Histone H3 Lysine 4 Trimethylation (H3K4me3), Lysine 27 Trimethylation (H3K27me3) and Lysine 27 Acetylation (H3K27AC) Contribute to the Transcriptional Repression of Solute Carrier Family 47 Member 2 in Renal Cell Carcinoma
PubMed | Hangzhou First Peoples Hospital, Zhejiang Agriculture And forestry University, Cancer Hospital of Zhejiang Province and Zhejiang University
Type: | Journal: Drug metabolism and disposition: the biological fate of chemicals | Year: 2016
In recent years, finding effective biomarkers for identifying early stage cancer and predicating prognosis is crucial for renal cell carcinoma (RCC) diagnosis and treatment. In this study, a dramatic decrease of the solute carrier family 47 member 2 (SLC47A2) mRNA in RCC comparing with the paired adjacent non-tumor tissues from patients at low TNM stage was observed. Thus, patients with SLC47A2 transcriptional repression are susceptible to RCC. Little is known about the regulation mechanism of SLC47A2. We found that it was a bivalent gene which was enriched with both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3). Loss of mixed lineage leukemia 1 (MLL1) binding at the gene promoter caused decreased H3K4me3 enrichment and H3K4me3/H3K27me3 ratio, subsequently repressed the expression of SLC47A2. These two epigenetic markers modulated the expression of SLC47A2 simultaneously, suggesting the regulation pattern for bivalent genes. Histone H3 lysine 27 acetylation (H3K27AC) also contributed to the expression of SLC47A2. An E2F1-HDAC10 complex catalyzed deacetylation of H3K27, then prevented the enrichment of H3K4me3, and finally reduced SLC47A2 expression. Consequently, the combined effect of all these factors determined SLC47A2 transcriptional repression in RCC tissues.
PubMed | Panyu Central Hospital, Cancer Hospital of Hunan Province, Wuhan University, Zhongshan Peoples Hospital and 17 more.
Type: Clinical Trial, Phase III | Journal: Lancet (London, England) | Year: 2016
Outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma and no well established first-line chemotherapy is available for the disease. We compared the efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma.In this multicentre, randomised, open-label, phase 3 trial, patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. Key inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and measurable lesions according to Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/mBetween Feb 20, 2012, and Oct 30, 2015, 362 patients were randomly assigned to a group (181 to the gemcitabine [plus cisplatin] group and 181 to the fluorouracil [plus cisplatin] group). Median follow-up time for progression-free survival was 194 months (IQR 121-356). The median progression-free survival was 70 months (44-109) in the gemcitabine group and 56 months (30-70) in the fluorouracil group (hazard ratio [HR] 055 [95% CI 044-068]; p<00001). A total of 180 patients in the gemcitabine group and 173 patients in the fluorouracil group were included in the safety analysis. Significantly different treatment-related grade 3 or 4 adverse events between the gemcitabine and fluorouracil groups were leucopenia (52 [29%] vs 15 [9%]; <00001), neutropenia (41 [23%] vs 23 [13%]; p=00251), thrombocytopenia (24 [13%] vs three [2%]; p=00007), and mucosal inflammation (0 vs 25 [14%]; <00001). Serious treatment-related adverse events occurred in seven (4%) patients in the gemcitabine group and ten (6%) in the fluorouracil group. Six (3%) patients in the gemcitabine group and 14 (8%) patients in the fluorouracil group discontinued treatment because of drug-related adverse events. No treatment-related deaths occurred in either group.Gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population.Sun Yat-Sen University Clinical Research 5010 Programme, Chinese National Natural Science Foundation project (grant numbers 81372502 and 81201917), the National High Technology Research and Development Program of China (863 program numbers 2012AA02A501 and 2012AA02A502), and the Natural Science Foundation of Guangdong (grant number S2013010016564).
Liu Y.,Zhejiang University |
Zheng X.,Zhejiang University |
Yu Q.,Zhejiang University |
Wang H.,Cancer Hospital of Zhejiang Province |
And 6 more authors.
Science Translational Medicine | Year: 2016
Renal cell carcinoma (RCC) is known for its multidrug resistance. Using data obtained from the cancer transcriptome database Oncomine and the proteome database The Human Protein Atlas, we identified the repression of organic cation transporter OCT2 as a potential factor contributing to oxaliplatin resistance in RCC. By analyzing OCT2 expression in collected patient tissues and commercial tissue microarray specimens, we demonstrated OCT2 repression in RCC at both transcription and protein levels. Epigenetic analysis revealed that the repressed OCT2 promoter in RCC is characterized by hypermethylated CpG islands and the absence of H3K4 methylation. Further mechanistic studies showed thatDNAhypermethylation blockedMYCactivation of OCT2 by disrupting its interaction with the E-Box motif, which prevented MYC from recruiting MLL1 to catalyze H3K4me3 at the OCT2 promoter and resulted in repressed OCT2 transcription. Targeting thismechanism, we designed a sequential combination therapy and demonstrated that epigenetic activation of OCT2 by decitabine sensitizes RCC cells to oxaliplatin both in vitro and in xenografts. Our study highlights the potential of translating "omics" data into the development of targeted therapies.
