Search

RESILIENT (CTRI/2018/02/011808) was a single arm, open label, phase II/III study to test if label agnostic therapy regimens guided by Encyclopedic Tumor Analysis (ETA) can offer meaningful clinical benefit for patients with relapsed refractory metastatic (r/r-m) malignancies. Patients with advanced refractory solid organ malignancies where disease had progressed following ≥2 lines of systemic treatments were enrolled in the trial. Patients received personalized treatment recommendations based on integrational comprehensive analysis of freshly biopsied tumor tissue and blood. The primary end points were Objective Response Rate (ORR), Progression Free Survival (PFS) and Quality of Life (QoL). Objective Response (Complete Response + Partial Response) was observed in 54 of 126 patients evaluable per protocol (ORR = 42.9%; 95% CI: 34.3%–51.4%, p < 0.0001). At study completion, Disease Control (Complete Response + Partial Response + Stable Disease) was observed in 114 out of 126 patients evaluable per protocol (CBR = 90.5%; 95% CI: 83.9% - 95.0%, p < 0.00001) and Disease Progression in 12 patients. Median duration of follow-up was 138 days (range 31 to 379). Median PFS at study termination was 134 days (range 31 to 379). PFS rate at 90 days and 180 days were 93.9% and 82.5% respectively. The study demonstrated that tumors have latent vulnerabilities that can be identified via integrational multi-analyte investigations such as ETA. This approach identified viable treatment options that could yield meaningful clinical benefit in this cohort of patients with advanced refractory cancers.

// Youhong Liu 1, 2, * , Yijun Liu 1, 2, * , Bowen Yuan 1, 2 , Linglong Yin 1, 2 , Yuchong Peng 1, 2 , Xiaohui Yu 1, 2 , Weibing Zhou 3 , Zhicheng Gong 4 , Jianye Liu 5, 6 , Leye He 5, 6 , Xiong Li 1, 2, 6 1 Center for Molecular Medicine, Xiangya Hospital, Central South University, China 2 Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, China 3 Department of Oncology, Xiangya Hospital, Central South University, China 4 Department of Pharmacy, Xiangya Hospital, Central South University, China 5 Department of Urology, The Third Xiangya Hospital, Central South University, China 6 Research Institute of Prostate Diseases, Central South University, China * These authors equally contributed to this paper Correspondence to: Xiong Li, email: lixiongxiangya@csu.edu.cn Keywords: PSA, FOXM1, gene transcription, androgen receptor, prostate cancer Received: November 11, 2016 Accepted: January 09, 2017 Published: February 09, 2017 ABSTRACT Androgen/AR is the primary contributor to prostate cancer (PCa) progression by regulating Prostate Specific Antigen (PSA) gene transcription. The disease inevitably evolves to androgen-independent (AI) status. Other mechanisms by which PSA is regulated and develops to AI have not yet been fully determined. FOXM1 is a cell proliferation-specific transcription factor highly expressed in PCa cells compared to non-malignant prostate epithelial cells, suggesting that the aberrant overexpression of FOXM1 contributes to PCa development. In addition to regulating AR gene transcription and cell cycle-regulatory genes, FOXM1 selectively regulates the gene transcription of KLK2 and PSA, typical androgen responsive genes. Screening the potential FOXM1-binding sites by ChIP-PCR, we found that FOXM1 directly binds to the FHK binding motifs in the PSA promoter/enhancer regions. AI C4-2 cells have more FOXM1 binding sites than androgen dependent LNCaP cells. The depletion of FOXM1 by small molecular inhibitors significantly improves the suppression of PSA gene transcription by the anti-AR agent Cadosax. This is the first report showing that FOXM1 promotes PCa progression by regulating PSA gene transcription, particularly in AI PCa cells. The combination of anti-AR agents and FOXM1 inhibitors has the potential to greatly improve therapy for late-stage PCa patients by suppressing PSA levels.

The mechanism of prostate cancer (PCa) progression towards the hormone refractory state remains poorly understood. Treatment options for such patients are limited and present a major clinical challenge. Previously, δ-catenin was reported to promote PCa cell growth in vitro and its increased level is associated with PCa progression in vivo. In this study we show that re-arrangements at Catenin Delta 2 (CTNND2) locus, including gene duplications, are very common in clinically significant PCa and may underlie δ-catenin overexpression. We find that δ-catenin in PCa cells exists in a complex with E-cadherin, p120, and α- and β-catenin. Increased expression of δ-catenin leads to its further stabilization as well as upregulation and stabilization of its binding partners. Resistant to degradation and overexpressed δ-catenin isoform activates Wnt signaling pathway by increasing the level of nuclear β-catenin and subsequent stimulation of Tcf/Lef transcription targets. Evaluation of responses to treatments, with androgen receptor (AR) antagonist and β-catenin inhibitors revealed that cells with high levels of δ-catenin are more resistant to killing with single agent treatment than matched control cells. We show that combination treatment targeting both AR and β-catenin networks is more effective in suppressing tumor growth than targeting a single network. In conclusion, targeting clinically significant PCa with high levels of δ–catenin with anti-androgen and anti β-catenin combination therapy may prevent progression of the disease to a castration-resistant state and, thus, represents a promising therapeutic strategy.

// Łukasz Kuźbicki 1 , Dariusz Lange 2 , Agata Stanek-Widera 2 , Agnieszka Glinska 1 and Barbara W. Chwirot 1 1 Department of Medical Biology, Faculty of Biology and Environment Protection, Nicolaus Copernicus University, Torun, Poland 2 Department of Tumor Pathology, Oncology Center – Maria Sklodowska-Curie Institute, Gliwice, Poland Correspondence to: Barbara W. Chwirot, email: bchwirot@umk.pl Keywords: RNF2 (Ring1B); intratumoral expression; immunohistochemistry; prognostic marker; cutaneous melanoma Received: October 18, 2017 Accepted: February 28, 2018 Published: April 03, 2018 ABSTRACT Recent studies involving melanoma cell lines suggest that enhanced expression of epigenetic regulator RNF2 supports proliferation and promotes metastasis. However, it is not clear to what extent those data apply to disease progression and prognosis for melanoma patients. Therefore the aim of the present study was to assess the prognostic power of RNF2 intratumoral expression by melanoma cells. RNF2 was detected immunohistochemically in standard formalin-fixed paraffin-embedded samples of 9 benign nevi, 60 melanomas and 24 nodal metastases. The lowest percentage of RNF2-positive melanocytes found in nevi was comparable to expression levels in normal skin. The RNF2 expression found in melanomas was significantly higher and it was even more enhanced in metastases. The increased occurrence of RNF2 expressing cells was positively correlated with longer patients’ overall survival. Moreover, a negative correlation was found between intratumoral RNF2 expression and number of generated metastatic lesions. Our data indicate that development of melanoma is associated with significant changes in RNF2 intratumoral expression and imply that at least for some patients the enhancement of the expression levels of RNF2 in both primary and metastatic lesions may be considered a favorable prognostic factor in melanoma.

