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1. chinaXiv:201605.01740 [pdf]

Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer

Zhang, Bo; Wei, Peng; Hao, Junfeng; Zhao, Lijing; Zhang, Fenglin; Wei, Taotao; Wang, Jing; Huang, Zhen; Wei, Peng; Liu, Ying; Tu, Yaping
Subjects: Biology >> Biophysics >> Oncology

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development.

submitted time 2016-05-15 Hits993Downloads468 Comment 0

2. chinaXiv:201605.01494 [pdf]

Identification of VEGFR2-Binding Peptides Using High Throughput Bacterial Display Methods and Functional Assessment

Pu, Kefeng; Yuan, Lihua; Chen, Lisha; Wang, Anxin; Zhou, Xuan; Zhu, Yimin; Pu, Kefeng; Chen, Lisha; Wang, Anxin; Pu, Kefeng; Chen, Lisha; Wang, Anxin; Zhang, Hailu
Subjects: Biology >> Biophysics >> Oncology

The signal transduction pathway initiated by vascular endothelial growth factor-vascular endothelial growth factor receptor 2 (VEGF-VEGFR2) plays an important role in the angiogenesis of tumors. The effective antagonists of VEGFR2 would behave as potent drugs for the treatment of malignant cancers. In our study, specific binding peptides with high affinity to VEGFR2 were obtained through bacterial display technology. Conserved motif (FF/YEXWGVK) among those peptide sequences was discovered. One of the selected peptides, VRBP1 (YDGNSFYEMWGVKPASES) was identified by screening the biased bacterial peptide library and its physiochemical feature was further characterized. The results of surface plasmon resonance (SPR) assay indicated that the dissociation constant (K-D) value of VRBP1 was 228.3 nM and this peptide competed with VEGF binding to VEGFR2. Particles conjugated with VRBP1 could recognize the human umbilical vein endothelial cells (HUVEC) which express VEGFR2 on the surface. Further therapeutic effect of VRBP1 was examined by in vivo experiments. VRBP1 could result in a significant decrease in tumor size of H460 xenografts. The results from the immunohistochemical assay showed that CD31 positive signals in VRBP1-treated group were fewer than those in the control ones. These data highlighted the potential of VEGFR2-binding peptides as effective molecules for cancer diagnosis and therapy.

submitted time 2016-05-12 Hits910Downloads419 Comment 0

3. chinaXiv:201605.01420 [pdf]

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

Chard, Louisa S.; Ahmed, Jahangir; El Khouri, Margueritte; Hughes, Jonathan; Lemoine, Nicholas R.; Wang, Yaohe; Maniati, Eleni; Hagemann, Thorsten; Wang, Pengju; Zhang, Zhongxian; Gao, Dongling; Wang, Jiwei; Cao, Fengyu; Lemoine, Nicholas R.; Wang, Yaohe; Wang, Shengdian; Li, Xiaozhu; Denes, Bela; Fodor, Istvan
Subjects: Biology >> Biophysics >> Oncology

Purpose: Vaccinia virus has strong potential as a novel therapeutic agent for treatment of pancreatic cancer. We investigated whether arming vaccinia virus with interleukin-10 (IL10) could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence, thus maximizing the oncolytic effect and antitumor immunity associated with vaccinia virus. Experimental Design: The antitumor efficacy of IL10-armed vaccinia virus (VVL Delta TK-IL10) and control VV Delta TK was assessed in pancreatic cancer cell lines, mice bearing subcutaneous pancreatic cancer tumors and a pancreatic cancer transgenic mouse model. Viral persistence within the tumors was examined and immune depletion experiments as well as immunophenotyping of splenocytes were carried out to dissect the functional mechanisms associated with the viral efficacy. Results: Compared with unarmed VVL Delta TK, VVL Delta TK-IL10 had a similar level of cytotoxicity and replication in vitro in murine pancreatic cancer cell lines, but rendered a superior antitumor efficacy in the subcutaneous pancreatic cancer model and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVL Delta TK-IL10 was dependent on CD4(+) and CD8(+), but not NK cells. Clearance of VVL Delta TK-IL10 was reduced at early time points compared with the control virus. Treatment with VVL Delta TK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8+ cells compared with VVL Delta TK. Conclusions: These results suggest that VVL Delta TK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer. (C) 2014 AACR.

submitted time 2016-05-12 Hits980Downloads412 Comment 0

4. chinaXiv:201605.01397 [pdf]

A better experimental method to detect the sensitivity of cancer cells to anticancer drugs after adenovirus-mediated introduction of two kinds of p53 in vivo

