James G Herman

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (354)3451.39 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Naked cuticle homolog2 (NKD2) is located in chromosome 5p15.3, which is frequently loss of heterozygosity in human colorectal and gastric cancers. In order to understand the mechanism of NKD2 in gastric cancer development, 6 gastric cancer cell lines and 196 cases of human primary gastric cancer samples were involved. Methylation specific PCR (MSP), gene expression array, flow cytometry, transwell assay and xenograft mice model were employed in this study. The expression of NKD1 and NKD2 was silenced by promoter region hypermethylation. NKD1 and NKD2 were methylated in 11.7% (23/196) and 53.1% (104/196) in human primary gastric cancer samples. NKD2 methylation is associated with cell differentiation, TNM stage and distant metastasis significantly (all P < 0.05), and the overall survival time is longer in NKD2 unmethylated group compared to NKD2 methylated group (P < 0.05). Restoration of NKD2 expression suppressed cell proliferation, colony formation, cell invasion and migration, induced G2/M phase arrest, and sensitized cancer cells to docetaxel. NKD2 inhibits SOX18 and MMP-2,7,9 expression and suppresses BGC823 cell xenograft growth. In conclusion, NKD2 methylation may serve as a poor prognostic and chemo-sensitive marker in human gastric cancer. NKD2 impedes gastric cancer metastasis by inhibiting SOX18.
    Oncotarget 09/2015; DOI:10.18632/oncotarget.5272 · 6.36 Impact Factor
  • Wenji Yan · James G Herman · Mingzhou Guo
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    ABSTRACT: Cancer genome sequencing has created an opportunity for precision medicine. Thus far, genetic alterations can only be used to guide treatment for small subsets of certain cancer types with these key alterations. Similar to mutations, epigenetic events are equally suitable for personalized medicine. DNA methylation alterations have been used to identify tumor-specific drug responsive markers. Methylation of MGMT sensitizes gliomas to alkylating agents is an example of epigenetic personalized medicine. Recent studies have revealed that 5-azacytidine and decitabine show activity in myelodysplasia, lung and other cancers. There are currently at least 20 kinds of histone deacetylase inhibitors in clinical testing. Inhibitors targeting other epigenetic regulators are being clinically tested, such as EZH2 inhibitor EPZ-6438.
    Epigenomics 09/2015; DOI:10.2217/epi.15.84 · 4.65 Impact Factor
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    ABSTRACT: Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14(ARF) and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 08/2015; DOI:10.1093/nar/gkv795 · 9.11 Impact Factor
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    ABSTRACT: Naked cuticle homolog 2 (NKD2) has been reported to antagonize Wnt signaling in zebrafish, mouse and mammals. The aim of this study is to investigate the epigenetic changes and mechanisms of NKD2 in human breast cancer development. Six breast cancer cell lines (MCF-7, ZR75-1, MDA-MB-468, MDA-MB-231, T47D and BT474) and 68 cases of primary human breast cancer were studied using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. The expression of NKD1 and NKD2 was regulated by promoter region methylation in breast cancer cells. No NKD1 methylation was found in primary human breast cancer. NKD2 was methylated in 51.4% (35/68) of human primary breast cancer samples. NKD2 methylation was significantly associated with reduction of NKD2 expression, and tumor stage (p < 0.05). NKD2 suppressed breast cancer cell proliferation both in vitro and in vivo. NKD2 induced G1/S arrest and inhibited Wnt signaling in breast cancer cells. In conclusion, NKD2 is frequently methylated in human breast cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses breast cancer proliferation by inhibiting Wnt signaling.