// Veronika Reidel 1 , Johanna Kauschinger 1 , Richard T. Hauch 1 , Catharina Muller-Thomas 1 , Niroshan Nadarajah 2 , Rainer Burgkart 3 , Burkhard Schmidt 4 , Dirk Hempel 5 , Anne Jacob 1 , Julia Slotta-Huspenina 6 , Ulrike Hockendorf 1 , Christian Peschel 1, 7 , Wolfgang Kern 2 , Torsten Haferlach 2 , Katharina S. Gotze 1, 7 , Stefanie Jilg 1, * and Philipp J. Jost 1, 7, * 1 Medizinische Klinik fur Hamatologie und Internistische Onkologie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 2 Munich Leukemia Laboratory (MLL), Munich, Germany 3 Klinik fur Orthopadie und Sportorthopadie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 4 Gemeinschaftspraxis Hamato-Onkologie Pasing, Munich, Germany 5 Onkologisches Zentrum Donauworth, Donauworth, Germany 6 Institut fur Pathologie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 7 Deutsche Konsortium fur translationale Krebsforschung (DKTK) of the German Cancer Research Center (DKFZ), Heidelberg, Germany * These authors contributed equally to this work Correspondence to: Philipp J. Jost, email: philipp.jost@tum.de Keywords: apoptosis; BCL-2 family; ABT-199; myelodysplastic syndromes; myeloid malignancy; Autophagy Received: November 14, 2017 Accepted: February 25, 2018 Published: April 03, 2018 ABSTRACT Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 . ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis.

Various intravesical therapies have been introduced into clinical practices for controlling non-muscle invasive bladder cancer (NMIBC). However, evidence with respect to the efficacy and safety of those intravesical therapies is very limited. Hence, we present a network meta-analysis in order to address this limitation in the current literature. The primary outcomes were the risk of tumor recurrence (TR), tumor progression (TP) and disease-specific mortality (DM). Secondary outcomes included the risk of fever, cystitis and haematuria. Conventional pair-wise and network meta-analysis were both performed for each endpoint. The surface under the cumulative ranking curve (SUCRA) was incorporated in our analysis for ranking the corresponding intravesical instillation interventions. In total, 23 randomized clinical trials (RCTs) were finally included in our study after irrelevant papers were screened out. Results of network meta-analysis suggested that Epirubicin (EPI) was less preferable than Bacille Calmette Guerin (BCG), BCG+EPI, BCG+ Isoniazid (INH), BCG+ Mytomicin C (MMC), Gemcitabine (GEM) and MMC with respect to TR. As suggested by the corresponding ranking probabilities and SUCRA, incorporating EPI or MMC into BCG may enhance the efficacy of BCG monotherapy.

// Nicolle M. Linnerth-Petrik 1 , Lisa A. Santry 1 , Roger Moorehead 2 , Manfred Jucker 3 , Sarah K. Wootton 1, * , Jim Petrik 2, * 1 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada 2 Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada 3 Center of Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany * These authors have contributed equally to this work Correspondence to: Jim Petrik, email: jpetrik@uoguelph.ca Keywords: ovarian cancer, Akt isoforms, Akt inhibitors, tumor development Received: March 21, 2016 Accepted: July 27, 2016 Published: August 11, 2016 ABSTRACT Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells ( Figure 1 ). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo . Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

Although various mechanisms of castration-resistant prostate cancer (CRPC) have been discovered, reliable biomarkers for monitoring CRPC progression are lacking. We sought to identify molecules that predict the progression of advanced prostate cancer (AdvPC) into CRPC. The study used primary-site samples (N=45 for next-generation sequencing (NGS); N=243 for real-time polymerase chain reaction) from patients with prostate cancer (PC). Five public databases containing microarray data of AdvPC and CRPC samples were analyzed. The NGS data showed that each progression step in PC associated with distinct gene expression profiles. Androgen receptor (AR) associated with tumorigenesis, advanced progression, and progression into CRPC. Analysis of the paired and unpaired AdvPC and CRPC samples in the NGS cohort showed that 15 genes associated with progression into CRPC. This was validated by cohort-1 and public database analyses. Analysis of the third cohort with AdvPC showed that higher serine peptidase inhibitor, Kazal type 1 (SPINK1) and lower Sp8 transcription factor (SP8) expression associated with progression into CRPC (log-rank test, both P

// Robert Aiken 1 , Magnus Axelson 2 , Johan Harmenberg 3 , Maria Klockare 3 , Olle Larsson 4 and Cecilia Wassberg 5 1 Rutgers-Cancer Institute of New Jersey, New Brunswick, NJ, U.S.A 2 Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden 3 Axelar AB, Karolinska Institutet Science Park, Solna, Sweden 4 Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden 5 Section of Radiology and Nuclear Medicine, Department of Molecular Medicine and Surgery, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden Correspondence to: Robert Aiken, email: ra615@cinj.rutgers.edu Keywords: IGF-1R, phase 1 clinical trial, mitotic catastrophe, signal transduction, tyrosine kinase inhibitor Received: March 09, 2017 Accepted: July 12, 2017 Published: September 06, 2017 ABSTRACT Purpose: Early phase I study of safety of AXL1717 in patients with recurrent or progressive malignant astrocytomas and evaluation of preliminary anti-tumor efficacy. Patients and methods: Nine patients fulfilling the set criteria were enrolled. Eight had recurrent glioblastoma and one gliosarcoma. Patients were treated with an oral suspension of AXL1717 (215-400 mg bid) cycle-by-cycle in 35-day cycles (28 days bid and 7 days off). Patients with progressive disease and/or toxicity-related dose delay of more than 14 days were withdrawn. Results: Four patients had tumor responses (44%) to AXL1717 treatment. Two of these had stable disease for 12 months (10 cycles at 215-300 mg bid). Due to MRI-detected progression they were then taken off the study. They died 8 and 12 months later, respectively. One patient was treated 8 months (6 cycles with 215 mg bid). He was withdrawn because of disease progression but died after another 25 months. The fourth patient having stable disease died of sepsis due to pancytopenia in the end of cycle 2 on 400 mg bid. A fifth patient underwent surgery after two cycles with 300 mg bid. Pathological analysis demonstrated abundant necrosis and small areas of viable tumor. After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later. The other 4 patients did not have any detectable responses and died within 3-13 months after trial entry. Neutropenia was the main adverse effect, which was easily detected and reversible in all but one patient. Conclusion: This clinical phase I study indicates that AXL1717 as a single agent is capable of producing prolonged stable disease and survival of patients with relapsed malignant astrocytomas. The drug was well tolerated. A new formulation of the drug will be used in further investigations in order to better define the optimal dose.

