Peng Huang

Sun Yat-Sen University of Medical Sciences, Shengcheng, Guangdong, China

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Publications (94)684.63 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionTriple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. TNBC is not amenable to endocrine therapy and often exhibit resistance to current chemotherapeutic agents, therefore, further understanding of the biological properties of these cancer cells and development of effective therapeutic approaches are urgently needed.Methods We first investigated the metabolic alterations in TNBC cells in comparison with other subtypes of breast cancer cells using molecular and metabolic analyses. We further demonstrated that targeting these alterations using specific inhibitors and siRNA approach could render TNBC cells more sensitive to cell death compared to other breast cancer subtypes.ResultsWe found that TNBC cells compared to estrogen receptor (ER) positive cells possess special metabolic characteristics manifested by high glucose uptake, increased lactate production, and low mitochondrial respiration which is correlated with attenuation of mTOR pathway and decreased expression of p70S6K. Re-expression of p70S6K in TNBC cells reverses their glycolytic phenotype to an active oxidative phosphorylation (OXPHOS) state, while knockdown of p70S6K in ER positive cells leads to suppression of mitochondrial OXPHOS. Furthermore, lower OXPHOS activity in TNBC cells renders them highly dependent on glycolysis and the inhibition of glycolysis is highly effective in targeting TNBC cells despite their resistance to other anticancer agents.Conclusions Our study shows that TNBC cells have profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis. Due to their impaired mitochondrial function, TNBC cells are highly sensitive to glycolytic inhibition, suggesting that such metabolic intervention may be an effective therapeutic strategy for this subtype of breast cancer cells.
    Breast cancer research: BCR 09/2014; 16(5):434. · 5.87 Impact Factor
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    ABSTRACT: Linear diaryliodonium salts are widely used as arylating reagents for C-C and C-X bond formation. Meanwhile, synthetic applications of cyclic iodoniums are relatively rare although they offer the opportunity to set up reaction cascades. We demonstrate an atom and step economical three-component reaction involving cyclic diphenyleneiodoniums, alkynes, and boronic acids, resulting in the construction of methylidenefluorenes in a single operation. Our route enables facile access to both symmetrical and unsymmetrical methylidenefluorene derivatives, compounds that have attracted interest due to their optical properties.
    Organic Letters 04/2014; · 6.14 Impact Factor
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    ABSTRACT: The purpose of this study is to identify miRNAs involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of 8 miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative RT-PCR analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR-214 was validated to be significantly down-regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR-214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model; whereas miR-214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR-214. Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 mRNA and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells. Moreover, miR-214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR-214 may serve as a potential marker to predict survival, and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;).
    Hepatology 03/2014; · 12.00 Impact Factor
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    ABSTRACT: Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemo-immunotherapy, but relapses to treatment-refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing FDA-approved small molecule drug to repurpose for CLL treatment. Auranofin (AF) (Ridaura®) is approved for use in treating rheumatoid arthritis but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular ROS levels, AF induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. Additionally, AF displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. AF overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, AF treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug Auranofin for clinical evaluation in the therapy of CLL.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC). We used quantitative real-time PCR and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and non-tumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and HIF1α. We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines, and growth of ESCC xenograft tumors in nude mice. Levels of eIF5A2 mRNA and protein were increased in over 40% of ESCC samples, compared with matched non-tumor tissues, along with levels of HIF1α and VEGF. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P<.001) and tissue invasion (P=.037), and shorter survival times of patients (P<.001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, whereas eIF5A2 knockdown or HIF1α inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and VEGF, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin. eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with upregulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases matastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway.
    Gastroenterology 02/2014; · 12.82 Impact Factor
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    ABSTRACT: Carbazole (IIIc) shows an outstanding ability to protect HT-22 neuronal cells from the damage induced by neurotoxins glutamate and homocysteic acid.
    ChemInform 01/2014; 45(4).