    Oncotarget 06/2015; 6(26). DOI:10.18632/oncotarget.4244 · 6.36 Impact Factor
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    ABSTRACT: We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
    Cell 06/2015; 161(7):1681 - 1696. DOI:10.1016/j.cell.2015.05.044 · 32.24 Impact Factor
  • Y Zhang · J Jackson · G Davies · J Herman · R Teboh Forbang
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    ABSTRACT: SBRT shows excellent tumor control and toxicity rates for patients with locally advanced pancreatic cancer (PCA). Herein, we evaluate the feasibility of using VMAT with ABC for PCA SBRT. Nine PCA patients previously treated via SBRT utilizing 11-beam step-and-shoot IMRT technique in our center were retrospectively identified, among whom eight patients received 3300cGy in 5 fractions while one received 3000cGy in 5 fractions. A VMAT plan was generated on each patient's planning CT in Pinnacle v9.8 on Elekta Synergy following the same PCA SBRT clinical protocol. Three partial arcs (182°-300°, 300°-60°, and 60°-180°) with 2°/4° control-point spacing were used. The dosimetric difference between the VMAT and the original IMRT plans was analyzed. IMRT QA was performed for the VMAT plans using MapCheck2 in MapPHAN and the total delivery time was recorded. To mimic the treatment situation with ABC, where patients hold their breath for 20-30 seconds, the delivery was intentionally interrupted every 20-30 seconds. For each plan, the QA was performed with and without beam interruption. Gamma analysis (2%/2mm) was used to compare the planned and measured doses. All VMAT plans with 2mm dose grid passed the clinic protocol with similar PTV coverage and OARs sparing, where PTV V_RxDose was 92.7±2.1% (VMAT) vs. 92.1±2.6% (IMRT), and proximal stomach V15Gy was 3.60±2.69 cc (VMAT) vs. 4.80±3.13 cc (IMRT). The mean total MU and delivery time of the VMAT plans were 2453.8±531.1 MU and 282.1±56.0 seconds. The gamma passing rates of absolute dose were 94.9±3.4% and 94.5±4.0% for delivery without and with interruption respectively, suggesting the dosimetry of VMAT delivery with ABC for SBRT won't be compromised. This study suggests that PCA SBRT using VMAT with ABC is a feasible technique without compromising plan dosimetry. The combination of VMAT with ABC will potentially reduce the SBRT treatment time.
    Medical Physics 06/2015; 42(6):3431. DOI:10.1118/1.4924787 · 2.64 Impact Factor
  • L Di Maso · R Teboh Forbang · Y Zhang · J Herman · J Lee
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    ABSTRACT: To explore the dosimetric consequences of uncorrected rotational setup errors during SBRT for pancreatic cancer patients. This was a retrospective study utilizing data from ten (n=10) previously treated SBRT pancreas patients. For each original planning CT, we applied rotational transformations to derive additional CT images representative of possible rotational setup errors. This resulted in 6 different sets of rotational combinations, creating a total of 60 CT planning images. The patients' clinical dosimetric plans were then applied to their corresponding rotated CT images. The 6 rotation sets encompassed a 3, 2 and 1-degree rotation in each rotational direction and a 3-degree in just the pitch, a 3-degree in just the yaw and a 3-degree in just the roll. After the dosimetric plan was applied to the rotated CT images, the resulting plan was then evaluated and compared with the clinical plan for tumor coverage and normal tissue sparing. PTV coverage, defined here by V33 throughout all of the patients' clinical plans, ranged from 92-98%. After an n degree rotation in each rotational direction that range decreased to 68-87%, 85-92%, and 88- 94% for n=3, 2 and 1 respectively. Normal tissue sparing defined here by the proximal stomach V15 throughout all of the patients' clinical plans ranged from 0-8.9 cc. After an n degree rotation in each rotational direction that range increased to 0-17 cc, 0-12 cc, and 0-10 cc for n=3, 2, and 1 respectively. For pancreatic SBRT, small rotational setup errors in the pitch, yaw and roll direction on average caused under dosage to PTV and over dosage to proximal normal tissue. The 1-degree rotation was on average the least detrimental to the normal tissue and the coverage of the PTV. The 3-degree yaw created on average the lowest increase in volume coverage to normal tissue. This research was sponsored by the AAPM Education Council through the AAPM Education and Research Fund for the AAPM Summer Undergraduate Fellowship Program.
    Medical Physics 06/2015; 42(6):3304. DOI:10.1118/1.4924255 · 2.64 Impact Factor
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    ABSTRACT: Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylation-mediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies.
