Publications by authors named "Chunping Yu"

29 Publications

  • Page 1 of 1

Baihe Wuyao decoction ameliorates CCl-induced chronic liver injury and liver fibrosis in mice through blocking TGF-β1/Smad2/3 signaling, anti-inflammation and anti-oxidation effects.

J Ethnopharmacol 2020 Dec 9;263:113227. Epub 2020 Aug 9.

School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China; Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan, 063210, China; Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, North China University of Science and Technology, Tangshan, 063210, China. Electronic address:

Ethnopharmacological Relevance: Baihe Wuyao decoction (BWD), a prescription of Traditional Chinese Medicines, composed of Lilium brownii var. viridulum Baker.(Lilii Bulbus) and Lindera aggregata (Sims) Kosterm. (Linderae Radix), has been used to treat epigastric pain and superficial gastritis for hundreds of years in China. Recently, some compounds obtained from Lilii Bulbus and Linderae Radix had active effects of hepatic protection or liver fibrosis alleviation. Thus, we aim to evaluate the effects of BWD on treatment of chronic liver injury and liver fibrosis induced by carbon tetrachloride (CCl) and to elucidate the possible molecular mechanism.

Materials And Methods: Mice were treated with BWD (low, medium and high dose), diammonium glycyrrhizinate or vehicle by oral gavage once daily, simultaneously intraperitoneal injected with a single dose of CCl (1 μl/g body weight) twice a week for consecutive 6 weeks. Next, all mice were sacrificed after fasted 12 h, and serums and liver tissues were harvested for analysis. The hepatic injury was detected by serum biomarker assay, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The hepatic histology and collagen were illustrated by hematoxylin-eosin staining and Sirius red staining respectively. The antioxidant capacity of liver tissues was evaluated by the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenization. The mRNA gene or protein expressions related to fibrosis, oxidative stress and inflammation molecules were performed by real-time quantitative PCR (RT-PCR) or Western-blot.

Results: BWD exhibited a good hepatic protection with ameliorating liver histological changes, decreasing serum AST and ALT contents, and reducing hepatic fibrosis with stimulation ECMs (such as Collagen1 and Collagen3) degradation. BWD inhibited hepatic stellate cells (HSCs) activation, promoted matrix metalloproteinase-2 (MMP2), MMP9, and MMP12 while suppressing tissue inhibitors of matrix metalloproteinase-1 (TIMP1) expression, and blocked traditional fibrosis TGF-β1/Smad2/3 signal pathway. Moreover, BWD exhibited anti-inflammation effect proved by the reduction of liver Interleukin-1β (IL-1β), TNF-α, IL-11 mRNA levels and promoted anti-oxidation effects determined by inhibition of liver MDA and iNOS levels while promoting liver SOD and Mn-SOD.

Conclusion: BWD ameliorates CCl-induced CLI and liver fibrosis which is correlated to its blocking TGF-β1/Smad2/3 signaling, anti-inflammation, and anti-oxidation effects. BWD, as a small traditional prescription, is a promising treatment for CLI and liver fibrosis through multiple pharmacological targets.
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http://dx.doi.org/10.1016/j.jep.2020.113227DOI Listing
December 2020

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Cancer Discov 2020 Aug 13;10(8):1174-1193. Epub 2020 May 13.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including loss, activating alterations in , and , and loss of estrogen receptor expression. experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired , or alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in , and -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR metastatic breast cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1390DOI Listing
August 2020

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

Oncotarget 2020 Jan 21;11(3):216-236. Epub 2020 Jan 21.

Eli Lilly and Company, Indianapolis, IN, USA.

The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.
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http://dx.doi.org/10.18632/oncotarget.27400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980627PMC
January 2020

Nkx2.8 Inhibits Epithelial-Mesenchymal Transition in Bladder Urothelial Carcinoma via Transcriptional Repression of .

Cancer Res 2018 03 8;78(5):1241-1252. Epub 2018 Jan 8.

State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Epithelial-to-mesenchymal transition (EMT) promotes metastasis, which is the main cause of bladder urothelial carcinoma-related death. Loss of the candidate tumor-suppressor gene Nkx2.8 has been associated with urothelial carcinoma lymph node metastasis. Here, we show that enforced expression of Nkx2.8 is sufficient to inhibit EMT, reduce motility, and blunt invasiveness of urothelial carcinoma cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of the EMT inducer Twist1 in urothelial carcinoma cells, at both the level of mRNA and protein accumulation. Nkx2.8 bound directly to the promoter region of this gene and transcriptionally repressed its expression. Twist1 upregulation reversed EMT inhibition by Nkx2.8, restoring the invasive phenotype of urothelial carcinoma cells. In clinical urothelial carcinoma specimens, expression of Nkx2.8 inversely correlated with Twist1 expression, and urothelial carcinoma patients with Nkx2.8 positivity and low Twist1 expression displayed the best prognosis. Our findings highlight the Nkx2.8-Twist1 axis as candidate target for therapeutic intervention in advanced urothelial carcinoma. These findings highlight a novel EMT signaling axis as a candidate target for therapeutic intervention in advanced urothelial carcinomas. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1545DOI Listing
March 2018

Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.

Cancer Cell 2017 Dec;32(6):761-776.e6

Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address:

Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.
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http://dx.doi.org/10.1016/j.ccell.2017.11.006DOI Listing
December 2017

DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury.

Kidney Int 2017 07 15;92(1):140-153. Epub 2017 Mar 15.

Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address:

The contribution of DNA methylation to diabetic nephropathy, especially the effect on podocyte integrity, is not clarified. Here we found that albuminuria in a db/db mouse model was markedly attenuated after treatment with a DNA methylation inhibitor. This was accompanied by alleviation of glomerular hypertrophy, mesangial matrix expansion, and podocyte injury. The expression of DNA methyltransferase 1 (Dnmt1), nuclear factor Sp1, and nuclear factor kappa B (NFκB)-p65 markedly increased in podocytes in vivo and in vitro under the diabetic state. The increased expression of Dnmt1 was attenuated after treatment with 5-azacytidine or 5-aza-2'-deoxycytidine or Dnmt1 knockdown, accompanied by restored decreased podocyte slit diaphragm proteins resulting from hypermethylation and improved podocyte motility. Further studies found that increased Sp1 and NFκB-p65 interacted in the nucleus of podocytes incubated with high glucose, and Sp1 bound to the Dnmt1 promoter region. The involvement of the Sp1/NFκB-p65 complex in Dnmt1 regulation was confirmed by the observation that Sp1 knockdown using mithramycin A or siRNA decreased Dnmt1 protein levels. The luciferase reporter assay further indicated that Dnmt1 was a direct target of Sp1. Thus, inhibition of DNA methylation may be a new therapeutic avenue for treating diabetic nephropathy. Hence, the Sp1/NFκB p65-Dnmt1 pathway may be exploited as a therapeutic target for protecting against podocyte injury in diabetic nephropathy.
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http://dx.doi.org/10.1016/j.kint.2017.01.010DOI Listing
July 2017

RhoA deficiency disrupts podocyte cytoskeleton and induces podocyte apoptosis by inhibiting YAP/dendrin signal.

BMC Nephrol 2016 07 7;17(1):66. Epub 2016 Jul 7.

Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou, 510080, China.

Background: Podocyte apoptosis is a major mechanism that leads to proteinuria in many kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. RhoA is one of Rho GTPases that has been well studied and plays a key role in regulating cytoskeletal architecture. Previous study showed that insufficient RhoA could result in rat aortic smooth muscle cell apoptosis. However, whether RhoA is involved in podocyte apoptosis remains unknown.

Methods: Culture podocytes were treated with LPS, ADR or siRNA for 48 h before harvest. Subcellular immunoblotting, qRT-PCR, immunofluorescence and flow cytometry were used to exam the expression and function of RhoA or YAP in podocytes.

Results: We found that the expression of RhoA and its activity were significantly decreased in LPS or ADR-injured podocytes, accompanying loss of stress fibers and increased cell apoptosis. Knocking down RhoA or its downstream effector mDia expression by siRNA also caused loss of stress fibers and podocyte apoptosis. Moreover, our results further demonstrated that RhoA deficiency could reduce the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Silenced dendrin expression significantly abolished RhoA, mDia or YAP deficiency-induced podocyte apoptosis.

Conclusion: RhoA deficiency could disrupt podocyte cytoskeleton and induce podocyte apoptosis by inhibiting YAP/dendrin signal. RhoA/mDia/YAP/dendrin signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary RhoA would be one potent way to prevent proteinuria kidney diseases.
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http://dx.doi.org/10.1186/s12882-016-0287-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936208PMC
July 2016

Lipopolysaccharide-induced podocyte injury is mediated by suppression of autophagy.

Mol Med Rep 2016 Jul 18;14(1):811-8. Epub 2016 May 18.

Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.

High-level autophagy has an important role in maintaining the stable state of podocytes. The present study explored the influence of lipopolysaccharide (LPS) on autophagic activity in podocytes and demonstrated its mechanistic involvement in LPS-induced injury. Conditionally immortalized podocytes were cultured in vitro and were treated with chloroquine (CQ), LPS, LPS+rapamycin or LPS+3‑methyladenine (3‑MA). The autophagic vesicles and endoplasmic reticulum were observed using transmission electron microscopy. The tandem mRFP‑GFP‑LC3 adenovirus was used to detect autophagosomes and autolysosomes. The expression levels of light chain 3‑II (LC3 II), beclin‑1, P62, CCAAT‑enhancer‑binding protein homologous protein (CHOP) and podocin were determined by western blot analysis. Autophagic vesicles were detected in podocytes under basic conditions. CQ was found to increase the protein levels of LC3 II in a time‑dependent manner (2, 4 or 6 h), confirming the high activity of autophagy in podocytes. Compared with the control group, LPS induced the expansion of the endoplasmic reticulum and high expression levels of CHOP, while decreasing the protein expression of podocin. Notably, podocytes treated with LPS showed decreases in LC3 II and beclin‑1 levels and autophagosome/autolysosome numbers, which was accompanied by high P62 levels. Furthermore, the autophagy enhancer rapamycin reversed the downregulation of LC3 II and podocin, and the upregulation of CHOP induced by LPS, while the autophagy inhibitor 3‑MA aggravated the effects of LPS. In conclusion, the present study demonstrated that LPS inhibited podocyte autophagy, which contributed to LPS-induced injury of podocytes.
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http://dx.doi.org/10.3892/mmr.2016.5301DOI Listing
July 2016

Genomic alterations and molecular subtypes of gastric cancers in Asians.

Chin J Cancer 2016 May 9;35:42. Epub 2016 May 9.

Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, 46258, USA.

Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or metastatic disease at diagnosis. Treatment options are limited, and the prognosis for advanced GCs is poor. The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs, including studies that focused exclusively on GCs in Asians. These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs. An analysis of gene expression data by the Asian Cancer Research Group (ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development. In this article, we review the ACRG GC project. We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.
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http://dx.doi.org/10.1186/s40880-016-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862075PMC
May 2016

The Difference in Prognosis between Renal Sinus Fat and Perinephric Fat Invasion for pT3a Renal Cell Carcinoma: A Meta-Analysis.

PLoS One 2016 18;11(2):e0149420. Epub 2016 Feb 18.

Department of Urology Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: In the current Tumour-Node-Metastasis (TNM) classification system for renal cell carcinoma (RCC), both renal sinus fat invasion (SFI) and perinephric fat invasion (PFI) are defined as T3a, suggesting that the prognosis should be similar for the two pathologic findings. Several studies, however, have reported a worse prognosis for SFI in patients with a T3a tumor. In order to compare the prognosis of these two pathologic findings (SFI versus. PFI) in a more comprehensive way, this meta-analysis was performed.

Methods: To identify relevant studies, Medline, Embase, Cochrane Library, and Scopus database were searched from the inception until October 2014. A meta-analysis was performed using Review Manager 5.2 and STATA 11. Pooled Odds ratio (OR) and/or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard association.

Results: A total of 6 studies including 1031 patients qualified for analysis. T3a RCC patients with SFI were significantly associated with poor cancer specific survival(CSS) (HR: 1.47, 95% CI: 1.19-1.83; P<0.001) compared to those with PFI. In T3aNx/N0M0 subgroup, SFI patients also showed a worse prognosis than those with PFI (CSS, HR: 1.94, 95% CI: 1.21-3.12; P = 0.006). T3a RCC patients with SFI had higher Furhman grade, greater possibility of lymph node metastasis, sarcomatoid differentiation and tumour necrosis. Main limitation is the relatively small number of included studies.

Conclusion: The present meta-analysis suggested that SFI is associated with worse CSS in patients with pT3a RCC. However, due to the small number of included studies, future studies with a large sample size are required to further verify our findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758757PMC
July 2016

Spironolactone inhibits podocyte motility via decreasing integrin β1 and increasing integrin β3 in podocytes under high-glucose conditions.

Mol Med Rep 2015 Nov 7;12(5):6849-54. Epub 2015 Sep 7.

Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.

Integrin β1 and β3 expression by podocytes is required to maintain glomerular structural integrity. Previous studies have shown that aldosterone (ALD) is involved in glomerular podocyte injury, and mineralocorticoid receptor (MR) blocker spironolactone effectively reduces proteinuria in patients with diabetic nephropathy. The present study was designed to observe the effects of spironolactone on β1 and β3 integrin expression and podocyte motility under in vitro diabetic conditions. Immortalized mouse podocytes were cultured in media containing normal glucose (NG) levels, high glucose (HG) or HG plus spironolacton. The expression of β1 and β3 integrin in podocytes was detected by reverse transcription quantitative polymerase chain reaction, immunofluorescence and western blot analyses. The effects of spironolacton on podocyte motility was further evaluated using a wound healing assay. HG stimulation markedly decreased mRNA and protein expression of integrin β1, and significantly increased mRNA and protein expression of integrin β3 in cultured podocytes. However, simultaneous treatment with spironolacton (10‑7 mol/l) significantly attenuated HG-mediated increases in integrin β3 and decreases in integrin β1 expression. Furthermore, the migration of podocytes induced by HG was abrogated by concomitant treatment with spironolacton. In conclusion, the present study suggested that HG decreased the expression of integrin β1 in cultured podocytes, accompanied with an increase of integrin β3. Spironolactone inhibited cell motility and stabilized podoctyes treated with HG, probably through partly normalizing the expression of integrin β1 and decreasing the expression of integrin β3.
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http://dx.doi.org/10.3892/mmr.2015.4295DOI Listing
November 2015

Utility of SAM68 in the progression and prognosis for bladder cancer.

BMC Cancer 2015 May 6;15:364. Epub 2015 May 6.

State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Background: Muscle invasive bladder cancer (MIBC) is often lethal and non-MIBC (NMIBC) can recur and progress, yet prognostic markers are currently inadequate. SAM68, a member of RNA-binding proteins, has been reported to contribute to progression of other cancers. The aim of this study is to investigate the potential utility of SAM68 in the progression and prognosis of bladder cancer.

Methods: Quantitative PCR and immunohistochemistry were utilized to examine the expression of SAM68 in ten pairs of MIBC and adjacent normal bladder urothelium, and eight pairs of MIBC and non-MIBC (NMIBC) tissues from the same patient. Moreover, SAM68 protein expression level and localization were examined by immunohistochemistry in 129 clinicopathologically characterized MIBC samples. Prognostic associations were determined by multivariable analysis incorporating standard prognostic factors.

Results: SAM68 expression was elevated in MIBC tissues compared with adjacent normal bladder urothelium, and was increased at both transcriptional and translational levels in MIBC tissues compared with NMIBC tissues of the same patient. For MIBC, high expression and nucleus-cytoplasm co-expression of SAM68 were associated with higher T-stage, higher N-stage and worse recurrence-free survival. Five-year recurrence-free survival was 80% and 52.9% for MIBC patients with low and high SAM68 expression, respectively (p = 0.001). SAM68 nucleus-cytoplasm co-expression associated with worse 5-year recurrence-free survival rate (49.2%) than SAM68 expression confined to the nucleus (82.5%) or cytoplasm (75.5%) alone. On multivariable analysis SAM68 expression level, SAM68 nucleus-cytoplasm co-expression, T-stage, and N-stage were all independent prognostic factors for recurrence-free survival of MIBC patients.