// Liyuan Guo 1 , Yan Peng 2 , Yuanyuan Meng 1 , Yunduo Liu 1 , Shangshang Yang 1 , Hong Jin 1 and Qi Li 1 1 Gynecological Cancer Department, Harbin Medical University Cancer Hospital, Harbin 150081, China 2 Disease Prevention Center, First Affiliated Hospital of Heilongjiang University of Chinese Traditional Medicine, Harbin 150040, China Correspondence to: Qi Li, email: qijarali@163.com Keywords: BRCA1/2, ovarian cancer, microRNA, long non-coding RNA, prognosis Received: June 08, 2017 Accepted: June 28, 2017 Published: July 26, 2017 ABSTRACT Emerging evidence shows that dysregulated expression of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were closely linked with disease progression, including cancers. However, the joint predictive power of miRNAs and lncRNAs in prognosis for ovarian cancer (OV) patients with wild-type BRCA1/2 is as yet unknown. In this study, we sought to assess the joint predictive power of miRNAs and lncRNAs by integrating miRNA and lncRNA expression profiles and clinical data of 281 OV patients with wild-type BRCA1/2 from The Cancer Genome Atlas (TCGA) project. Finally, we identified an integrated miRNA-lncRNA signature composing of two lncRNAs ( LINC01234 and CCDC144NL-AS1 ) and two miRNAs ( miR-637 and miR-129-5p ) which can effectively classify OV patients with wild-type BRCA1/2 into groups with the good and poor outcome. The prognostic value of the integrated miRNA-lncRNA signature was validated in the testing cohort and entire TCGA cohort. Multivariate analysis demonstrated the independence of the integrated miRNA-lncRNA signature of known other clinical factors. Further analysis suggested that patients who were in the low-risk group based on the signature achieved a better CR from platinum-based chemotherapy compared with patients in the high-risk group. Our results indicated that this integrated miRNA-lncRNA signature may have important clinical implications for risk stratification of ovarian cancer patients with wild-type BRCA1/2.

Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Emerging evidence suggests that ovarian cancer cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in ovarian cancer remains elusive. We tested the utility of two natural ERβ agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERβ ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERβ agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERβ agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERβ interacts with p65 subunit of NF-κB and ERβ overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERβ agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.

// Qin Yuan 1, * , Jiayin Song 2, * , Weiwei Yang 3 , Hongyan Wang 1 , Qianyu Huo 1 , Jie Yang 1 , Xiaoxu Yu 3 , Yunde Liu 1 , Chen Xu 4 and Huijing Bao 1 1 School of Laboratory Science, Tianjin Medical University, Tianjin, China 2 The Department of Clinical Laboratory, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 3 The Department of Laboratory Science, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China 4 The Department of Laboratory Science, Tianjin Fourth Central Hospital, Tianjin, China * These authors have contributed equally to this work Correspondence to: Huijing Bao, email: kris_10713@126.com Chen Xu, email: skyalong1028@163.com Yunde Liu, email: yundeliu@163.com Keywords: ovarian cancer, metastasis, CA125, Wnt pathway, cut-off value Received: September 30, 2016 Accepted: May 04, 2017 Published: June 07, 2017 ABSTRACT CA125 has been used extensively to screen for neoplasms, especially in ovarian cancer. The serum CA125 level can be used as a better prognosis evaluation and it may dynamic monitoring the disease progression. We explored the effect of CA125 on ovarian cancer cell migration and its underlying mechanism. Transwell assays showed that exposure to 0.2 μg/ml or 0.4 μg/ml CA125 for 48 h increased migration of A2780 and OVCAR-3 ovarian cancer cells. This effect of CA125 was blocked addition of 200 ng/ml DKK-1, a Wnt pathway inhibitor. Conversely, addition of CA125 reversed the inhibitory effect of Wnt inhibition in A2780 cells pretreated with DKK-1. Examination of CA125 levels in serum from 97 ovarian cancer patients revealed no relationship between a patient’s age or CA125 level currently used clinically for ovarian cancer diagnosis and metastasis. However, using receiver operating characteristic (ROC) curves, we identified a new cut-off value for the serum CA125 concentration (82.9 U/ml) that is predictive of metastasis. The area under the curve is 0.632. This new cut-off value has the potential to serve as a clinically useful indicator of metastasis in ovarian cancer patients.

// Chin-Chou Wang 1, 2, 3, * , Chia-Cheng Tseng 1, 4, * , Huang-Chih Chang 1, 4 , Kuo-Tung Huang 1, 4 , Wen-Feng Fang 1, 3 , Yu-Mu Chen 1 , Cheng-Ta Yang 5 , Chang-Chun Hsiao 4, 6, ** , Meng-Chih Lin 1, ** , Chi-Kung Ho 2, ** and Hon-Kan Yip 6, 7, 8, 9, 10, ** 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan 4 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan 6 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Division of cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 9 Department of Nursing, Asia University, Taichung, Taiwan 10 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan * These authors contributed equally to this work and should be considered co-first authors ** These authors contributed equally to this work and should be considered co-correspondence authors Correspondence to: Hon-Kan Yip, email: han.gung@msa.hinet.net Keywords: advanced non-small cell lung cancer, microparticles, disease control, disease progression Received: January 09, 2017 Accepted: April 25, 2017 Published: June 06, 2017 ABSTRACT We investigated whether circulating microparticles (MPs) could serve as prognostic biomarkers in non-small cell lung cancer (NSCLC) patients. We enrolled 25 control subjects and 136 NSCLC patients categorized into disease-progression (DP, n=42) and disease-control (DC, n=94) groups. Flow cytometric analysis showed that levels of four types of circulating microparticles (EDAc-MPs, EDAp-MPs, PDAc-MPs and PDAp-MPs) were higher in the study patients than the control subjects ( P < 0.04). DP patients showed poor initially performance status and more non-adenocarcinomas than DC patients. DC patients showed more EGFR mutations and poorer performance to targeted therapy than DP patients ( P < 0.01). Three months after therapy, the levels of all four types of circulating MPs were lower in DC than DP patients ( P < 0.02), and were comparable to the levels in control subjects. In addition, the levels of circulating MPs after 3 months accurately predicted one-year prognostic outcomes ( P < 0.05). This study showed that circulating MPs are valuable prognostic biomarkers in advanced NSCLC patients.

// Qiang Cai 1, * , Longyang Jin 1, * , Shouhua Wang 1 , Di Zhou 1 , Jiandong Wang 1 , Zhaohui Tang 1 and Zhiwei Quan 1 1 Department of General Surgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200092, China * These authors have contributed equally to this work Correspondence to: Zhiwei Quan, email: zhiwquan@sina.com Keywords: lncRNA UCA1, gallbladder cancer, EZH2, p21, E-cadherin Received: April 05, 2017 Accepted: April 28, 2017 Published: May 25, 2017 ABSTRACT A growing number of studies indicated that long non-coding RNAs (lncRNAs) determine some cellular processes in cancer, such as proliferation, metastasis and differentiation. Urothelial carcinoma associated 1 (UCA1), an lncRNA, had been reported for its overexpression and oncogenic effect on various human cancers. In this study, we found that UCA1 was significantly overexpressed in gallbladder cancer (GBC) and positively correlated with tumor size, lymph node metastasis, TNM stage and short survival time. Moreover, UCA1 promoted GBC cell proliferation and metastasis in vitro and tumor growth in vivo . Mechanically, we identified that UCA1 promoted GBC progression through recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p21 and E-cadherin, and epigenetically suppressing their transcript.