    Epigenetics: official journal of the DNA Methylation Society 05/2015; 10(7). DOI:10.1080/15592294.2015.1050173 · 4.78 Impact Factor
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    ABSTRACT: BCL6B, a homologue of BCL6, has been reported to be frequently methylated in human gastric cancer. The epigenetic change and the function of BCL6B remains to be elucidated in colorectal cancer. 7 colorectal cancer cell lines (RKO, HT-29, DLD1, LOVO, HCT116, SW480, SW620) and 102 cases of primary colorectal cancer samples were used in this study. Semi-quantitative RT-PCR, methylation specific PCR (MSP), Flow cytometry and western blot were employed. Loss of BCL6B expression was found in HT29, RKO LOVO, SW480, SW620 and DLD1 cells, and reduced expression was found in HCT116 cell line. Complete methylation was found in HT29, RKO, LOVO, SW480, SW620 and DLD1 cells, partial methylation was detected in HCT116 cells. Restoration of BCL6B expression was induced by 5-Aza treatment in these colorectal cancer cells. BCL6B was methylated in 79.4% (81/102) of primary human colorectal cancer and reduced expression was associated with promoter region hypermethylation (p < 0.05). Methylation of BCL6B is associated with late stage (p < 0.05) and lymph node metastasis (p < 0.05). Re-expression of BCL6B inhibited cell proliferation, invasion and migration in RKO and HT29 cells. BCL6B activated P53 signaling and induced apoptosis, Re-expression of BCL6B sensitized RKO and HT29 cells to 5-fluorouracil. In conclusion, BCL6B was frequently methylated in human colorectal cancer and its expression was regulated by promoter region methylation. Methylation of BCL6B is a prognostic and chemo-sensitive marker in colorectal cancer. BCL6B suppresses colorectal cancer growth by activating P53 signaling.
    American Journal of Cancer Research 05/2015; 5(2):651-62. · 4.17 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignances and the second leading cause of cancer related death worldwide. RASSF10 is located on chromosome 11p15.2, a region that shows frequent loss of heterozygosity (LOH) in several cancer types. Our previous study found that RASSF10 suppresses colorectal cancer growth by activating P53 signaling. To explore the epigenetic changes and the mechanism of RASSF10 in human HCC, 69 cases of primary HCC, twenty cases of normal liver tissue samples and 17 HCC cell lines were involved in this study. We found that RASSF10 was methylated in 82.6% (57/69) of human primary HCC and methylation of RASSF10 was significantly associated with tumor size (P < 0.05) and TNM stage (P < 0.05). The expression of RASSF10 was regulated by promoter region methylation. Restoration of RASSF10 expression suppressed cell proliferation, induced apoptosis and G2/M phase arrest, as well as sensitized cells to docetaxel and activated P53 signaling in HepG2 and QGY7703 cells. In conclusion, we demonstrated that RASSF10 is frequently methylated in human HCC and its methylation is a potential docetaxel resistant marker. Our data also indicate that RASSF10 suppresses human HCC growth by activating P53 signaling.
    Genes & cancer 05/2015; 6(5-6):231-40.
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    ABSTRACT: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as potential marker for ccRCC survival. We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate hazard ratios (HR) and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using Likelihood-Ratio tests. Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P=0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR(95%CI)=1.66(1.12-2.45)) and TNM stage, tumor size and Fuhrman grade (HR(95%CI)=1.89(1.25-2.85)). Multivariate models performed better with than without CDO1 promoter methylation status (Likelihood-Ratio P=0.003). Survival curves were validated in an independent series of 280 ccRCC cases from the Cancer Genome Atlas (TCGA; Wilcoxon P<0.001). CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it could be a novel molecular marker to determine ccRCC prognosis. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 04/2015; 21(15). DOI:10.1158/1078-0432.CCR-14-2049 · 8.72 Impact Factor
  • AACR 106th Annual Meeting 2015; 04/2015
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    ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution.
    Genes & cancer 03/2015; 6(1-2):38-48.