Conclusions: SAM68 expression is increased in MIBC when compared to normal urothelium and NMIBC, and appears to be a potentially useful prognostic marker for MIBC.
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http://dx.doi.org/10.1186/s12885-015-1367-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425873PMC
May 2015

Necroptosis, a novel form of caspase-independent cell death, contributes to renal epithelial cell damage in an ATP-depleted renal ischemia model.

Mol Med Rep 2014 Aug 13;10(2):719-24. Epub 2014 May 13.

Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.

Acute kidney injury (AKI) induced by renal ischemia is a common clinical problem associated with a high morbidity and mortality. The present study investigated whether necroptosis was present in an in vitro renal ischemia model and whether the addition of necrostatin-1 (Nec-1) has a protective effect. In addition, whether autophagy was inhibited following the use of Nec-1 was also examined. When apoptosis was inhibited by z-VAD‑fmk and energy was depleted with antimycin A for 1 h, the morphological abnormalities of human proximal tubular epithelial (HK-2) cells were markedly attenuated, and the cell viability was significantly improved following incubation with Nec-1. LC3-II/I ratios and LC3-II/GAPDH ratios demonstrated a statistically significant decrease in the Nec-1 + tumor necrosis factor (TNF)-α + z-VAD-fmk + antimycin A (1 h) group compared with the control group. In conclusion, the present study suggested that necroptosis was present in HK-2 cells subjected to TNF-α stimulation and energy depletion. Nec-1 inhibits a caspase‑independent necroptotic pathway involving autophagy and may have therapeutic potential to prevent and treat renal ischemic injury.
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http://dx.doi.org/10.3892/mmr.2014.2234DOI Listing
August 2014

Mechanisms of vitamin D₃ metabolite repression of IgE-dependent mast cell activation.

J Allergy Clin Immunol 2014 May 22;133(5):1356-64, 1364.e1-14. Epub 2014 Jan 22.

Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia; University of South Australia, Adelaide, Australia. Electronic address:

Background: Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo.

Objective: We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2D3 can repress IgE-dependent mast cell activation through mast cell-25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell-VDR activity.

Methods: We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of PCA responses in WBB6F1-Kit(W/W-v) or C57BL/6J-Kit(W-sh/W-sh) mice engrafted with mast cells that did or did not express VDR or CYP27B1.

Results: Here we show that mouse and human mast cells can convert 25OHD3 to 1α,25(OH)2D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D3 metabolites significantly reduced the magnitude of skin swelling associated with IgE-mediated PCA reactions in vivo; a response that required functional mast cell-VDRs and mast cell-CYP27B1.

Conclusion: Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.
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http://dx.doi.org/10.1016/j.jaci.2013.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154631PMC
May 2014

Pharmacokinetics of moxifloxacin in critically ill patients with impaired renal function undergoing pulse high-volume haemofiltration.

Int J Antimicrob Agents 2013 Sep 20;42(3):244-9. Epub 2013 Jul 20.

Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou 510080, China.

Moxifloxacin is an 8-methoxy quinolone with a broad spectrum of activity against clinically important pathogens. The aim of this study was to investigate the pharmacokinetics of intravenous (i.v.) moxifloxacin in critically ill patients with impaired renal function undergoing pulse high-volume haemofiltration (PHVHF) (n=8) to provide a reference for clinical rational moxifloxacin use in these patients. Blood and ultrafiltrate samples were obtained following i.v. infusion of a single 400 mg moxifloxacin dose. Concentrations of moxifloxacin in serum and ultrafiltrate were determined by HPLC analysis with fluorometric detection. Pharmacokinetics of moxifloxacin in plasma and ultrafiltrate were best described by a two-compartment model. Peak and trough serum moxifloxacin concentrations were 4.84 ± 1.85 mg/L and 1.17 ± 0.73 mg/L, respectively, at the arterial port after a single i.v. 400 mg dose. The mean elimination half-life was 4.82 ± 2.13 h, the volume of distribution was 82.63 ± 24.69 L and the calculated AUC(0-12) was 26.91 ± 10.96 mgh/L. Total clearance was 14.36 ± 8.44 L/h and the clearance of haemofiltration was 1.67 ± 0.95 L/h.C(max)/MIC(90) ratios and predicted AUC(0-24)/MIC(90) ratios were above the cut-off points for common pathogens that indicate clinical success. A single 400 mg i.v. dose of moxifloxacin is safe and efficacious in the treatment of critically ill patients infected with clinically common pathogens and impaired renal function undergoing PHVHF. It also should be kept in mind that the standard dose is not sufficient for this population infected with pathogens with a higher MIC(90) (0.5 mg/L).
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http://dx.doi.org/10.1016/j.ijantimicag.2013.06.007DOI Listing
September 2013

NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice.

Br J Pharmacol 2013 Sep;170(2):426-39

Southern Medical University, Guangzhou, China; Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Background And Purpose: Podocyte injury plays a key role in the development of diabetic nephropathy (DN). We have recently shown that 11R-VIVIT, an inhibitor of cell-permeable nuclear factor of activated T-cells (NFAT), attenuates podocyte apoptosis induced by high glucose in vitro. However, it is not known whether 11R-VIVIT has a protective effect on DN, especially podocyte injury, under in vivo diabetic conditions. Hence, we examined the renoprotective effects of 11R-VIVIT in diabetic db/db mice and the possible mechanisms underlying its protective effects on podocyte injury in vivo and in vitro.

