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Wang L.,The First Hospital of NingboZhejiang | Dong J.-Z.,The First Hospital of NingboZhejiang | Xiong L.,Fuzhou Pulmonary Hospital of Fujian | Wang L.,Taizhou Central Hospital | And 4 more authors.
International Journal of Clinical and Experimental Medicine | Year: 2017

Liver fibrosis, a serious threat to human health, still lacks of effective anti-fibrosis treatment. Studies have found that EGF plays an important role in liver fibrosis. The purpose of this study was to investigate the effect of Gifitinib, an EGFR inhibitor, on liver fibrosis of mice. Experiment was divided into three groups, the control group, the liver fibrosis group and Gifitinib intervention group. The liver fibrosis model was induced by intraperitoneal injection with carbon tetrachloride (CCl4) three times per week for 8 weeks in liver fibrosis group and Gifitinib intervention group. The mice in Gifitinib intervention group were intraperitoneal injection of Gifitinib after six weeks injection of CCl4. Meanwhile, mice in liver fibrosis group were only intraperitoneal injection with equal volume of solvent. Mas-son staining was applied to observe the liver histology change. The expression of mRNA and protein were assessed by PCR and western blot. Previously, we found that serum levers of ALT, AST in Gifitinib intervention group were lower than that in liver fibrosis group; Alb levels were higher than that in liver fibrosis group. The protein and mRNA levers of TGF-β1 and α-SMA were gradually increased along with the progress of liver fibrosis and obviously down-regulated by Gifitinib intervention as compared to the liver fibrosis group. © 2017, E-Century Publishing Corporation. All rights reserved.


Hu Z.,Beijing Normal University | Hu Z.,China National Institute of Biological Sciences | Wan X.,China National Institute of Biological Sciences | Hao R.,BeiGene Beijing Co. | And 11 more authors.
PLoS ONE | Year: 2015

Amplification, overexpression, and somatic mutation of the HER2 gene have been reported to play a critical role in tumorigenesis of various cancers. The HER2 H878Y mutation was recently reported in 11% of hepatocellular carcinoma (HCC) patients. However, its functional impact on the HER2 protein and its role in tumorigenesis has not been determined. Here, we show that HER2 H878Y is a gain-of-function mutation. Y878 represents a phosphorylation site, and phospho-Y878 interacts with R898 residue to stabilize the active conformation of HER2, thereby enhancing its kinase activity. H878Y mutant is transforming and the transformed cells are sensitive to HER2 kinase inhibitors. Thus, our study reveals the following novel mechanism underlying the tumorigenic function of the HER2 H878Y mutation: The introduction of a tyrosine residue into the kinase activation loop via mutagenesis modulates the conformation of the kinase, thereby enhancing its activity. © 2015 Hu et al.


Hu Z.,Beijing Normal University | Hu Z.,China National Institute of Biological Sciences | Hu Y.,Beijing Normal University | Hu Y.,China National Institute of Biological Sciences | And 6 more authors.
Oncotarget | Year: 2015

HER2, a well established oncogenic member of EGFR family, is among the most intensely investigated kinase drug targets. In contrast to hotspot mutations of EGFR, few mutations of HER2 locate in activation loop within kinase domain. We previously reported the molecular mechanism underlying hyper kinase activity of HER2H878Y, a mutation located in activation loop. However, its tumorigenicity in vivo and relevant therapeutics remain to be determined. Here, we report for the first time that HER2H878Y was tumorigenic in vivo in lung adenocarcinoma transgenic mouse model. Induced expression of HER2H878Y in lung epithelial compartments resulted in formation of poorly differentiated lung adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. Strikingly, we found that these tumors depended on continuous expression of HER2H878Y for maintenance. Typical HER2 downstream signaling mediators, including PLCγ1, STAT5 and AKT, were hyperactivated in HER2H878Y driven lung tumors. More importantly, administration of HKI-272, a tyrosine kinase inhibitor (TKI), efficiently shrank HER2H878Y driven tumors in transgenic mouse model. Moreover, we found that combinational treatment with HKI272 and mTOR inhibitor, Rapamycin, showed a superior cytotoxicity to H878Y mutant transformed cells and enhanced activity to elicit apoptosis and inhibit growth in situ in tumorous area. Our work therefore showed that HER2H878Y mutant was a reasonable drug target. Hence, our work supported the assessment of HKI-272/rapamycin treatment in clinical trials.