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    Xin Li · Jie Yu · Malcolm V Brock · Qian Tao · James G Herman · Ping Liang · Mingzhou Guo
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    ABSTRACT: BCL6B is a potential tumor suppressor in human gastric cancer, but the regulation and mechanism of BCL6B in human hepatocellular carcinogenesis remain unclear. This study is to explore the epigenetic change and mechanism of BCL6B in human hepatocellular carcinoma (HCC). Nineteen hepatic cancer cell lines, 50 cases of adjacent tissue and 149 cases of HCC samples were employed. BCL6B is methylated in 100% (19/19) of human HCC cell lines, 40.0% (20/50) of adjacent tissue samples and 86.6% (129/149) of primary cancer samples. Methylation of BCL6B is associated with HBV positive (p < 0.05). But no association was found with age, sex, tumor size, differentiation, TNM stage, recurrence and survival. Loss of BCL6B expression was found in 19 of completely methylated HCC cell lines. BCL6B was re-expressed after 5-aza-2'-deoxycytidine treatment. Restoration of BCL6B expression suppressed cell proliferation, induced apoptosis and G1/S arrest in HCC cells. The expression of EGR1, a key component of p53 signaling, was increased after re-expression BCL6B in HCC cells. Re-expression of BCL6B activated p53 signaling and sensitized HCC cells to 5-fluorouracil. BCL6B is frequently methylated in human HCC and the expression of BCL6B is regulated by promoter region hypermethylation. BCL6B activates p53 signaling by increasing EGR1 expression in HCC.
    Oncotarget 03/2015; 75(15 Supplement). DOI:10.1158/1538-7445.AM2015-2950 · 6.36 Impact Factor
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    ABSTRACT: DNA methylation occurs commonly in non-small cell lung cancer (NSCLC). We sought to determine the frequency and relationship of methylation of key genes involved in the pathways of mitotic checkpoint control, DNA damage repair, apoptosis, and growth factor signaling in these patients. We analyzed the DNA methylation status of eight genes (CHFR, FANCF, MGMT, p16, DAPK, ASC or TMS-1, RAR-B, and CRBP1) using nested methylation-specific PCR (MSP) on over 314 paraffin-embedded, human non-small cell lung cancer samples. We determined the methylation frequency of each gene in addition to the association of the methylation of each gene with other members of the panel. Methylation was a common event in these samples. Our methylation analysis showed frequencies of methylation of 10% for CHFR, 14% for FANCF, 30% for MGMT, 29% for p16, 17% for DAPK, 33% for ASC, 38% for RAR-B, and 7% for CRBP1. There was a strong correlation between methylation of the mitotic G2-M checkpoint gene, CHFR, and methylation of other genes in our panel involved in DNA damage repair (FANCF and MGMT) and apoptosis (DAPK and ASC) but not with other genes in our panel, including p16 (the G1-S checkpoint gene), CRBP1, or RAR-B. In addition, MGMT methylation strongly correlated with the pro-apoptotic gene, ASC. There are distinct associations of methylated genes in non-small cell lung cancer involving DNA damage repair, apoptosis, and the G2-M mitotic checkpoint control. Further studies are warranted to determine whether these methylation patterns have implications for prognosis in addition to prediction of response to chemotherapeutic agents commonly used in the treatment of non-small cell lung cancer, such as radiotherapy and platinum- or taxane-based chemotherapy.
    Discovery medicine 03/2015; 19(104):151-8. · 3.63 Impact Factor
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    ABSTRACT: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.
