS arising from endometriosis is rare. Complete tumor resection in ESS arising from endometriosis may reduce the recurrence rate.
    Gynecologic and Obstetric Investigation 09/2012; · 1.10 Impact Factor
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    ABSTRACT: Tumor-associated epigenetic alterations including DNA methylation and histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Expression of H3K4me3 and the histone methyltransferase (HMT) SET and MYND domain-containing protein 3 (SMYD3) was studied by Western blotting and immunohistochemistry in cell lines and tumor tissue microarray from a well-characterized series of HCC patients (n = 168). The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue microarray from another independent HCC patients cohort (n = 147) was used for validation studies. Expression of H3K4me3 and SMYD3 were enhanced in HCC cell lines. In tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < .0001), especially in early-stage HCC patients (TNM I/II). Furthermore, both univariate and multivariate analyses revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio, 3.592; 95% confidence interval, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P < .0001). In conclusion, H3K4me3 level defines unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome and can thus be a novel predictor for poor prognosis of HCC patients, especially at TNM I/II stage.
    Human pathology 03/2012; 43(9):1425-35. · 2.81 Impact Factor
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    ABSTRACT: Polo-like kinase 4 (PLK4), belonging to serine/threonine kinase family, is critical for centriole replication and cell cycle progression. PLK4 has been proposed as a tumor suppressor in hepatocellular carcinoma (HCC). However, its expression and significance in HCC have not been well studied. In the present study, we found that PLK4 was markedly downregulated in both HCC cell lines and fresh cancer tissues, using quantitative real-time-PCR and western blot. Immunohistochemistry data also revealed that decreased expression of PLK4 was present in 72.4% (178/246) of HCC tissues, compared with the corresponding adjacent nontumorous tissues. Furthermore, PLK4 expression significantly correlated with clinicopathological parameters, including clinical stage (P=0.034), serum α-fetoprotein (AFP) (P=0.019) and tumor size (P=0.032). Moreover, HCC patients with low PLK4 expression survived shorter than those with high PLK4 expression, as indicated by overall survival (P=0.002) and disease-free survival (P=0.012) assessed by the Kaplan-Meier method. In addition, multivariate analysis suggested PLK4 as an independent predictor of overall survival (HR, 0.556; 95%CI, 0.376-0.822; P=0.003) and disease-free survival (HR, 0.547; 95%CI, 0.382-0.783; P=0.001). Collectively, our study demonstrated that PLK4 was remarkably downregulated in HCC and could be served as a potential prognostic marker for patients with this deadly disease.
    PLoS ONE 01/2012; 7(7):e41293. · 3.53 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. We studied 204 patients with de novo DLBCL (107 treated with first-line CHOP; 97 treated with first-line R-CHOP), patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10, and MUM1 protein expression. The relationships between clinical characteristics, survival data, and immunophenotype (IHC) were studied. The 5-year overall survival (OS) in the CHOP and R-CHOP groups was 50.4% and 66.6% (P = 0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP or not (65.0% versus 40.9%; P = 0.011). In contrast, there is no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% versus 61.3%; P = 0.141). In non-GCB subtype, additional rituximab improved survival better than CHOP (61.3% versus 40.9%; P = 0.0303). These results indicated that addition of rituximab to standard chemotherapy eliminates the prognostic value of IHC-defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL.
    The Scientific World Journal 01/2012; 2012:897178. · 1.22 Impact Factor
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    ABSTRACT: SIRT3, a mitochondrial sirtuin belonging to nicotinamide adenine nucleotide (NAD) dependent deacetylases, is implicated in metabolism, longevity and carcinogenesis. SIRT3 expression and its significance in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we demonstrated that SIRT3 expression in HCC tissue was much lower than that in paracarcinoma tissue, at both mRNA and protein levels. The cutoff value for low SIRT3 expression in HCC was defined according to receiver operating characteristic curve (ROC) analysis. As disclosed by immunohistochemistry (IHC) results, low SIRT3 expression was present in 67.3% (167/248) of HCC cases. Furthermore, low expression of SIRT3 was significantly correlated to differentiation (P = 0.013), clinical stage (P = 0.005), serum AFP level (P<0.01), tumor multiplicity (P = 0.026) and relapse (P = 0.028). Moreover, Kaplan-Meier analysis indicated that low SIRT3 expression associated with unfavorable overall survival (P<0.01) and recurrence-free survival (P = 0.004). The prognostic impact of SIRT3 was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low SIRT3 expression was an independent poor prognostic marker for overall survival (Hazard Ratio (HR) 0.555, 95% confidence interval (95% CI) 0.344-0.897, P = 0.016). Collectively, we conclude that SIRT3 is decreased in HCC and is a novel unfavorable marker for prognosis of patients with this fatal disease.
    PLoS ONE 01/2012; 7(12):e51703. · 3.53 Impact Factor
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    ABSTRACT: The tumor suppressor in lung cancer 1 (TSLC1) has been identified as a putative tumor suppressor gene in non-small cell lung cancer. Although loss of TSLC1 has been observed in a number of human malignancies, the expression levels of TSLC1 gene in ovarian cancer and its clinical or prognostic significance have not been investigated. Protein expression levels of TSLC1 was explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimen consisting of 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors, and 160 invasive ovarian carcinomas. The TSLC1 immunohistochemical staining results were then correlated with various clinicopathologic parameters and patient prognosis using various statistical models. Significantly decreased, or complete loss of, protein expression of the TSLC1 gene was observed in 59% ovarian carcinomas, 45% borderline tumors, and 7% cystadenomas, but in none of the normal ovaries (0%). In ovarian carcinomas, decreased TSLC1 expression was significantly correlated with lymph node metastasis (pN, P = 0.001), distant metastasis (pM, P = 0.028), and more advanced International Federation of Gynecology and Obstetrics stages (P = 0.008). By univariate survival analysis on the ovarian carcinoma cohorts, decreased TSLC1 protein expression was significantly associated with shortened patient survival (mean: 26.9 months in tumors with complete loss of TSLC1 vs 63.1 months in tumors with significantly decreased TSLC1 vs 94.3 months in tumors with normal levels of TSLC1; P < 0.001). By multivariate analysis, TSLC1 protein expression remained as a significant and independent prognostic factor for the prediction of patient survival (P = 0.003). Decreased protein expression of the TSLC1 gene might be important in conferring a more aggressive behavior in ovarian carcinoma. Thus, TSLC1 may be used as an independent prognostic molecular marker for patients with ovarian carcinoma.
    International Journal of Gynecological Cancer 04/2011; 21(3):486-93. · 1.94 Impact Factor