// Li Yang 1, * , Xiao-Lu Lin 1, * , Wei Liang 3, * , Seng-Wang Fu 4, * , Wen-Feng Lin 1, * , Xiao-Qing Tian 1 , Yun-Jie Gao 1 , Hao-Yan Chen 2 , Jun Dai 1 and Zhi-Zheng Ge 1 1 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China 2 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China 3 Department of Digestive Endoscopy, Provincial Clinic Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China 4 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China * These authors have contributed equally to this work Correspondence to: Zhi-Zheng Ge, email: zhizhengge@aliyun.com Jun Dai, email: lx19980507@126.com Keywords: GPR116, prognosis, metastasis, colorectal carcinoma Received: March 22, 2017 Accepted: May 01, 2017 Published: May 25, 2017 ABSTRACT Previous studies have found that G-protein-coupled receptor 116 (GPR116) is a regulator of breast cancer metastasis. However, the role of GPR116 in colorectal carcinoma (CRC) carcinogenesis and progression is unknown. In this study, We found GPR116 expression was significantly up-regulated in CRC specimens compared with corresponding non-cancerous tissues. Increased GPR116 expression in CRC was correlated with histological differentiation and distant metastasis. In addition, high expression of GPR116 was significantly associated with poor overall survival of CRC patients, which was also confirmed by GSE14333, GSE17536 and GSE33113 datasets from the Gene Expression Omnibus (GEO). Furthermore, we demonstrated that the ability of proliferation and invasion of CRC cell lines HCT116 and LOVO was markedly reduced after transfected with siRNA-GPR116. Meanwhile, GPR116 may drive EMT in CRC cells through AKT/EKR signaling pathway, resulting in metastasis. Thus, GPR116 may be a novel reliable prognostic indicator and a risk factor in CRC progression.

// Sascha Kuerti 1, * , Leticia Oliveira-Ferrer 1, * , Karin Milde-Langosch 1 , Barbara Schmalfeldt 1 , Karen Legler 1 , Linn Woelber 1 , Katharina Prieske 1 , Sven Mahner 2 and Fabian Trillsch 2 1 Department of Gynaecology and Gynaecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany 2 Department of Obstetrics and Gynaecology, University of Munich, Munich 81377, Germany * These authors have contributed equally to this work Correspondence to: Fabian Trillsch, email: Fabian.Trillsch@med.uni-muenchen.de Keywords: ovarian cancer, (VEGF)-A, -C, -D, mesenchymal phenotype, tumour dissemination, lymph node metastases Received: February 20, 2017 Accepted: March 31, 2017 Published: May 18, 2017 ABSTRACT Background: Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for progression of epithelial ovarian cancer (EOC). Vascular endothelial growth factor (VEGF) mediated angiogenesis has been identified as an important mechanism promoting tumour progression. Methods: Tumour tissue of 100 patients with EOC was analysed for protein expression of vascular endothelial growth factor (VEGF)-A, -C, -D by Western Blot analysis. Expression patterns in patients with ‘extensive intraperitoneal’ metastases (pT3c pN1 and pT3b-pT3c pN0, n=80) were compared to patients with ‘predominantly retroperitoneal’ metastases (pT1a-pT3b, pN1, n=20). Overall and progression-free survival was analysed by Kaplan-Meier method. Results: While no significant differences in expression levels among the different modes of metastases were noted for VEGF-A and -D, VEGF-C expression was significantly higher in the group of predominantly retroperitoneal metastases compared to the group with extensive intraperitoneal metastases. Patients with high VEGF-C expression had a significantly worse overall survival compared to patients with low expression levels. Conclusions: Retroperitoneal tumour progression in EOC patients is associated with high VEGF-C expression. VEGF-C may serve as a molecular marker to identify patients with assumed high risk for lymphatic metastases, who might benefit from specific treatment strategies.

// Yihong Zhou 1 , Xi Chu 1 , Fei Deng 1 , Liang Tong 1 , Guoxiong Tong 1 , Ye Yi 1 , Jianye Liu 1 , Jin Tang 1 , Yuxin Tang 1 , Yang Xia 2 and Yingbo Dai 1 1 Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China 2 Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas, USA Correspondence to: Yingbo Dai, email: // Keywords : adenosine A2b receptor, bladder urothelial carcinoma, prognosis, MAPK signaling Received : March 14, 2017 Accepted : May 01, 2017 Published : May 12, 2017 Abstract The adenosine A2b receptor (A2bR) was considered to play an oncogenic role in many human malignancies. However, the expression and molecular function of A2bR in bladder urothelial carcinoma (BUC) have not been well elucidated. Herein, we found that the expression of A2bR was higher than other adenosine receptors in BUC tissues and cells, and it was upregulated in BUC tissues compared with matched normal bladder tissues. Furthermore, high expression of A2bR was associated with poor prognosis of patients with BUC. In addition, suppression of A2bR inhibited the proliferation, migration and invasion of BUC cells and arrested the cell cycle at the G1 phase. Finally, we demonstrated that downregulation of A2bR inhibited the proliferation, migration and invasion of BUC in part via the MAPK signaling pathway, increasing the levels of P21 but decreasing the levels of cyclin B1, D, E1, MMP-2 and MMP-9. Overexpression of MMP-2 could rescue BUC cells migration and invasion. Thus, the present study indicates that A2bR may play a potential oncogenic role in BUC progression and act as a potential biomarker to identify BUC patients with poor clinical outcomes.

Wenjinghuoluo prescription, a traditional Chinese medicine compound treatment of rheumatoid arthritis characterized by wind-cold-dampness arthralgia, contains five herbs, namely, C. cassia Presl., Cinnamomum cassia Presl., Paeonia lactiflora Pall., Saposhnikovia divaricate (Turcz.) Schischk., and Clematis chinensis Osbeck. We have reported that WJHL could inhibit the production of inflammatory mediators in immune cells. This study explored the effect and mechanism of WJHL on collagen-induced arthritis mice. WJHL could significantly improve clinical arthritic conditions; inhibit bone erosion and osteophyte formation in joints; decrease expression of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17); reduce protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3 and gene expression levels of JAK2, STAT3, IL-17A, RORγt mRNA; elevate osteoprotegerin and Foxp3 mRNA levels and lower Th17 cell proportions in splenocytes. Results suggest that WJHL, specifically regulating the JAK2/STAT3 pathway and Th17 cells, may be a promising herbal medicine candidate for the treatment of RA.