PubMed | Beijing Normal University, The General Hospital of Peoples Liberation Army 301 Hospital, Fuzhou Pulmonary Hospital of Fujian, China National Institute of Biological Sciences and China Japan Friendship Hospital
Type: Journal Article | Journal: Oncotarget | Year: 2015

HER2, a well established oncogenic member of EGFR family, is among the most intensely investigated kinase drug targets. In contrast to hotspot mutations of EGFR, few mutations of HER2 locate in activation loop within kinase domain. We previously reported the molecular mechanism underlying hyper kinase activity of HER2H878Y, a mutation located in activation loop. However, its tumorigenicity in vivo and relevant therapeutics remain to be determined. Here, we report for the first time that HER2H878Y was tumorigenic in vivo in lung adenocarcinoma transgenic mouse model. Induced expression of HER2H878Y in lung epithelial compartments resulted in formation of poorly differentiated lung adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. Strikingly, we found that these tumors depended on continuous expression of HER2H878Y for maintenance. Typical HER2 downstream signaling mediators, including PLC1, STAT5 and AKT, were hyperactivated in HER2H878Y driven lung tumors. More importantly, administration of HKI-272, a tyrosine kinase inhibitor (TKI), efficiently shrank HER2H878Y driven tumors in transgenic mouse model. Moreover, we found that combinational treatment with HKI272 and mTOR inhibitor, Rapamycin, showed a superior cytotoxicity to H878Y mutant transformed cells and enhanced activity to elicit apoptosis and inhibit growth in situ in tumorous area. Our work therefore showed that HER2H878Y mutant was a reasonable drug target. Hence, our work supported the assessment of HKI-272/rapamycin treatment in clinical trials.


PubMed | Chinese Academy of Sciences, Fuzhou Pulmonary Hospital of Fujian, China National Institute of Biological Sciences, Beijing Normal University and 5 more.
Type: Journal Article | Journal: PloS one | Year: 2015

Amplification, overexpression, and somatic mutation of the HER2 gene have been reported to play a critical role in tumorigenesis of various cancers. The HER2 H878Y mutation was recently reported in 11% of hepatocellular carcinoma (HCC) patients. However, its functional impact on the HER2 protein and its role in tumorigenesis has not been determined. Here, we show that HER2 H878Y is a gain-of-function mutation. Y878 represents a phosphorylation site, and phospho-Y878 interacts with R898 residue to stabilize the active conformation of HER2, thereby enhancing its kinase activity. H878Y mutant is transforming and the transformed cells are sensitive to HER2 kinase inhibitors. Thus, our study reveals the following novel mechanism underlying the tumorigenic function of the HER2 H878Y mutation: the introduction of a tyrosine residue into the kinase activation loop via mutagenesis modulates the conformation of the kinase, thereby enhancing its activity.


He L.,Fudan University | Zhou C.,Tongji University | Zhao S.,Huazhong University of Science and Technology | Weng H.,Fuzhou Pulmonary Hospital of Fujian | Yang G.,Beijing Hospital Of Tcm Affiliated To Capital University Of Medicine Science
Anti-Cancer Drugs | Year: 2015