Experimental Approach: Type 2 diabetic db/db mice received i.p. injections of 11R-VIVIT (1 mg·kg(-1)) three times a week and were killed after 8 weeks. Immortalized mouse podocytes were cultured under different experimental conditions.

Key Results: 11R-VIVIT treatment markedly attenuated the albuminuria in diabetic db/db mice and also alleviated mesangial matrix expansion and podocyte injury. However, body weight, food and water intake, and glucose levels were unaffected. It also attenuated the increased NFAT2 activation and enhanced urokinase-type plasminogen activator receptor (uPA receptor) expression in glomerulor podocytes. In cultured podocytes, the increased nuclear accumulation of NFAT2 and uPA receptor expression induced by high glucose treatment was prevented by 11R-VIVIT or NFAT2-knockdown; this was accompanied by improvements in the filtration barrier function of the podocyte monolayer.

Conclusions And Implications: The NFAT inhibitor 11R-VIVIT might be a useful therapeutic strategy for protecting podocytes and treating DN. The calcinerin/NFAT2/uPA receptor signalling pathway should be exploited as a therapeutic target for protecting podocytes from injury in DN.
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http://dx.doi.org/10.1111/bph.12292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834765PMC
September 2013

1,25-dihydroxyvitamin D(3) inhibits podocyte uPAR expression and reduces proteinuria.

PLoS One 2013 31;8(5):e64912. Epub 2013 May 31.

Southern Medical University, Guangzhou, China.

Background: Accumulating studies have demonstrated that 1,25-Dihydroxyvitamin D(3) (1,25(OH)2D3) reduces proteinuria and protects podocytes from injury. Recently, urokinase receptor (uPAR) and its soluble form have been shown to cause podocyte injury and focal segmental glomerulosclerosis (FSGS). Here, our findings showed that 1,25(OH)2D3 did inhibit podocyte uPAR expression and attenuate proteinuria and podocyte injury.

Methodology/principal Findings: In this study, the antiproteinuric effect of 1,25(OH)2D3 was examined in the lipopolysaccharide mice model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model(NTX rats). uPAR protein expression were tested by flow cytometry, immune cytochemistry and western blot analysis, and uPAR mRNA expression by real-time quantitative PCR in cultured podocytes and kidney glomeruli isolated from mice and rats. Podocyte motility was observed by transwell migration assay and wound healing assay. Podocyte foot processes effacement was identified by transmission electron microscopy. We found that 1,25(OH)2D3 inhibited podocyte uPAR mRNA and protein synthesis in LPS-treated podocytes, LPS mice and NTX rats, along with 1,25(OH)2D3 reducing proteinuria in NTX rats and LPS mice.1,25(OH)2D3 reduced glomerulosclerosis in NTX rats and alleviated podocyte foot processes effacement in LPS mice. Transwell migration assay and wound healing assay showed that LPS-induced podocyte motility, irrespective of random or directed motility, were substantially reduced by 1,25(OH)2D3.

Conclusions/significance: Our results demonstrated that 1,25(OH)2D3 inhibited podocyte uPAR expression in vitro and in vivo, which may be an unanticipated off target effect of 1,25(OH)2D3 and explain its antiproteinuric effect in the 5/6 nephrectomy rat FSGS model and the LPS mouse model of transient proteinuria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064912PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669128PMC
January 2014

miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1.

J Pathol 2012 Aug 23;227(4):470-80. Epub 2012 May 23.

Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.

SPHK1 expression is elevated in gastric cancer and is associated with shorter survival times for patients. However, the molecular mechanism of SPHK1 up-regulation in gastric cancer remains unclear. In the present study, we report that miR-124 down-regulated SPHK1 expression by directly targeting its 3'-untranslated region (3'-UTR) and that miR-124 expression was inversely correlated with SPHK1 expression in gastric cancer samples. Furthermore, we demonstrated that, similar to the effect of silencing SPHK1, up-regulation of miR-124 markedly inhibited proliferation and tumourigenicity of gastric cancer cells both in vitro and in vivo. This was found to be mechanistically associated with induction of cyclin-dependent kinase inhibitors p21$^{{\rm Cip1}}$ and p27$^{{\rm Kip1}}$, enhancement of the transcriptional activity of FOXO1 and suppression of AKT activity. Moreover, we showed that the re-introduction of SPHK1 (without the 3'-UTR), but not with the 3'-UTR, could abrogate the miR-124-mediated induction of p21$^{{\rm Cip1}}$ and p27$^{{\rm Kip1}}$, as well as rescue the miR-124-induced proliferation inhibition. Together, these results suggest that miR-124 has an important role in the suppression of gastric cancer and presents a novel mechanism of miRNA-mediated SPHK1 expression in cancer cells.
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http://dx.doi.org/10.1002/path.4030DOI Listing
August 2012

The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway.

Carcinogenesis 2012 Mar 4;33(3):678-86. Epub 2012 Jan 4.