For patients with advanced hepatocellular carcinoma (HCC), sorafenib is the only systemic treatment recommended by international guidelines. We recently reported that HCC patients with a low MoRAL (model to predict tumor recurrence after LDLT) score (≤ 314.8) have excellent treatment outcomes after living-donor liver transplantation (LDLT), even though they are beyond the Milan criteria. In the present study, we investigated whether LDLT offers a better treatment outcome than sorafenib for patients with HCC beyond the Milan criteria according to the MoRAL score. A retrospective cohort study of 325 consecutive patients who were treated with either LDLT (n = 122) or sorafenib (n = 203) for HCC beyond the Milan criteria from 2005 to 2014 at a tertiary hospital was performed. The primary and secondary endpoints were overall survival (OS) and time-to-progression. When baseline characteristics were balanced using inverse probability weighting, OS was significantly longer in the LDLT group than in the sorafenib group (5-year OS rate, 71.9% vs. 4.9%; HR=0.1; P < 0.001). The LDLT group exhibited a significantly lower risk of tumor progression (5-year recurrence rate, 34.7% vs. 96%; HR=0.14; P < 0.001) than the sorafenib group. The increase in OS with LDLT was predominantly among patients with a low MoRAL score (5-year OS rate, 81.1% vs. 5.8%; HR=0.06; P < 0.001) compared with those with a high MoRAL score (5-year OS rate, 28.3% vs. 4.3%; HR = 0.42; P = 0.047). Patients with a low MoRAL score and without extrahepatic metastasis or hepatic vein invasion might be good candidates for LDLT instead of sorafenib treatment if there is a willing living related donor.

// Xiao Luo 1, * , Yerfan Jiaerken 1, * , Xinfeng Yu 1 , Peiyu Huang 1 , Tiantian Qiu 1 , Yunlu Jia 3 , Kaicheng Li 1 , Xiaojun Xu 1 , Zhujing Shen 1 , Xiaojun Guan 1 , Jiong Zhou 2 and Minming Zhang 1 , for The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 Department of Radiology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 2 Department of Neurology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Minming Zhang, email: zhangminming@zju.edu.cn Keywords: apolipoprotein E (APOE), cerebral small-vascular disease (CSVD), white matter hyperintensities (WMH), dilated perivascular space (dPVS), cognition Abbreviations: APOE: apolipoprotein E; CSVD: cerebral small-vascular disease; WMH: white matter hyperintensities; dPVS: dilated perivascular space; MBs: microbleeds Received: December 29, 2016 Accepted: April 07, 2017 Published: May 09, 2017 ABSTRACT Objective: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method: There were 135 healthy elderly (including e2, e4 allele carriers and e3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer’s disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results: We found that APOE e4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE e4 carriers had significantly decreased Aβ 1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and e4 allele was related with declining trend of cognition. Conclusion: Our findings suggested APOE e4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and e4 allele can exert long-term detrimental effects on individual’s trajectory of cognition.

// Zhu Liang 1 , Rui Kong 2 , Zhan He 1 , Li-Yao Lin 1 , Shan-Shan Qin 3 , Chun-Yuan Chen 1 , Zhan-Qiang Xie 1 , Fei Yu 3 , Guo-Qian Sun 1 , Chun-Guang Li 4 , Da Fu 3 , Geng-Xi Jiang 4 , Jie Chen 1 and Yu-Shui Ma 3, 5 1 Department of Cardiothoracic Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China 2 Medical College of Soochow University, Soochow 215006, China 3 Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China 4 Department of Thoracic Surgery, Changhai Hospital of Second Military Medical University, Shanghai 200433, China 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China Correspondence to: Geng-Xi Jiang, email: jiang9909@hotmail.com Jie Chen, email: liangzhuwsh@163.com Yu-Shui Ma, email: mayushui2015@126.com Keywords: ITGB1, miR-493-5p, biomarker, survival, target Received: February 17, 2017 Accepted: April 19, 2017 Published: May 07, 2017 ABSTRACT Increasing evidence supports that microRNA (miRNA)-mediated gene regulation plays a significant functional role in cancer progression. To investigate the expression and clinical significance of ITGB1 in non small cell lung cancer (NSCLC), the expression levels of ITGB1 in NSCLC tissues and human normal lung tissues were analyzed in silico using genes microarray, KEGG pathway and hierarchical clustering analysis followed by validation with quantitative RT-PCR. Our results showed that ITGB1 was upregulated in NSCLC tissues when compared with normal lung tissues. Survival analysis based on the qRT-PCR data established that ITGB1 expression was attentively related to the prognosis of NSCLC, and patients with higher ITGB1 expression had shorter overall survival (OS). Moreover, ITGB1 was confirmed to be a direct target of miR-493-5p. Furthermore, concomitant high expression of ITGB1 and low expression of miR-493-5p correlated with a shorter median OS and PFS in NSCLC patients. In conclusion, our results provide the first evidence that ITGB1 is a direct target of miR-493-5p suggesting that ITGB1 and miR-493-5p may have potential prognostic value and may be useful as tumor biomarkers for the diagnosis of NSCLC patients.

// Kuo-Liang Chiu 1, 4, 5, * , Yu-Sen Lin 1, 8, * , Ting-Ting Kuo 7 , Chia-Chien Lo 7 , Yu-Kai Huang 7 , Hsien-Fang Chang 6 , Eric Y. Chuang 6 , Ching-Chan Lin 1, 9 , Wei-Chung Cheng 2, 3 , Yen-Nien Liu 10 , Liang-Chuan Lai 6, 11 and Yuh-Pyng Sher 1, 2, 7 1 Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan 2 Graduate Institute of BioMedical Sciences, China Medical University, Taichung 404, Taiwan 3 Research Center for Tumor Medical Science, China Medical University, Taichung 404, Taiwan 4 Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu-Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan 5 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan 6 Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei 100, Taiwan 7 Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan 8 Division of Thoracic Surgery, China Medical University Hospital, Taichung 404, Taiwan 9 Division of Hematology and Oncology, China Medical University Hospital, Taichung 404, Taiwan 10 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan 11 Graduate Institute of Physiology, National Taiwan University, Taipei 106, Taiwan * These authors contributed equally to this work Correspondence to: Yuh-Pyng Sher, email: ypsher@mail.cmu.edu.tw Liang-Chuan Lai, email: llai@ntu.edu.tw Keywords: lung cancer, ADAM9, EGFR, miR-1, CDCP1 Received: November 30, 2016 Accepted: April 19, 2017 Published: May 07, 2017 ABSTRACT MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9 -knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3′-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.