This pilot study assesses the safety and efficacy of once-daily, oral levofloxacin monotherapy in Chinese patients with low-risk febrile neutropenia. In this prospective, single-arm, open-label, multicenter clinical trial, 46 adult Chinese patients with solid tumors and low-risk febrile neutropenia were included. Patients received oral levofloxacin monotherapy (500mg orally/day) until day 12, followed by 7 days of follow-up (day 19). Body temperature was measured three times per day. On days 2, 3, 5-7, 9, 12, and 19, disease symptoms and vital signs were recorded, adverse drug reactions were assessed, and blood samples were collected to determine the whole-blood cell count and the absolute neutrophil count. Blood cultures and chest radiographs were performed simultaneously until negative results were found. Oral levofloxacin was effective and well tolerated in 97.6% of patients irrespective of the cancer type and cause of fever. Body temperature began to decline in 24.4, 68.3, and 90.2% of patients, respectively, at 12, 24, and 48h after initiating levofloxacin therapy. On days 5 and 7, 95.1 and 97.6% of the patients had complete defervescence, respectively. The median time for absolute neutrophil count recovery to at least 1500/mm after initiation of treatment was 3 days. Only one patient reported mild diarrhea. This pilot study showed that oral levofloxacin quickly and effectively reduced fever, initiated neutrophil recovery, and was well tolerated in Chinese low-risk febrile neutropenic patients with solid tumors. Further study is needed to compare patient data of levofloxacin with the standard amoxicillin/ciprofloxacin protocol in this population for both safety and efficacy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Wang L.-P.,Wenzhou University | Dong J.-Z.,Wenzhou University | Xiong L.-J.,Fuzhou Pulmonary Hospital of Fujian | Shi K.-Q.,Wenzhou University | And 5 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2014

The aim of this study was to elucidate the effect of bone morphogenetic protein-7 (BMP-7) on liver fibrosis induced by carbon tetrachloride (CCl4) in vivo and on the hepatic stellate cells (HSC) activation in vitro. In vivo, thirty male ICR mice were randomly allocated to three groups, the control group (n = 6), the CCl4 group (n = 18) and the BMP-7+CCl4 group (n = 6). The model of liver fibrosis was induced by intraperitoneal injection with CCl4 three times per week lasting for 12 weeks in CCl4 group and the BMP-7+CCl4 group. After 8 weeks injection with CCl4, mice were intraperitoneal injected with human recombinant BMP-7 in BMP-7+CCl4 group. Meanwhile, mice in the CCl4 group were only intraperitoneal injection with equal amount of saline. The degree of liver fibrosis was assessed by HE and Masson's staining. PCR and western blot were used to detect mRNA and protein levels. In BMP-7+CCl4 group, serum levels of alanine aminotransferase (ALT) and aminotransferase (AST) were decreased and serum albumin (Alb) was increased. Meanwhile, the expressions of transforming growth factor-β1 (TGF-β1) and a-smooth muscle actin (a-SMA) were down-regulated by BMP-7 intervention as compared to the CCl4 group (P < 0.05). Furthermore, BMP-7 also suppressed the expression of epidermal growth factor receptor (EGFR) and phosphorylated-epidermal growth factor receptor (pEGFR). HE and Masson stain showed that liver damage was alleviated in BMP-7+CCl4 group. In vitro study, expression of EGFR, TGF-β1 and a-SMA were down regulated by BMP-7 dose-dependently, indicating it might effect on suppression of HSC activation. Therefore, our data indicate BMP-7 was capable of inhibiting liver fibrosis and suppressing HSCs activation, and these effects might rely on its crosstalk with EGFR and TGF-β1. We suggest that BMP-7 may be a potential reagentfor the prevention and treatment of liver fibrosis.


Lin P.-C.,Fujian Medical University | He J.-Y.,Fujian Medical University | Le Y.-Y.,Fuzhou Pulmonary Hospital of Fujian | Du K.-X.,Fujian Medical University | And 5 more authors.
BioMed Research International | Year: 2016