State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

Invasive bladder cancer is a lethal disease for which effective prognostic markers as well as potential therapy targets are still lacking. Nkx2.8 (Nk2 homeobox 8), a novel member of the NK-2 gene family, was reported to play an important role in the development and progression of human cancer. Herein, we reported that Nkx2.8 was markedly reduced in bladder cancer tissues compared with matched adjacent normal urothelial tissues. Nkx2.8 levels were inversely correlated with advanced T classification, N classification, tumor multiplicity, high proliferation index (Ki-67) and poor survival of patients. Furthermore, we found that overexpression of Nkx2.8 in bladder cancer cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing Nkx2.8 dramatically enhanced cell proliferation. Moreover, we demonstrated that overexpression of Nkx2.8 resulted in G(1)/S phase arrest, accompanied by upregulation of p27(Kip1), downregulation of cyclin D1 and p-FOXO3a and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G(1)/S transition, downregulation of p27(Kip1), upregulation of cyclin D1 and p-FOXO3a and increase of MEK/ERK pathway activity. These findings suggest that Nkx2.8 plays a potential tumor suppressor role in bladder cancer progression and represents a valuable clinical prognostic marker of this disease.
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http://dx.doi.org/10.1093/carcin/bgr321DOI Listing
March 2012

Knockdown of stomatin-like protein 2 (STOML2) reduces the invasive ability of glioma cells through inhibition of the NF-κB/MMP-9 pathway.

J Pathol 2012 Feb 5;226(3):534-43. Epub 2011 Dec 5.

State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.

Stomatin-like protein 2 (STOML2), a member of the stomatin family, has been reported to be up-regulated in several types of human cancers. The clinical significance and biological role of STOML2 in gliomas remain largely unknown. Here, we describe the significantly up-regulated expression of STOML2 in glioma cell lines and glioma tissues at both the transcriptional and translational levels. Silencing endogenous STOML2 in glioma cells and primary glioma cells drastically reduced their migratory speed and invasive ability, associated with induction of matrix metallopeptidase 9 (MMP-9). We also demonstrated that knockdown of STOML2 significantly inhibited the transcriptional activity of NF-κB and repressed the expression levels of NF-κB target genes, including MMP-9. A luciferase reporter assay revealed that the impact of STOML2 on MMP-9 expression is NF-κB-dependent. Immunohistochemical analysis showed that the up-regulation of STOML2 was significantly correlated with the WHO histological grade of gliomas (p < 0.001). Patients with higher STOML2 expression levels had an overall shorter survival time, whereas patients with lower expression of STOML2 had a longer survival time. A multivariate analysis revealed that STOML2 expression might be an independent prognostic indicator for the survival of glioma patients. Taken together, our results suggest that overexpression of STOML2 is associated with glioma aggressiveness and may represent an independent prognostic factor for the outcome of glioma patients.
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http://dx.doi.org/10.1002/path.3008DOI Listing
February 2012

Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a.

Clin Cancer Res 2011 May 29;17(10):3089-99. Epub 2011 Mar 29.

State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Zhongshan School of Medicine, Guangzhou, Guangdong, China.

Purpose: Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotinllin-1 (FLOT1), a marker of lipid rafts, is involved in the progression of cancer, but the precise mechanism remains unclear. The aim of the present study was to examine the role of FLOT1 on the tumorigenesis of breast cancer cells and its clinical significance in progression of the disease.

Experimental Design: FLOT1 expression was analyzed in 212 paraffin-embedded, archived clinical breast cancer samples by using immunohistochemistry (IHC). The effect of FLOT1 on cell proliferation and tumorigenesis was examined in vitro and in vivo. Western blotting and luciferase reporter analyses were carried out to identify the effects of downregulating FLOT1 on expression of cell cycle regulators and transcriptional activity of FOXO3a.

Results: IHC analysis revealed high expression of FLOT1 in 129 of the 212 (60.8%) paraffin-embedded archived breast cancer specimens. The overall expression level of FLOT1 significantly correlated with clinical staging and poor patient survival of breast cancer. Strikingly, we found that silencing FLOT1 inhibited proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo, which was further shown to be mechanistically associated with suppression of Akt activity, enhanced transcriptional activity of FOXO3a, upregulation of cyclin-dependent kinase inhibitor p21(Cip1) and p27(Kip1), and downregulation of the CDK regulator cyclin D1.

Conclusions: FLOT1 plays an important role in promoting proliferation and tumorigenesis of human breast cancer and may represent a novel prognostic biomarker and therapeutic target for the disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3068DOI Listing
May 2011

Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a.

PLoS One 2010 Dec 23;5(12):e15797. Epub 2010 Dec 23.

State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, China.

FOXO transcription factors are key tumor suppressors in mammalian cells. Until now, suppression of FOXOs in cancer cells was thought to be mainly due to activation of multiple onco-kinases by a phosphorylation-ubiquitylation-mediated cascade. Therefore, it was speculated that inhibition of FOXO proteins would naturally occur through a multiple step post-translational process. However, whether cancer cells may downregulate FOXO protein via an alternative regulatory mechanism is unclear. In the current study, we report that expression of miR-96 was markedly upregulated in breast cancer cells and breast cancer tissues compared with normal breast epithelial cells (NBEC) and normal breast tissues. Ectopic expression of miR-96 induced the proliferation and anchorage-independent growth of breast cancer cells, while inhibition of miR-96 reduced this effect. Furthermore, upregulation of miR-96 in breast cancer cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-96 downregulated FOXO3a expression by directly targeting the FOXO3a 3'-untranslated region. Taken together, our results suggest that miR-96 may play an important role in promoting proliferation of human breast cancer cells and present a novel mechanism of miRNA-mediated direct suppression of FOXO3a expression in cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009749PMC
December 2010

Vitamin D(3) signalling to mast cells: A new regulatory axis.

Int J Biochem Cell Biol 2011 Jan 23;43(1):41-6. Epub 2010 Oct 23.

Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, South Australia, Australia.