    Nature 01/2015; 517(7536):576-582. DOI:10.1038/nature14129 · 41.46 Impact Factor
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    ABSTRACT: Aim: To examine epigenetic changes and the function of HOXA11 in human gastric cancer (GC). Materials & methods: Seven GC cell lines, five cases of normal gastric mucosa and 112 cases primary GC samples were used in this study. Results: Expression of HOXA11 and lack of promoter region methylation were found in NCI-N87, MKN45, BGC823 and HGC27 cells. Loss of expression and complete methylation were found in AGS gastric cancer cells. Reduced expression and partial methylation were found in MGC803 and SGC7901 cells. Restoration of HOXA11 expression was induced by 5-aza-2'-deoxycytidine. HOXA11 was methylated in 81.25% (91/112) of primary GCs. The presence of methylation was associated with male gender, tumor size, tumor differentiation and lymph node metastasis (all p < 0.05). Restoration of HOXA11 expression reduced cell proliferation, invasion, migration and induced apoptosis and G2/M phase arrest. HOXA11 was found to inhibit Wnt signaling by upregulating NKD1 expression. Conclusion: Epigenetic silencing of HOXA11 promotes GC proliferation, migration and invasion through activation of Wnt signaling.
    Epigenomics 01/2015; 7(2):1-13. DOI:10.2217/epi.14.92 · 4.65 Impact Factor
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    ABSTRACT: RASSF10 has previously been reported to be frequently methylated in a number of malignancies. To understand the importance of RASSF10 inactivation in colorectal carcinogenesis, eight colorectal cancer cell lines, 89 cases of primary colorectal cancer and 5 cases of normal colorectal mucosa were examined. Methylation specific PCR, western blot, siRNA, gene expression array and xenograft mice were employed. The expression of RASSF10 was regulated by promoter regional methylation in colorectal cancer cells. RASSF10 was methylated in 60.7% (54/89) of primary colorectal cancers and was positively associated with tumor stage (p < 0.05) and metastasis (p < 0.05). Restoration of RASSF10 led to inhibition of colorectal cancer cell proliferation in vitro and in vivo and increased apoptosis. Gene expression arrays discovered RASSF10 inhibition of MDM2 expression as a mediator of these effects, which was confirmed with RT- PCR and western blot. RASSF10 was shown to activate P53 signaling in RKO and HCT116 cells after UV exposure, and sensitized these cells to docetaxel. In conclusion, our study demonstrates RASSF10 is frequently methylated in human colorectal cancer leading to loss of expression. RASSF10 normally suppresses human colorectal cancer growth by activating P53 signaling in colorectal cancer, and restored expression sensitizes colorectal cancer to docetaxel.
    Oncotarget 12/2014; 75(15 Supplement). DOI:10.1158/1538-7445.AM2015-1064 · 6.36 Impact Factor
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    ABSTRACT: Identifying biomarkers in body fluids may improve the non-invasive detection of colorectal cancer (CRC). Previously we identified N-Myc downstream-regulated gene 4 (NDRG4) and GATA binding protein 5 (GATA5) methylation as promising biomarkers for CRC in stool DNA. Here, we examined the utility of NDRG4, GATA5, and two additional markers (Forkhead box protein E1 (FOXE1) and spectrin repeat containing nuclear envelope 1 (SYNE1)) promoter methylation as biomarkers in plasma DNA. Quantitative methylation-specific PCR was performed on plasma DNA from 220 CRC patients and 684 non-cancer controls, divided in a training and test set. Receiver operating characteristic analysis was performed to measure the area under the curve of GATA5, NDRG4, SYNE1 and FOXE1 methylation. Functional assays were performed in SYNE1 and FOXE1 stably transfected cell lines. The sensitivity of NDRG4, GATA5, FOXE1 and SYNE1 methylation in all stages of CRC (154 cases, 444 controls) was 27% (95%CI=20%-34%), 18% (95%CI=12%-24%), 46% (95%CI=38%-54%) and 47% (95%CI=39%-55%), with a specificity of 95% (95%CI=93%-97%), 99% (95%CI=98%-100%), 93% (95%CI=91%-95%) and 96% (95%CI=94%-98%) respectively. Combining SYNE1 and FOXE1, increased the sensitivity to 56% (95%CI=48%-64%), while the specificity decreased to 90% (95%CI=87%-93%) in the training set and to 58% sensitivity (95%CI=46%-70%) and 91% specificity (95%CI=80%-100%) in a test set (66 cases, 240 controls). SYNE1 overexpression showed no major differences in cell proliferation, migration and invasion compared to controls. Overexpression of FOXE1 significantly decreased the number of colonies in SW480 and HCT116 cell lines. Overall our data suggests that SYNE1 and FOXE1 are promising markers for CRC detection. Copyright © 2014, American Association for Cancer Research.