// Qi-Min Wang 1 , Yu-Yu Xu 1 , Shang Liu 1 and Ze-Gang Ma 1, 2 1 Department of Physiology, School of Basic Medicine, Medical College of Qingdao University, Qingdao, China 2 Institute of Brain Science and Disorders, Qingdao University, Qingdao, China Correspondence to: Ze-Gang Ma, email: mazegang2000@163.com Keywords: L-type calcium channel, isradipine, dopamine neuron, iron accumulation, Parkinson’s disease Received: March 13, 2017 Accepted: April 12, 2017 Published: May 04, 2017 ABSTRACT The aim of this study is to investigate the effects of L-type calcium channels (LTCCs) on MPTP-induced dopamine (DA) neuron degeneration and iron accumulation in the substantia nigra (SN) of mice. By real-time PCR and western blots, we first quatified expressions of L-type Cav1.2 and Cav1.3 calcium channel α1 subunits in the SN of experimental mice treated with MPTP. We found that the expressions of Cav1.2 and Cav1.3 calcium channel α1 subunits markedly increased after MPTP treatment for 2 and 3 weeks. Secondly, we observed the effects of isradipine, a LTCC antagonist, on MPTP-induced DA neuron degeneration and iron accumulation in the SN. Our results showed that isradipine treatment prevented against MPTP-induced Cav1.2 and Cav1.3 calcium channel α1 subunits up-regulation in the SN. We also found that isradipine prevented against MPTP-induced DA neuron depletion in the SN and partly restored the DA content in the striatum. Moreover, we found that isradipine inhibited the increase of iron positive cells in the SN of the MPTP-treated mice. Finally, we investigated the effects of isradipine on cellular iron accumulation in the dopaminergic MES23.5 cell line. Our studies showed that MPP + treatment accelerated iron influx in the MES23.5 cells. Treatment with Bayk8644 further aggravated iron accumulation. Treatment with isradipine prevented against MPP + -induced iron influx in the MES23.5 cells. These results suggest that up-regulation of LTCCs may be responsible for the DA neuron degeneration in the MPTP-treated mice, The LTCCs may directly contribute to iron influx into DA neurons, and isradipine may suppress cellular iron accumulation and prevents neurodegeneration.

// Arun Satelli 1, * , Izhar Batth 1, * , Zachary Brownlee 1 , Abhishek Mitra 1 , Shouhao Zhou 2 , Hyangsoon Noh 1 , Christina R. Rojas 1 , Heming Li 1 , Qing H. Meng 3 and Shulin Li 1 1 Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * These authors contributed equally to this work Correspondence to: Shulin Li, email: sli4@mdanderson.org Qing H. Meng, email: qhmeng@mdanderson.org Keywords: prostate cancer, epithelial mesenchymal transition, circulating tumor cells, vimentin, castration resistance Received: April 28, 2016 Accepted: April 21, 2017 Published: May 04, 2017 ABSTRACT Recent advances in the field of circulating tumor cells (CTC) have shown promise in this liquid biopsy-based prognosis of patient outcome. However, not all of the circulating cells are tumor cells, as evidenced by a lack of tumor-specific markers. The current FDA standard for capturing CTCs (CellSearch) relies on an epithelial marker and cells captured via CellSearch cannot be considered to have undergone EMT. Therefore, it is difficult to ascertain the presence and relevance of any mesenchymal or EMT-like CTCs. To address this gap in technology, we recently discovered the utility of cell-surface vimentin (CSV) as a marker for detecting mesenchymal CTCs from sarcoma, breast, and colon cancer. Here we studied peripheral blood samples of 48 prostate cancer (PCA) patients including hormone sensitive and castration resistant sub-groups. Blood samples were analyzed for three different properties including our own CSV-based CTC enumeration (using 84-1 mAb against CSV), CellSearch-based epithelial CTC counts, and serum prostate-specific antigen (PSA) quantification. Our data demonstrated that in comparison with CellSearch, the CSV-based method had greater sensitivity and specificity. Further, we observed significantly greater numbers of CTCs in castration resistant patients as measured by our CSV method but not CellSearch. Our data suggests CSV-guided CTC enumeration may hold prognostic value and should be further validated as a possible measurement of PCA progression towards the deadly, androgen-independent form.

// Hsiang-Ying Lee 1, 3, 4, 8 , Bi-Wen Yeh 3, 4 , Ti-Chun Chan 5, 6 , Kei-Fu Yang 2, 3 , Wei-Ming Li 2, 3, 4, 7 , Chun-Nung Huang 3, 4 , Hung-Lung Ke 3, 4 , Ching-Chia Li 3, 4, 8 , Hsin-Chih Yeh 2, 3, 4, 7 , Peir-In Liang 9 , Yow-Ling Shiue 6 , Wen-Jeng Wu 2, 3, 4, 8, 10, 11, 12 and Chien-Feng Li 5, 9, 11, 13, 14, 15 1 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 6 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 7 Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan 8 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 9 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 10 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 11 Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan 12 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan 13 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 14 National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan 15 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Chien-Feng Li, email: angelo.p@yahoo.com.tw Wen-Jeng Wu, email: wejewu@kmu.edu.tw Keywords: urothelial carcinoma, transcriptome, SULF1, prognosis Received: November 25, 2016 Accepted: April 17, 2017 Published: May 03, 2017 ABSTRACT Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 ( SULF1 ) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro . In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.

// Fabrice Barlesi 1, 2 , Diane-Charlotte Imbs 2 , Pascale Tomasini 1 , Laurent Greillier 1 , Melissa Galloux 1 , Albane Testot-Ferry 1 , Melanie Garcia 3 , Xavier Elharrar 1 , Annick Pelletier 1 , Nicolas Andre 2, 4 , Celine Mascaux 1 , Bruno Lacarelle 2, 3 , Raouf El Cheikh 2 , Raphael Serre 2 , Joseph Ciccolini 2, 3 and Dominique Barbolosi 2 1 Aix Marseille University, APHM, Marseille Early Phases Cancer Trials Center CLIP, Marseille, France 2 Aix Marseille University, SMARTc Unit, INSERM U911, Marseille, France 3 Aix Marseille University, APHM, Department of Pharmacology, Marseille, France 4 Aix Marseille University, APHM, Department of Pediatric Hematology and Oncology, Marseille, France Correspondence to: Fabrice Barlesi, email: fabrice.barlesi@ap-hm.fr Keywords: lung cancer, mesothelioma, mathematical modeling, vinorelbine, metronomic Received: March 24, 2017 Accepted: April 19, 2017 Published: May 02, 2017 ABSTRACT Introduction: Using mathematical modelling allows to select a treatment’s regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. Results: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1–32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine’s AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). Materials and Methods: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. Conclusions: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

Prostate cancer (PCa) is the second leading cause of death from cancer in men. The mechanism underlying tumorigenesis and development of PCa is largely unknown. Here, we identified Kinesin family member 14 (KIF14) as a novel candidate oncogene in PCa. We found that KIF14 was overexpressed in multiple PCa cell lines and primary PCa tissues. Knockdown of KIF14 in DU145 and PC3 prostate cancer cells suppressed cell proliferation, induced cell cycle arrest and apoptosis. Transcriptome analysis by RNA-sequencing demonstrated that KIF4 suppression led to transcriptional changes of genes involved in p53 and TGF-beta signaling pathway. In addition, upregulated expression of GADD45A, GADD45B, p21, PIDD and Shisa5, which contribute to growth arrest and apoptosis induction, and downregulated CCNB1 that promotes cell cycle progression were confirmed by quantitative real-time PCR after KIF4 knockdown. We further found that KIF14 protein level was positively correlated with T stage and Gleason Score. Patients with higher KIF14 expression had shorter overall survival time than those with lower KIF14 expression. Thus, our data indicate that KIF14 could act as a potential oncogene that contributes to tumor progression and poor prognosis in PCa, which may represent a novel and useful prognostic biomarker for PCa.