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    ABSTRACT: Activation of K-ras and inactivation of p16 are the most frequently identified genetic alterations in human pancreatic epithelial adenocarcinoma (PDAC). Mouse models engineered with mutant K-ras and deleted p16 recapitulate key pathological features of PDAC. However, a human cell culture transformation model that recapitulates the human pancreatic molecular carcinogenesis is lacking. In this study, we investigated the role of p16 in hTERT-immortalized human pancreatic epithelial nestin-expressing (HPNE) cells expressing mutant K-ras (K-rasG12V). We found that expression of p16 was induced by oncogenic K-ras in these HPNE cells and that silencing of this induced p16 expression resulted in tumorigenic transformation and development of metastatic PDAC in an orthotopic xenograft mouse model. Our results revealed that PI3K/Akt, ERK1/2 pathways and TGFα signaling were activated by K-ras and involved in the malignant transformation of human pancreatic cells. Also, p38/MAPK pathway was involved in p16 up-regulation. Thus, our findings establish an experimental cell-based model for dissecting signaling pathways in the development of human PDAC. This model provides an important tool for studying the molecular basis of PDAC development and gaining insight into signaling mechanisms and potential new therapeutic targets for altered oncogenic signaling pathways in PDAC.
    PLoS ONE 01/2014; 9(7):e101452. · 3.73 Impact Factor
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    ABSTRACT: N-Acyl-N,O-acetals are present in a number of bioactive natural products, and this unusual functional group can act as a synthetic precursor to unstable reactive N-acylimines. In this paper, a variety of N-acyl-O-ethyl-N,O-acetals was concisely prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)4). The method also offers a new strategy to make other O-alkyl-N,O-acetals. Furthermore, this strategy was extended to the synthesis of an analogue of the natural product turtschamide.
    Organic Letters 12/2013; · 6.14 Impact Factor
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    ABSTRACT: The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer (CRC). Three CRC cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of CRC cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of CRC cells to oxaliplatin. Flow cytometry was used to examine changes in the cell cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived CRC tumors from patients treated with oxaliplatin-based regimens. Bmal1 overexpression inhibited CRC cell proliferation and increased CRC sensitivity to oxaliplatin in three CRC cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of CRC patients with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; p=0.043). The progression free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; p=0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2/M arrest by activating the ATM pathway. Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in CRC.
    Clinical Cancer Research 11/2013; · 7.84 Impact Factor
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    ABSTRACT: Elevated aerobic glycolysis in cancer cells (Warburg effect) has been observed in many tumor types including nasopharyngeal carcinoma (NPC), which can often be detected clinically using FDG-PET. However, the role of glycolysis in supporting the growth of NPC cells and its therapeutic implications still remain to be investigated. In the present study, we showed that the LDH inhibitor oxamate significantly suppressed NPC cell proliferation in vitro and tumor growth in vivo, yet exhibited minimum toxicity to normal nasopharyngeal epithelial cells in vitro and was well tolerated in mice. Moreover, oxamate exhibited cytotoxic effect in NPC cells under hypoxia. Mechanistic study showed that oxamate significantly inhibited LDH activity, leading to a substantial decrease in glucose uptake and lactate production. Combination of oxamate with a mitochondrial respiratory complex I inhibitor resulted in a significant depletion of cellular ATP and a synergistic killing of cancer cells. Our results suggest that inhibition of glycolysis by oxamate is an effective therapeutic strategy for treatment of NPC and that combination of this compound with mitochondrial-targeted agents may improve the therapeutic activity.
    International Journal of Oncology 08/2013; · 2.66 Impact Factor
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    ABSTRACT: Carbazole moiety is an important scaffold with a variety of biological applications, for example, anti-oxidative stress. Our previous synthesized carbazoles were screened for their neuroprotective properties against two individual oxidative stresses. Some of the new carbazole derivatives were observed with modest to good neuroprotective effects on neuronal cells HT22 against cell injury induced by glutamate or homocysteic acid (HCA). Substituents introduced to the carbazole ring system play crucial roles in their biological activities. In particular, a bulky group favors the neuroprotective activity of the compounds. One of the new compounds, 6, showed the best neuroprotective effects, which might result from its anti-oxidative activity with a GSH-independent mechanism. These findings might provide an alternative strategy for the development of novel carbazole derivatives for the treatment of CNS diseases such as Alzheimer's disease.