Excessive sun exposure or high acute doses of ultraviolet (UV)-B radiation promote cutaneous inflammation and genetic mutations, both of which can ultimately contribute to skin carcinogenesis. A major mediator synthesized in the epidermis in response to UVB irradiation is the secosteroid hormone vitamin D(3), and as such, considerable attention is now turning to the many physiologic processes that it regulates. Recent studies have uncovered an immunoregulatory interaction between vitamin D(3) and dermal mast cells for optimal protection against pathogenic outcomes associated with chronic UVB irradiation of the skin. Most biological effects of vitamin D(3), such as the regulation of transcription in target genes, occur when it binds to its nuclear receptor; however, some actions can also occur via a non-genomic signalling pathway. This review will focus on the relative importance of both pathways in the regulation of vitamin D(3)-mediated UVB protection and will highlight exciting recent findings that point to new research directions.
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http://dx.doi.org/10.1016/j.biocel.2010.10.011DOI Listing
January 2011

miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-β.

Biochem Biophys Res Commun 2010 Nov 8;402(1):135-40. Epub 2010 Oct 8.

State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.

Aberrant activation of nuclear factor-kappa B (NF-κB) pathway has been proven to play important roles in the development and progression of cancers. Activation of NF-κB via the classical pathway is modulated by IκBs kinase (IKK-β). However, the mechanism underlying the epigenetic regulation of IKK-β/NF-κB pathway remains largely unknown. In this study, we found that the expression level of miR-218 was markedly downregulated in glioma cell lines and in human primary glioma tissues. Upregulation of miR-218 dramatically reduced the migratory speed and invasive ability of glioma cells. Furthermore, we showed that ectopically expressing miR-218 in glioma cells resulted in downregulation of matrix metalloproteinase-9 (MMP-9) and reduction in NF-κB transactivity at a transcriptional level, but inhibition of miR-218 enhanced the expression of MMP-9 and transcriptional activity of NF-κB. Moreover, we showed that miR-218 inactivated the NF-κB pathway through downregulating IKK-β expression by directly targeting the 3'-untranslated region (3'-UTR) of IKK-β. Taken together, our results suggest that miR-218 plays an important role in preventing the invasiveness of glioma cells, and our results present a novel mechanism of miRNA-mediated direct suppression of IKK-β/NF-κB pathway in gliomas.
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http://dx.doi.org/10.1016/j.bbrc.2010.10.003DOI Listing
November 2010

Evidence that vitamin D(3) promotes mast cell-dependent reduction of chronic UVB-induced skin pathology in mice.

J Exp Med 2010 Mar 1;207(3):455-63. Epub 2010 Mar 1.

Division of Human Immunology, Centre for Cancer Biology, South Australia, Australia.

Mast cell production of interleukin-10 (IL-10) can limit the skin pathology induced by chronic low-dose ultraviolet (UV)-B irradiation. Although the mechanism that promotes mast cell IL-10 production in this setting is unknown, exposure of the skin to UVB irradiation induces increased production of the immune modifying agent 1alpha,25-dihydroxyvitamin D(3) (1alpha,25[OH](2)D(3)). We now show that 1alpha,25(OH)(2)D(3) can up-regulate IL-10 mRNA expression and induce IL-10 secretion in mouse mast cells in vitro. To investigate the roles of 1alpha,25(OH)(2)D(3) and mast cell vitamin D receptor (VDR) expression in chronically UVB-irradiated skin in vivo, we engrafted the skin of genetically mast cell-deficient WBB6F(1)-Kit(W/W-v) mice with bone marrow-derived cultured mast cells derived from C57BL/6 wild-type or VDR(-/-) mice. Optimal mast cell-dependent suppression of the inflammation, local production of proinflammatory cytokines, epidermal hyperplasia, and epidermal ulceration associated with chronic UVB irradiation of the skin in Kit(W/W-v) mice required expression of VDR by the adoptively transferred mast cells. Our findings suggest that 1alpha,25(OH)(2)D(3)/VDR-dependent induction of IL-10 production by cutaneous mast cells can contribute to the mast cell's ability to suppress inflammation and skin pathology at sites of chronic UVB irradiation.
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http://dx.doi.org/10.1084/jem.20091725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839149PMC
March 2010

Expression and cytoplasmic localization of SAM68 is a significant and independent prognostic marker for renal cell carcinoma.

Cancer Epidemiol Biomarkers Prev 2009 Oct 15;18(10):2685-93. Epub 2009 Sep 15.

State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Cancer Center, Zhongshan School of Medicine, Guangzhou 510060, PR China.

Purpose: This retrospective study aimed to examine the expression and localization of SAM68 (Src-associated in mitosis, 68 kDa) in a larger cohort of surgical specimens of renal cell carcinoma and their correlation with the progression of human renal cell carcinoma.

Experimental Design: The protein and mRNA expression levels of SAM68 in normal renal tubular epithelial cells, renal cell carcinoma cell lines, as well as nine pairs of renal cell carcinoma and matched tumor-adjacent renal tissues were examined using reverse transcription-PCR and Western blot. Moreover, SAM68 protein expression and localization in 241 clinicopathologically characterized renal cell carcinoma samples were examined by immunohistochemistry. Prognostic and diagnostic associations were examined by statistical analyses.