// Kun He 1 , Xiwen Zhu 1 , Yan Liu 4 , Chunmu Miao 1 , Tao Wang 1 , Peizhi Li 1 , Lei Zhao 2 , Yaxi Chen 2 , Junhua Gong 1 , Can Cai 4 , Jinzheng Li 1 , Shengwei Li 1 , Xiong Z. Ruan 2, 3 , Jianping Gong 1 1 Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China 2 Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China 3 Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, United Kingdom 4 Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China Correspondence to: Jianping Gong, email: gongjianping11@126.com Shengwei Li, email: lishengwei11@163.com Keywords: NLRP3 inflammasome, Kupffer cell, non-alcoholic fatty liver disease, IL-1β Received: March 20, 2017 Accepted: April 17, 2017 Published: April 27, 2017 ABSTRACT NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP −/− (thioredoxin-interacting protein) and NLRP3 −/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3 −/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP −/− but not NLRP3 −/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3.

// Min A. Jhun 1 , Milan S. Geybels 1, 2 , Jonathan L. Wright 1, 3 , Suzanne Kolb 1 , Craig April 4 , Marina Bibikova 4 , Elaine A. Ostrander 5 , Jian-Bing Fan 4 , Ziding Feng 6 and Janet L. Stanford 1, 7 1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 2 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 3 Department of Urology, University of Washington School of Medicine, Seattle, WA, USA 4 Department of Oncology, Illumina, Inc., San Diego, CA, USA 5 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA 6 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA Correspondence to: Janet L. Stanford, email: jstanfor@fredhutch.org Keywords: gene expression, Gleason score, prostate cancer, recurrence, metastasis Received: February 17, 2017 Accepted: March 30, 2017 Published: April 26, 2017 ABSTRACT Prostate cancer (PCa) is a leading cause of cancer-related mortality worldwide. Gleason score (GS) is one of the best predictors of PCa aggressiveness, but additional tumor biomarkers may improve its prognostic accuracy. We developed a gene expression signature of GS to enhance the prediction of PCa outcomes. Elastic net was used to construct a gene expression signature by contrasting GS 8-10 vs. ≤6 tumors in The Cancer Genome Atlas (TCGA) dataset. The constructed signature was then evaluated for its ability to predict recurrence and metastatic-lethal (ML) progression in a Fred Hutchinson (FH) patient cohort (N=408; N Recurrence =109; N MLprogression =27). The expression signature included transcripts representing 49 genes. In the FH cohort, a 25% increase in the signature was associated with a hazard ratio (HR) of 1.51 (P=2.7×10 −5 ) for recurrence. The signature’s area under the curve (AUC) for predicting recurrence and ML progression was 0.68 and 0.76, respectively. Compared to a model with age at diagnosis, pathological stage and GS, the gene expression signature improved the AUC for recurrence (3%) and ML progression (6%). Higher levels of the signature were associated with increased expression of genes in cell cycle-related pathways and decreased expression of genes in androgen response, estrogen response, oxidative phosphorylation, and apoptosis. This gene expression signature based on GS may improve the prediction of recurrence as well as ML progression in PCa patients after radical prostatectomy.

The effect of postmastectomy radiotherapy (PMRT) on T1-2 breast cancer patients with 1-3 positive axillary lymph nodes is controversial up to now. The purpose of this study was to evaluate the impact of postmastectomy radiotherapy for these patients. The prognostic factor effecting locoregional free-survival (LRFS) was also analyzed. In the retrospective clinical data of 1674 eligible patients, survival analysis was performed using the method of Kaplan-Meier and the log-rank test. Cox regression analysis was applied to identify the significant prognostic factors. We found PMRT increased 5-year LRFS (p=0.003), but could not improve 5-year disease-free survival or overall survival statistically. For patients without PMRT, multivariate analysis revealed that age, lymph node ratio and molecule subtype were risk factors effecting LRFS. To further analyze the role of PMRT, we grouped all the patients into low risk group (0 or 1 risk factor) and high risk group (2 or 3 risk factors) depending on these risk factors. We found that in low-risk group, PMRT increased only 5-year LRFS (p=0.012). However, in high-risk group, PMRT increased both 5-year LRFS (p=0.005) and 5-year disease-free survival (p=0.033), but could not improve 5-year overall survival statistically. Thus, these data provide the evidence that PMRT could improve LRFS for T1-2 breast cancer patients with 1-3 positive axillary lymph nodes. Additionally, PMRT could improve LRFS and disease-free survival for high risk patients. Age, lymph node ratio and molecule subtype were high risk factors effecting LRFS in our study.

Resistance to systemic therapy is a major problem in metastatic breast cancer (MBC) that can be explained by initial tumor heterogeneity as well as by evolutionary changes during therapy and tumor progression. Circulating tumor cells (CTCs) detected in a liquid biopsy can be sampled and characterized repeatedly during therapy in order to monitor treatment response and disease progression. Our aim was to investigate how CTC derived gene expression of treatment predictive markers (ESR1/HER2) and other cancer associated markers changed in patient blood samples during six months of first-line systemic treatment for MBC. CTCs from 36 patients were enriched using CellSearch (Janssen Diagnostics) and AdnaTest (QIAGEN) before gene expression analysis was performed with a customized gene panel (TATAA Biocenter). Our results show that antibodies against HER2 and EGFR were valuable to isolate CTCs unidentified by CellSearch and possibly lacking EpCAM expression. Evaluation of patients with clinically different breast cancer subgroups demonstrated that gene expression of treatment predictive markers changed over time. This change was especially prominent for HER2 expression. In conclusion, we found that changed gene expression during first-line systemic therapy for MBC could be a possible explanation for treatment resistance. Characterization of CTCs at several time-points during therapy could be informative for treatment selection.

// Junli Xue 1, 2 , Chunhua Chen 2 , Manlong Qi 2, 3 , Yan Huang 2 , Lin Wang 2, 4 , Yong Gao 1 , Haidong Dong 5 and Kun Ling 2 1 Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55902, USA 3 Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China 4 Department of Oncology, Guangzhou Red Cross Hospital, Guangzhou 510220, Guangdong Province, China 5 Department of Urology, Mayo Clinic, Rochester, MN 55902, USA Correspondence to: Kun Ling, email: ling.kun@mayo.edu Yong Gao, email: drgaoyon@163.com Keywords: PD-L1, triple negative breast cancer, PIPKIγ, NF-κB, AKT Received: December 16, 2016 Accepted: April 01, 2017 Published: April 15, 2017 ABSTRACT The programmed death-ligand 1 (PD-L1), by binding to PD-1 on the surface of immune cells, activates a major immune checkpoint pathway. Elevated expression of PD-L1 in tumor cells mediates tumor-induced T-cell exhaustion and immune suppression; therefore protect the survival of tumor cells. Although blockade of the PD-1/PD-L1 axis exhibits great potential in cancer treatment, mechanisms driving the up-regulation of PD-L1 in tumor cells remain not fully understood. Here we found that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) is required for PD-L1 expression in triple negative breast cancer cells. Depletion of PIPKIγ inhibits both intrinsic and induced PD-L1 expression. Results from further analyses suggest that PIPKIγ promotes the transcription of the PD-L1 gene by activating the NF-κB pathway in these cells. These results demonstrate that PIPKIγ-dependent expression of PD-L1 is likely important for the progression of triple negative breast cancer.