Wang, Hui; Li, WeiYing; Lai, BaiTang; Yang, XueHui; Zhang, ChunYan; Zhu, YunZhong; Li, JinZhao
Subjects: Biology >> Biophysics >> Oncology

p53 plays an important role in drug responses by regulating cell cycle progression and inducing programmed cell death. The C-terminal of p53 self-regulates the protein negatively; however, whether it affects the sensitivity of cancer cells to anticancer drugs is unclear. In this study, two experimental methods were used to compare the sensitivity to anticancer drugs of human lung 801D cancer cells transfected with adenovirus bearing either full-length p53 or the deleted-C-terminal p53 in vivo. Adenovirus-mediated deliveries of full-length or deleted-C-terminal p53 were performed after development of tumors (the first method) or by infection into cells before xenotransplantation (the second method). The results showed that infection with the deleted-C-terminal p53 increased 801D cell sensitivity to anticancer drugs in the second, but not in the first method, as indicated by greater tumor-inhibition rates. In addition, compared with the first method, the second method resulted in viruses with more uniformly infected cells and the infection rates between groups were similar. This yielded smaller within-group variations and greater uniformity among transplanted tumors. The second method could circumvent the difficulties associated with intratumoral injection. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

submitted time 2016-05-12 Hits790Downloads327 Comment 0

5. chinaXiv:201605.01394 [pdf]

USP33 mediates Slit- Robo signaling in inhibiting colorectal cancer cell migration

Huang, Zhaohui; Zhang, Binbin; Quan, Cao; Bian, Zehua; Hua, Dong; Huang, Zhaohui; Cheng, Haipeng; Chen, Xiaoping; Fushimi, Kazuo; Wu, Jane Y.; Wen, Pushuai; Kong, Ruirui; Chen, Mengmeng; Liu, Jianghong; Zhu, Li; Wu, Jane Y.; Zhang, Zhenfeng; Du, Xiang
Subjects: Biology >> Biophysics >> Oncology

Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor-suppressing gene for CRC by mediating the inhibitory function of Slit-Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.

submitted time 2016-05-12 Hits769Downloads339 Comment 0

6. chinaXiv:201605.01351 [pdf]

CD163+CD14+macrophages, a potential immune biomarker for malignant pleural effusion

Wang, Fei; Yang, Li; Gao, Qun; Huang, Lan; Zhang, Yi; Wang, Fei; Zhang, Yi; Gao, Qun; Wang, Liping; Zhang, Yi; Wang, Jing; Wang, Shengdian; Zhang, Bin
Subjects: Biology >> Biophysics >> Oncology

Malignant pleural effusion (MPE) is a common complication caused by malignant diseases. However, subjectivity, poor sensitivity, and substantial false-negative rates of cytology assay hamper accurate MPE diagnosis. The aim of this study was to assess whether CD163+CD14+ tumor-associated macrophages (TAMs) could be used as a biomarker for enabling sensitive and specific MPE diagnosis. Pleural effusion samples and peripheral blood samples were collected from 50 MPE patients and 50 non-malignant pleural effusion (NMPE) patients, respectively. Flow cytometry was performed to analyze cell phenotypes, and RT-qPCR was used to detect cytokine expression in these monocytes and macrophages. A blinded validation study (n = 40) was subsequently performed to confirm the significance of CD163+CD14+ TAMs in MPE diagnosis. Student's t test, rank sum test, and receiver operating characteristic curve analysis were used for statistical analysis. Notably, CD163+CD14+ cell frequency in MPE was remarkably higher than that in NMPE (P < 0.001). In a blinded validation study, a sensitivity of 78.9 % and a specificity of 100 % were obtained with CD163+CD14+ TAMs as a MPE biomarker. In total (n = 140), by using a cutoff level of 3.65 %, CD163+CD14+ cells had a sensitivity of 81.2 % and a specificity of 100 % for MPE diagnosis. Notably, MPE diagnosis by estimating CD163+CD14+ cells in pleural effusion could be obtained one week earlier than that obtained by cytological examination. CD163+CD14+ macrophages could be potentially used as an immune diagnostic marker for MPE and has better assay sensitivity than that of cytological analysis.

submitted time 2016-05-11 Hits980Downloads442 Comment 0

7. chinaXiv:201605.01317 [pdf]

Gavage of D-Ribose induces A beta-like deposits, Tau hyperphosphorylation as well as memory loss and anxiety-like behavior in mice

Wu, Beibei; Wei, Yan; Wang, Yujing; Su, Tao; Liu, Ying; He, Rongqiao; He, Rongqiao; He, Rongqiao; Wu, Beibei; Wang, Yujing; Zhou, Lei
Subjects: Biology >> Biophysics >> Oncology