Results: SAM68 was markedly overexpressed in renal cell carcinoma cell lines and renal cell carcinoma tissues at both the transcriptional and translational levels. Immunohistochemical analysis revealed high SAM68 protein expression in 129 of the 241 (53.5%) paraffin-embedded archival renal cell carcinoma specimens. Moreover, there was a significant correlation between SAM68 expression and pathologic stage (P < 0.001), T classification (P = 0.003), N classification (P = 0.001), M classification (P = 0.006), and Fuhrman grade (P < 0.001). Patients with higher SAM68 expression had shorter overall survival time than patients with lower SAM68 expression, and the cytoplasmic localization of SAM68 significantly correlated with clinicopathologic grade and outcome. Multivariate analysis indicated that SAM68 protein overexpression and cytoplasmic localization were independent predictors for poor survival of renal cell carcinoma patients.

Conclusions: Our results suggest that SAM68 could represent a novel and useful prognostic marker for renal cell carcinoma. High SAM68 expression and cytoplasmic localization are associated with poor overall survival in renal cell carcinoma patients.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0097DOI Listing
October 2009

Over-expression of AEG-1 significantly associates with tumour aggressiveness and poor prognosis in human non-small cell lung cancer.

J Pathol 2009 Nov;219(3):317-26

State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong 510060, People's Republic of China.

Astrocyte elevated gene 1 (AEG-1), a novel oncoprotein, has been implicated in oncogenesis and cancer progression in various types of human cancers. The clinical significance and biological role of AEG-1 in non-small cell lung cancer (NSCLC), however, remain unclear. In the present study, we found that the expression of AEG-1 was markedly up-regulated in NSCLC cell lines and NSCLC tissues at the level of both transcription and translation. Ectopically expressed AEG-1 enhanced the migratory and invasive abilities of NSCLC cells, whereas knockdown of endogenous AEG-1 by specific shRNAs significantly inhibited these abilities. The function of AEG-1 on metastasis modulation was associated with the activation of the PI3K-Akt and NF-kappaB signalling pathways. Furthermore, we showed high expression of AEG-1 in 99/200 (49.5%) paraffin-embedded archival NSCLC specimens. Moreover, statistical analysis displayed a significant correlation in AEG-1 expression with the clinical stage (p < 0.001), T classification (p = 0.001), N classification (p = 0.015), distant metastasis (p = 0.004) and differentiation (p = 0.027). Patients with higher AEG-1 expression had an overall shorter survival time, whereas patients with lower expression of AEG-1 had a better survival time. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of NSCLC patients. Taken together, our results suggest that elevated expression of AEG-1 plays an important role in the aggressiveness of NSCLC, leading to a poor clinical outcome.
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http://dx.doi.org/10.1002/path.2595DOI Listing
November 2009

Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis.

Carcinogenesis 2009 May 20;30(5):894-901. Epub 2009 Mar 20.

State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, People's Republic of China.

Astrocyte elevated gene-1 (AEG-1), upregulated in various types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the functional significance of AEG-1 in human esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we showed the expression of AEG-1 was markedly upregulated in esophageal cancer cell lines and surgical ESCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 80 of 168 (47.6%) paraffin-embedded archival ESCC specimens exhibited high levels of AEG-1 expression. Statistical analysis suggested the upregulation of AEG-1 was significantly correlated with the clinical staging of the ESCC patients (P = 0.001), T classification (P = 0.002), N classification (P = 0.034), M classification (P = 0.021) and histological differentiation (P = 0.035) and those patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression might be an independent prognostic indicator of the survival of patients with ESCC. Furthermore, we found that ectopic expression of AEG-1 in ESCC cells could significantly enhance cell proliferation and anchorage-independent growth ability. Conversely, silencing AEG-1 by short hairpin RNAi caused an inhibition of cell growth and anchorage-independent growth ability on soft agar. Moreover, we demonstrated that the upregulation of AEG-1 could reduce the expression of p27(Kip1) and induce the expression of cyclin D1 through the AKT/FOXO3a pathway. Our findings suggest that the AEG-1 protein is a valuable marker of ESCC progression and that the upregulation of AEG-1 plays an important role in the development and pathogenesis of human ESCC.
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http://dx.doi.org/10.1093/carcin/bgp064DOI Listing
May 2009

Expression of a B-cell-restricted isoform of CD45 is associated with maturity in rat serosal and connective-tissue mast cells.

Immunology 2008 Dec;125(4):558-69

Institute for Medical Microbiology, Technische Universität München, Munich, Germany.

Fas-associated protein with death domain/mediator of receptor induced toxicity (FADD/MORT1) was first described as a transducer of death receptor signalling but was later recognized also to be important for proliferation of T cells. B-cell lymphoma 3 (Bcl-3) is a relatively little understood member of the nuclear factor (NF)-kappaB family of transcription factors. We recently found that Bcl-3 is up-regulated in T cells from mice where FADD function is blocked by a dominant negative transgene (FADD-DN). To understand the importance of this, we generated FADD-DN/bcl-3(-/-) mice. Here, we report that T cells from these mice show massive cell death and severely reduced proliferation in response to T-cell receptor (TCR) stimulation in vitro. Transgenic coexpression of Bcl-2 (FADD-DN/bcl-3(-/-)/vav-bcl-2 mice) rescued the survival but not the proliferation of T cells. FADD-DN/bcl-3(-/-) mice had normal thymocyte numbers but reduced numbers of peripheral T cells despite an increase in cycling T cells in vivo. However, activation of the classical NF-kappaB and extracellular regulated kinase (ERK) pathways and expression of interleukin (IL)-2 mRNA upon stimulation were normal in T cells from FADD-DN/bcl-3(-/-) mice. These data suggest that FADD and Bcl-3 regulate separate pathways that both contribute to survival and proliferation in mouse T cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612556PMC
http://dx.doi.org/10.1111/j.1365-2567.2008.02930.xDOI Listing
December 2008