    Cancer Prevention Research 12/2014; 8(2). DOI:10.1158/1940-6207.CAPR-14-0198 · 4.44 Impact Factor
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    ABSTRACT: Thyroid cancer is the most common endocrine malignant disease and the incidence is increasing. DACT2 was found frequently methylated in human lung cancer and hepatocellular carcinoma. To explore the epigenetic change and the role of DACT2 in thyroid cancer, 7 thyroid cancer cell lines, 10 cases of non-cancerous thyroid tissue samples and 99 cases of primary thyroid cancer samples were involved in this study. DACT2 was expressed and unmethylated in K1, SW579, FTC-133, TT, W3 and 8505C cell lines. Loss of expression and complete methylation was found in TPC-1 cells. Restoration of DACT2 expression was induced by 5-aza-2'deoxycytidine treatment. It demonstrates that the expression of DACT2 was regulated by promoter region methylation. In human primary papillary thyroid cancer, 64.6% (64/99) was methylated and methylation of DACT2 was related to lymph node metastasis (p<0.01). Re-expression of DACT2 suppresses cell proliferation, invasion and migration in TPC-1 cells. The activity of TCF/LEF was inhibited by DACT2 in wild-type or mutant β-catenin cells. The activity of TCF/LEF was increased by co-transfecting DACT2 and Dvl2 in wild-type or mutant β-catenin cells. Overexpression of wild-type β-catenin promotes cell migration and invasion in DACT2 stably expressed cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were decreased and the level of phosphorylated β-catenin (p-β-catenin) was increased after restoration of DACT2 expression in TPC-1 cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were increased and the level of p-β-catenin was reduced after knockdown of DACT2 in W3 and SW579 cells. These results suggest that DACT2 suppresses human papillary thyroid cancer growth and metastasis by inhibiting Wnt signaling. In conclusion, DACT2 is frequently methylated in papillary thyroid cancer. DACT2 expression was regulated by promoter region methylation. DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling.
    PLoS ONE 11/2014; 9(11):e112336. DOI:10.1371/journal.pone.0112336 · 3.23 Impact Factor

Publication Stats

55k Citations
3,451.39 Total Impact Points


  • 2015
    • University of Pittsburgh
      • Hillman Cancer Center
      Pittsburgh, Pennsylvania, United States
  • 2012–2015
    • Chinese PLA General Hospital (301 Hospital)
      Peping, Beijing, China
  • 1989–2015
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Surgery
      • • Institute of the History of Medicine
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2005–2014
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 1998–2014
    • Johns Hopkins Medicine
      • • Department of Medical Oncology
      • • Sidney Kimmel Comprehensive Cancer Center
      Baltimore, Maryland, United States
  • 2013
    • Emory University
      Atlanta, Georgia, United States
  • 2011
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2009–2011
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands
  • 2008
    • Mercy Medical Center
      Baltimore, Maryland, United States
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 2006
    • Shinshu University
      • Department of Surgery
      Shonai, Nagano, Japan
  • 2004
    • Tokyo Medical and Dental University
      • Department of Molecular Oncology
      Edo, Tōkyō, Japan
  • 2003–2004
    • Maastricht University
      • Pathologie
      Maastricht, Provincie Limburg, Netherlands
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
  • 2002
    • Universidad de Navarra
      Iruña, Navarre, Spain
    • Centro Nacional de Investigaciones Oncológicas
      • Molecular Pathology Programme
      Madrid, Madrid, Spain
  • 2001
    • Sarcoma Oncology Center
      Santa Monica, California, United States
  • 2000
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 1998–2000
    • Lovelace Respiratory Research Institute
      • Respiratory Immunology and Asthma Program
      Albuquerque, New Mexico, United States
  • 1999
    • Hospital de la Santa Creu i Sant Pau
      Barcino, Catalonia, Spain