In addition to D-Glucose, D-Ribose is also abnormally elevated in the urine of type 2 diabetic patients, establishing a positive correlation between the concentration of uric D-Ribose and the severity of diabetes. Intraperitoneal injection of D-Ribose causes memory loss and brain inflammation in mice. To simulate a chronic progression of age-related cognitive impairment, we orally administered D-Ribose by gavage at both a low and high dose to 8 week-old male C57BL/6J mice daily for a total of 6 months, followed by behavioral, histological and biochemical analysis. We found that long-term oral administration of D-Ribose impairs spatial learning and memory, accompanied by anxiety-like behavior. Tau was hyperphosphorylated at AT8, S396, S214 and T181 in the brain. A beta-like deposition was also found in the hippocampus for the high dose group. D-Glucose-gavaged mice did not show significant memory loss and anxiety-like behavior under the same experimental conditions. These results demonstrate that a long-term oral administration of D-Ribose not only induces memory loss with anxiety-like behavior, but also elevates A beta-like deposition and Tau hyperphosphorylation, presenting D-Ribose-gavaged mouse as a model for agerelated cognitive impairment and diabetic encephalopathy.

submitted time 2016-05-11 Hits852Downloads374 Comment 0

8. chinaXiv:201605.01310 [pdf]

Molecular architecture of the ErbB2 extracellular domain homodimer

Hu, Shi; Guo, Huaizu; Qian, Weizhu; Hou, Sheng; Li, Bohua; Guo, Yajun; Hu, Shi; Guo, Huaizu; Qian, Weizhu; Hou, Sheng; Li, Bohua; Guo, Yajun; Hu, Shi; Sun, Yuna; Rao, Zihe; Hu, Shi; Sun, Yuna; Rao, Zihe; Lou, Zhiyong; Hu, Shi
Subjects: Biology >> Biophysics >> Oncology

Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a "back to head" interaction, in which a protruding beta-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I-III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.

submitted time 2016-05-11 Hits799Downloads388 Comment 0

9. chinaXiv:201605.01302 [pdf]

Identification of a novel EXT1 mutation in patients with hereditary multiple exostosis by exome sequencing

Wu, Song; Duan, Li; Zhu, Weiming; Zhang, Shiquan; Yang, Guosheng; Liu, Chunxiao; Li, Weiping; Yang, Lei; Guo, Lijun; Wang, Yongqiang; He, Meijian; He, Yingying; Cai, Zhiming; Wang, Daping; Wu, Song; Liu, Hongjie; Hu, Xiaoxiao; Liu, Hongjie; Jia, Wenlong; Yang, Zhao
Subjects: Biology >> Biophysics >> Oncology

Hereditary multiple exostosis (HME) is an autosomal inherited skeletal disease whose etiology is not fully understood. To further understand the genetic spectrum of the disease, we analyzed a five-generation Chinese family with HME that have observable inheritance. Exome sequencing was performed on three HME individuals and three unaffected individuals from the family. A downstream study confirmed a new C deletion at codon 442 on exon 5 of the exostosin-1 (EXT1) gene as the only pathogenic site which generated a stop codon and caused the truncation of the protein. We rediscovered the deletion in other affected individuals but not in the unaffected individuals from the family. Upon immunohistochemistry assay, we found that the EXT1 protein level of the patients with the novel mutation in our study was less than the level in the patients without the EXT1 mutation from another unrelated family. For a deeper understanding, we analyzed the mutation spectrum of the EXT1 gene. The present study should facilitate a further understanding of HME.

submitted time 2016-05-11 Hits813Downloads362 Comment 0

10. chinaXiv:201605.01295 [pdf]

Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation

Wang, Huiru; Wu, Yanhong; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Wang, Huiru; Wu, Yanhong; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Wang, Huiru; Wu, Yanhong; Wang, Lin; Zhou, Chunxia; Ma, Wenbo; Zhang, Youhui; Zhang, Shuren; Sun, Qing
Subjects: Biology >> Biophysics >> Oncology

Granzyme M is a serine protease known to be often expressed by natural killer cells and induce target cells apoptosis in combination with perforin. However, we detected granzyme M expression in murine and human cancer cell lines and human tumor samples in our study. Granzyme M increased chemoresistance, colony-formation, cytokine secretion and invasiveness in vitro. Most importantly, granzyme M facilitated tumor growth and metastasis in vivo. Granzyme M induced the epithelial-mesenchymal transition (EMT) in cancer cells associated with STAT3 activation. Our study revealed the role of granzyme M expressed by tumor in chemoresistance, invasion, metastasis and EMT.

submitted time 2016-05-11 Hits786Downloads341 Comment 0

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