    European journal of medicinal chemistry 08/2013; 68C:81-88. · 3.27 Impact Factor
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    ABSTRACT: Alterations in energy metabolism play a major role in cancer development. Aconitase (ACO2) is an essential enzyme located in the mitochondria and catalyzes the interconversion of citrate and isocitrate in the tricarboxylic acid cycle. Recent studies suggest that the expression of ACO2 may be altered in certain types of cancer. The purpose of this study was to examine ACO2 expression in clinical tumor specimens from patients with gastric cancer and to evaluate the clinical relevance of ACO2 expression in gastric cancer. A total of 456 paraffin-embedded gastric cancer tissues and 30 pairs of freshly frozen tissues were used in this study. Real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemical staining were performed to measure ACO2 expression in tumor tissues and matched adjacent non-tumorous tissues. The results showed that the expression of ACO2 was significantly down-regulated in gastric cancer tissues compared with matched adjacent nontumorous tissues and was associated with clinical stage (p = 0.001), T classification (p = 0.027), N classification (p = 0.012), M classification (p = 0.002), and pathological differentiation states (p = 0.036). Patients with lower ACO2 expression had a shorter survival time than those with higher ACO2 expression. Univariate and multivariate analyses indicated that ACO2 expression functions as an independent prognostic factor (p < 0.001). Our data suggested that ACO2 could play an important role in gastric cancer and may potentially serve as a prognostic biomarker.
    Medical Oncology 06/2013; 30(2):552. · 2.14 Impact Factor
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    ABSTRACT: Cancer has long been considered a disease that mimics an "unhealed wound," with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α), IL-6, IL-1β, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.
    Neoplasia (New York, N.Y.) 04/2013; 15(4):409-20. · 5.48 Impact Factor
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    ABSTRACT: By design: A truncated superstolide A, a simplified analogue of the potent anticancer marine macrolide superstolide A, was designed and successfully synthesized by a highly efficient and convergent approach. The biological evaluation showed that this compound maintains the potent anticancer activity of the original natural product superstolide A.
    Angewandte Chemie International Edition 02/2013; · 11.34 Impact Factor
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    ABSTRACT: Tumor microenvironment plays a major role in cancer development. Understanding how the stroma affects epithelial transformation will provide a basis for new preventive strategies. Recent evidences suggest that oxidative stress in stroma may play a role in cancer progression and loss of p53 function in the stromal cells were associated with poor prognosis and high tumor recurrence. However, the underlying mechanisms remain poorly understood. Here, we investigated the role of p53 loss in fibroblasts on epithelial transformation and the mechanistic involvement of reactive species. Using 3D-organotypic culture and other assays, we report that the stroma containing p53-deficient fibroblasts could transform the non-tumorigenic epithelial cells of oral and ovarian tissues origins to become invasive through reactive nitrogen species (RNS)-mediated release of cytokine ICAM1. The p53-deficient fibroblasts have increased RNS production and accumulation of oxidative DNA damage products associated with specific up-regulation of endothelial nitric oxide synthase (eNOS). Suppression of RNS production by siRNA of eNOS or antioxidant NAC reduced ICAM1 expression and prevented the stroma-mediated epithelial invasion. Our study uncovers the novel mechanism by which redox alteration associated with loss of p53 in stromal fibroblasts function as a key inducer of epithelial transformation and invasion via RNS-mediated-ICAM1 signaling. Thus, modulation of the redox signaling in microenvironment may serve as a new approach to prevent epithelial transformation and suppress cancer invasion.