Shi X.,Cancer Hospital of Zhejiang Province
Zhonghua zhong liu za zhi [Chinese journal of oncology] | Year: 2013
To observe the clinical efficacy and safety of pemetrexed or gemcitabine combined with carboplatin as the first-line therapy in elderly patients with advanced non-small cell lung cancer (NSCLC). Seventy patients aged 70 years or over with stage IIIb-IV NSCLC were equally and randomly divided into pemetrexed plus cisplatin group (PC) and gemcitabine plus carboplatin group (GC). Patients in the PC group received pemetrexed (PEM) 500 mg/m(2) on day 1, and carboplatin (CBP) AUC5 on day 1 for 21-day cycle. Patients in the GC group received gemcitabine 1000 mg/m(2) on days 1 and 8, CBP AUC5 on day 1 for a 21-day cycle. In the PC and GC groups, CR 0 and 0, PR 10 and 8, response rates 28.6% and 22.9% were observed, respectively. There was no statistically significant difference between the two groups (χ(2) = 0.299, P = 0.584). The 1-year and 2-year survival rates of the PC and GC groups were 48.6% vs. 45.7% and 11.4% vs. 11.4%, respectively, with a median survival of 11.00 and 10.00 months, without a statistically significant difference between the two groups (χ(2) = 0.01, P = 0.919). Regarding toxicities, the incidences of neutropenia/thrombocytopenia, nausea and vomiting (grade III ∼ IV) in the GC group were significantly higher than those in the PC group (P < 0.05). According to the observer scale of lung cancer symptoms, the post-treatment scores improved in both the two groups, and with no significant difference between them (P > 0.05). PC and GC show similar efficacy for elderly NSCLC patients, however, the toxicities in PC patients are lower than those in GC patients. Thus, pemetrexed combined with carboplatin is an effective chemotherapeutic regimen for advanced NSCLC in elderly patients.
Wang Y.,Cancer Hospital of Zhejiang Province |
Wang Y.,Zhejiang University |
Ding L.,Zhejiang University |
Wang X.,Zhejiang University |
And 7 more authors.
American Journal of Translational Research | Year: 2012
As a nature phytoalexin found in grapes, resveratrol has been proposed as a potential drug for cancer chemoprevention and treatment. However, its poor bioavailability limits its potential clinical application. Pterostilbene, the natural dimethylated analog of resveratrol with greater bioavailability, was confirmed to inhibit tumor growth both in vivo and in vitro, demonstrating its potential for further clinical application. In the current study, we found that pterostilbene could markedly inhibit the growth of two independent breast cancer cell lines. Both apoptosis and cell cycle arrest as well as the inhibition of wnt singling was induced by pterostilbene. The dominant-active mutant of β- catenin could reverse the growth inhibitory effect of pterostilbene, indicating that the inhibition of wnt signaling is important to the growth inhibitory effect of pterostilbene. Interestingly, pterostilbene induced autophagy and blockage of autophagy augmented pterostilbene-induced growth inhibition, suggesting that the combination of autophagy inhibitors with pterostilbene and other therapeutics such as endocrine drugs could serve as a new and promising strategy for the treatment of breast cancer cells.
Xu Y.-J.,Cancer Hospital of Zhejiang Province |
Zheng X.,Cancer Hospital of Zhejiang Province
Chinese Journal of Cancer Biotherapy | Year: 2010
Radiotherapy combined with chemotherapy is the standard therapy strategy for locally advanced unresectable non-small cell lung cancer (NSCLC); however, this treatment is intolerable for some NSCLC patients and its therapy outcome seems to have reached a "platform". Epidermal growth factor receptor (EGFR) inhibitors may enhance radiosensitivity of NSCLC cells by increasing the cells in G2/M phase, reducing the cells in S phase, inhibiting phosphorylation of multi proteins in EGFR signal transduction pathway, and inhibiting the proliferation of NSCLC cells. The initial clinical results of radiotherapy or chemoradiotherapy in combination with EGFR-TKI show certain efficacy, but the long-term outcome is uncertain. Gefitinib combined with chemoradiotherapy resulted in a longer median survival and higher 2-year survival rate than the single therapy group; further randomized phase III trials are needed to validate the efficacy of the combination treatment. Above all, radiotherapy or chemoradiotherapy combined with EGFR inhibitors has great potential for patients with locally advanced unresectable non-small cell lung cancer and is worthy of further study.