Purpose. This study aimed to evaluate the characteristics of the HVGGSSV peptide, exploring radiation-guided delivery in a mouse model of nasopharyngeal carcinoma. Methods. Mice with CNE-1 nasopharyngeal carcinoma were assigned to two different groups treated with Cy7-NHS and Cy7-HVGGSSV, respectively. Meanwhile, each mouse received a single dose of 3 Gy radiation. Biological distribution of the recombinant peptide was assessed on an in vivo small animal imaging system. Results. The experimental group showed maximum fluorescence intensity in irradiated tumors treated with Cy7-labeled HVGGSSV, while untreated (0 Gy) control tumors showed lower intensity levels. Fluorescence intensities of tumors in the right hind limbs of experimental animals were 7.84 × 10 7 ± 1.13 × 10 7, 1.35 × 10 8 ± 2.66 × 10 7, 4.05 × 10 8 ± 1.75 × 10 7, 5.57 × 10 8 ± 3.47 × 10 7, and 9.26 × 10 7 ± 1.73 × 10 7 photons/s/cm2 higher compared with left hind limb values at 1, 2, 15, 24, and 48 h, respectively. Fluorescence intensities of tumor in the right hind limbs of the experimental group were 1.66 × 10 8 ± 1.71 × 10 7, 1.51 × 10 8 ± 3.23 × 10 7, 5.38 × 10 8 ± 1.96 × 10 7, 5.89 × 10 8 ± 3.57 × 10 7, and 1.62 × 10 8 ± 1.69 × 10 7 photons/s/cm2 higher compared with control group values at 1, 2, 15, 24, and 48 h, respectively. Fluorescence was not specifically distributed in the control group. Compared with low fluorescence intensity in the heart, lungs, and tumors, high fluorescence distribution was found in the liver and kidney at 48 h. Conclusions. HVGGSSV was selectively bound to irradiated nasopharyngeal carcinoma, acting as a targeting transport carrier for radiation-guided drugs that are mainly metabolized in the kidney and liver. © 2016 Pei-cheng Lin et al.


Shi Q.,Fuzhou Pulmonary Hospital of Fujian | Chen Q.,Fuzhou Pulmonary Hospital of Fujian | Xie Q.,Fuzhou Pulmonary Hospital of Fujian | Xiao S.,Fuzhou Pulmonary Hospital of Fujian | And 2 more authors.
Journal of Shanghai Jiaotong University (Medical Science) | Year: 2015

Objective: To jointly detect the differences of mRNA expressions of ERCC1, RRM1, TYMS, and TUBB3 of non-small cell lung cancer (NSCLC) patients with wild type epidermal growth factor receptor (EGFR) and explore the effects of expressions of 4 genes on the efficacy and prognosis of chemotherapy. Methods: Patients with wild type EGFR were screened by xTAG liquid phase chip method from samples of 353 NSCLC patients. The mRNA expression levels of 4 genes were detected by real-time PCR. Patients with wild type EGFR were divided into the high expression group (expressions of 4 genes were high) and low expression group (expressions of 4 genes were low). The median progression free survival and median overall survival of two groups were compared after chemotherapy. Results: A total of 227 NSCLC patients with wild type EGFR were screened. The differences of mRNA expression levels of 4 genes of patients were not statistically significant (P>0.05) except differences between smoking and non-smoking patients. There were 27 patients in the high expression group and 53 patients in the low expression group. The differences of the objective remission rate (ORR) (14.8% vs 41.5%, P<0.05), disease control rate (DCR) (40.7% vs 81.1%, P<0.05), median progression free survival (3.3 m vs 4.9 m, P=0.001), and median overall survival (7.1 m vs 8.1 m, P=0.048) of two groups were statistically significant. Cox multivariate analysis showed that the high expression of 4 genes was independent risk factor of prognosis for NSCLC patients with wild type EGFR after chemotherapy (HR=1.92; 95%CI: 1.10-3.42). Conclusion: High mRNA expressions of ERCC1, TYMS, TUBB3, and RRM1 in cancer tissue of NSCLC patients with wild type EGFR indicate that they are resistant to chemotherapeutic drugs. Joint detection of expressions of 4 genes is helpful for choosing chemotherapy plans. ©, 2015, Editorial Department of Journal of Shanghai Second Medical University. All right reserved.

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