    Free Radical Biology & Medicine 01/2013; · 5.27 Impact Factor
  • Medecine sciences: M/S 01/2013; 29(1):36-8. · 0.56 Impact Factor
  • Shijun Wen, Daqian Zhu, Peng Huang
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    ABSTRACT: Mitochondria are double membrane-enveloped organelles that play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. They function as main generators of ATP, metabolites for the construction of macromolecules and reactive oxygen species. In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with upregulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published. This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.
    Future medicinal chemistry 01/2013; 5(1):53-67. · 3.31 Impact Factor
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    ABSTRACT: OSW-1 is a natural product with potent antitumor activity against various types of cancer cells, but the exact mechanisms of action remain to be defined. In this study, we showed that OSW-1 effectively killed leukemia cells at the sub-nM concentrations through a unique mechanism by causing a time-dependent elevation of cytosolic Ca2+ prior to induction of apoptosis. Mechanistic study revealed that this compound inhibited the sodium-calcium exchanger (NCX1) on the plasma membrane, leading to an increase in cytosolic Ca2+ and a decrease in cytosolic Na+. The elevated cytosolic Ca2+ caused mitochondrial calcium overload and resulted in a loss of mitochondrial membrane potential (MMP), release of cytochrome c, and activation of caspase-3. Furthermore, OSW-1 also caused a Ca2+-dependent cleavage of the survival factor GRP78, and thus further potentiated the cytotoxic effect. Inhibition of Ca2+ entry into the mitochondria by the uniporter inhibitor RU360 or by cyclosporine A significantly prevented the OSW-1-induced cell death, indicating the important role of mitochondria in mediating the cytotoxic activity. The extremely potent activity of OSW-1 against leukemia cells and its unique mechanism of action suggest that this compound may be potentially useful in the treatment of leukemia.
    Journal of Biological Chemistry 12/2012; · 4.65 Impact Factor
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    ABSTRACT: Platinum (Pt)-based chemotherapy is an important regimen in the clinical treatment of cancer, but development of drug resistance presents a major challenge. One key mechanism involved in resistance to Pt drugs is the decrease of intracellular Pt due to the drug efflux through the glutathione (GSH)-mediated export, and this is particularly significant in cancer cells with stem-cell like properties. In the present study, we showed that two Pt-resistant human cancer cell lines exhibited stem-cell like EMT properties, had high cellular GSH and accumulated significantly less cellular Pt compared to their parental cells, and failed to undergo apoptosis when exposed to Pt at the drug concentrations toxic to the parental cells. Importantly, we found that the natural compound β-phenylethyl isothiocyanate (PEITC) was able to effectively abolish this drug resistant mechanism by effective depletion of cellular GSH, leading to a significant increase in cellular Pt as well as DNA-bound Pt. A combination of PEITC and Pt showed a striking synergistic anticancer activity both in vitro and in vivo, as evidenced by an increase in drug-induced apoptosis, a loss of colony formation capacity, and significant suppression of tumor growth in mice. Taken together, our study shows a promising therapeutic strategy to overcome drug resistance to platinum-based chemotherapy and may potentially have broad implications in clinical treatment of cancer.
    Biochemical pharmacology 12/2012; · 4.25 Impact Factor
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    ABSTRACT: Development of effective therapeutic strategies to eliminate Cancer stem cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide, but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with temozolomide achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere formation ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties.
    Stem Cells 11/2012; · 7.70 Impact Factor

Publication Stats

6k Citations
684.63 Total Impact Points

Institutions

  • 2014
    • Sun Yat-Sen University of Medical Sciences
      • Cancer Institute
      Shengcheng, Guangdong, China
  • 2010–2014
    • Sun Yat-Sen University Cancer Center
      Shengcheng, Guangdong, China
  • 2013
    • Sun Yat-Sen University
      Shengcheng, Guangdong, China
  • 1997–2013
    • University of Texas MD Anderson Cancer Center
      • • Department of Molecular Pathology
      • • Department of Experimental Therapeutics
      Houston, TX, United States
  • 2008
    • University of Texas Health Science Center at San Antonio
      • Cancer Therapy & Research Center
      San Antonio, TX, United States