Wang J.,Cancer Hospital of Zhejiang Province |
Fang J.,Cancer Hospital of Zhejiang Province
Journal of medical case reports | Year: 2014
INTRODUCTION: Ectopic thyroid is characterized by the presence of thyroid tissue in a site other than in its usual pretracheal region. It is a rare condition among the thyroid diseases. Dural ectopic thyroid present in the cervical and anterior mediastinal has not been reported.CASE PRESENTATION: A 45-year-old Chinese woman presented with a nonfunctional ectopic thyroid located both in the cervical and anterior mediastinum. The ectopic thyroid was removed under video-assisted thoracoscopic surgery using a transverse neck incision and her postoperative period has been uneventful thus far.CONCLUSIONS: Ectopic thyroid is a rare condition among the thyroid diseases, and its location in the anterior mediastinum is even more uncommon. Less than 15 cases have been reported in the last four decades. This is the first case of ectopic thyroid to appear in both the cervical and anterior mediastinum at same time. Masses in the anterior mediastinal are usually thymoma, lymphoma, pheochromocytoma and germ cell tumors. Ectopic thyroid in this area is quite rare so this case enhances our understanding of the diagnosis of mediastinal masses.
Yang Y.,Cancer Hospital of Zhejiang Province |
Cai Z.,Zhejiang University |
Zhong H.,Cancer Hospital of Zhejiang Province
Chinese Journal of Cancer Biotherapy | Year: 2016
Objective:To explore response of tumor-specific cytotoxic T lymphocyte (CTL) induced by dendritic cells (DCs) sensitized with exosomes that derived from heat-shocked gastric cancer cell. Methods: exosomes from mice murine foregastric cancer (MFC) cells (Exo), heat-shocked MFC cells (Exo/HS), and lysates (Lys) of MFC cells were prepared, respectively. Morphology of the exosomes was observed by electron microscopy and protein components of the exosomes were detected by Western blotting. DCs generated from murine bone marrow were cultured and sensitiaed with Exo/HS, Exo and Lys, and the prepared DCs vaccines were termed as DC-Exo/HS, DC-Exo, and DC-Lys, respectively. Also, DCs were sensitized with exosomes from heat-shocked MFC tumor cells that transfected with HSP70 siRNA. Phenotypes of DCs were detected by flow cytometry. Mice were immunized with DC-Exo/HS, DC-Exo, DC-Ly, DC, or PBS respectively; the proliferation of splenic T cells was measured by 3H-TdR and activity of spleen CTL was measured by LDH. MFC cells-bearing mouse models were constructed to examine immunotherapy effects of the DCs vaccines. Results: exosomes were confirmed as small membranous vesicles with electron microscopy. Detection of Western blotting showed that Exo/HS contained high level of HSP70. Flow cytometry demonstrated that the exosomes from heat-shocked MFC cells could significantly up-regulate expressions of MHC-II, CD80, CD86 and CD40 molecules on the DCs, and interference with HSP70 siRNA could down-regulate expressions of MHC-II, CD80, CD86 and CD40 molecules on the DCs sensitized with the exosomes from heat-shocked MFC tumor cells. Results of 3H-TdR showed that proliferation ability of T cells in DC-Exo/HS group was markedly enhanced as compared with those in DC-Exo, DC-Lys, DC and PBS groups (P<0.01). Results of LDH showed that higher level of CTL activity was induced in DC-Exo/HS group as compared with those in DC-Exo, DC-Lys, DC or PBS (P<0.01), and induced CTL activity in HSP70 siRNA group was significantly lower than that in control siRNA group (P<0.01). Results of the immunotherapies showed that inhibitive effect of DC-Exo/HS on tumor in the carcinoma-bearing mice was significantly better than those of all the other groups (P<0.01). Conclusion: DCs sensitized with exosomes that derived from heat-shocked gastric cancer cell could induce efficient antitumor immune response. © 2016, Editorial office of Chinese Journal of Cancer Biotherapy. All Rights Reserved.
PubMed | Cancer Hospital of Zhejiang Province
Type: | Journal: Journal of medical case reports | Year: 2014
Ectopic thyroid is characterized by the presence of thyroid tissue in a site other than in its usual pretracheal region. It is a rare condition among the thyroid diseases. Dural ectopic thyroid present in the cervical and anterior mediastinal has not been reported.A 45-year-old Chinese woman presented with a nonfunctional ectopic thyroid located both in the cervical and anterior mediastinum. The ectopic thyroid was removed under video-assisted thoracoscopic surgery using a transverse neck incision and her postoperative period has been uneventful thus far.Ectopic thyroid is a rare condition among the thyroid diseases, and its location in the anterior mediastinum is even more uncommon. Less than 15 cases have been reported in the last four decades. This is the first case of ectopic thyroid to appear in both the cervical and anterior mediastinum at same time. Masses in the anterior mediastinal are usually thymoma, lymphoma, pheochromocytoma and germ cell tumors. Ectopic thyroid in this area is quite rare so this case enhances our understanding of the diagnosis of mediastinal masses.