// Xuefei Sun 1, * , Jing Liu 1, * , Yaming Wang 2 , Xueyan Bai 1 , Yuedan Chen 1 , Jun Qian 1 , Hong Zhu 1 , Fusheng Liu 3 , Xiaoguang Qiu 4 , Shengjun Sun 5 , Nan Ji 6 and Yuanbo Liu 1 1 Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 2 Department of Neurosurgery, Navy General Hospital, Beijing, China 3 Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 5 Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China * These authors contributed equally to this work Correspondence to: Yuanbo Liu, email: yuanbol@ccmu.edu.cn Keywords: primary central nervous system lymphoma, rituximab, high-dose methotrexate, cytarabine, survival Received: December 21, 2016 Accepted: April 02, 2017 Published: April 13, 2017 ABSTRACT Purpose: High-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen). Results: The patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone ( p = .011). The most common grade 1–3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS. Materials and Methods: We retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3–6 courses of 3.5 g/m 2 methotrexate on day 1; 0.5–1 g/m 2 cytarabine on day 2; and 5–10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m 2 on day 0. All patients repeated the treatment every 3 weeks. Conclusions: High-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.

// Na Liu 1 , Liuqing Xu 1 , Yingfeng Shi 1 , Lu Fang 1 , Hongwei Gu 1 , Hongrui Wang 1 , Xiaoqiang Ding 2 and Shougang Zhuang 1, 3 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China 2 Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China 3 Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA Correspondence to: Shougang Zhuang, email: szhuang@lifespan.org Xiaoqiang Ding, email: ding.xiaoqiang@zs-hospital.sh.cn Keywords: hyperuricemic nephropathy, ERK1/2, TGF-β/Smad signaling pathway, urate transporters, inflammation Received: November 16, 2016 Accepted: February 20, 2017 Published: April 10, 2017 ABSTRACT The pathogenesis of hyperuricemia-induced chronic kidney disease is largely unknown. In this study, we investigated whether extracellular signal–regulated kinases1/2 (ERK1/2) would contribute to the development of hyperuricemic nephropathy (HN). In a rat model of HN induced by feeding mixture of adenine and potassium oxonate, increased ERK1/2 phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, in parallel with diminished levels of renal function and increased urine microalbumin excretion. Administration of U0126, which is a selective inhibitor of the ERK1/2 pathway, improved renal function, decreased urine microalbumin and inhibited activation of renal interstitial fibroblasts as well as accumulation of extracellular proteins. U0126 also inhibited hyperuricemia-induced expression of multiple profibrogenic cytokines/chemokines and infiltration of macrophages in the kidney. Furthermore, U0126 treatment suppressed xanthine oxidase, which mediates uric acid production. It also reduced expression of the urate anion exchanger 1, which promotes reabsorption of uric acid, and preserved expression of organic anion transporters 1 and 3, which accelerate uric acid excretion in the kidney of hyperuricemic rats. Finally, U0126 inhibited phosphorylation of Smad3, a key mediator in transforming growth factor (TGF-β) signaling. In cultured renal interstitial fibroblasts, inhibition of ERK1/2 activation by siRNA suppressed uric acid-induced activation of renal interstitial fibroblasts. Collectively, pharmacologic targeting of ERK1/2 can alleviate HN by suppressing TGF-β signaling, reducing inflammation responses, and inhibiting the molecular processes associated with elevation of blood uric acid levels in the body. Thus, ERK1/2 inhibition may be a potential approach for the prevention and treatment of hyperuricemic nephropathy.

// Thomas J. Schnoeller 1 , Florian Jentzmik 1, 2 , Andres J. Schrader 3 and Julie Steinestel 3 1 Department of Urology, Ulm University Medical Center, Ulm, Germany 2 Department of Urology, St. Elisabeth Hospital, Ravensburg, Germany 3 Department of Urology, Muenster University Medical Center, Muenster, Germany Correspondence to: Julie Steinestel, email: Julie.steinestel@ukmuenster.com Keywords: prostate cancer, tumor biology, biomarker, cholesterol, statin therapy Received: February 13, 2017 Accepted: March 14, 2017 Published: April 07, 2017 ABSTRACT Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p

// Pengfei Chen 1, 2, 3, * , Fan Wang 1, 2, * , Juerong Feng 1, 2 , Rui Zhou 1, 2 , Ying Chang 1, 2 , Jing Liu 1, 2 and Qiu Zhao 1, 2 1 Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China 2 Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China 3 Department of Gastroenterology, The Central Hospital of Enshi Autonomous Prefecture, Enshi, China * These authors contributed equally to this work Correspondence to: Qiu Zhao, email: zhaoqiuwhu@163.com Keywords: hepatocellular carcinoma, co-expression network analysis, hub genes, metastasis risk, prognosis Received: January 31, 2017 Accepted: March 21, 2017 Published: April 06, 2017 ABSTRACT Hepatocellular carcinoma (HCC) has a high incidence and mortality worldwide, and its carcinogenesis and progression are influenced by a complex network of gene interactions. A weighted gene co-expression network was constructed to identify gene modules associated with the clinical traits in HCC ( n = 214). Among the 13 modules, high correlation was only found between the red module and metastasis risk (classified by the HCC metastasis gene signature) (R 2 = –0.74). Moreover, in the red module, 34 network hub genes for metastasis risk were identified, six of which (ABAT, AGXT, ALDH6A1, CYP4A11, DAO and EHHADH) were also hub nodes in the protein-protein interaction network of the module genes. Thus, a total of six hub genes were identified. In validation, all hub genes showed a negative correlation with the four-stage HCC progression ( P for trend 1). RNA-sequencing data of 142 HCC samples showed consistent results in the prognosis. Gene set enrichment analysis (GSEA) demonstrated that in the samples with any hub gene highly expressed, a total of 24 functional gene sets were enriched, most of which focused on amino acid metabolism and oxidation. In conclusion, co-expression network analysis identified six hub genes in association with HCC metastasis risk and prognosis, which might improve the prognosis by influencing amino acid metabolism and oxidation.

Gastrointestinal malignancy is a severe public health threat worldwide, and survival for most types of gastrointestinal cancer is very poor. Therefore, finding better cancer biomarkers to diagnose gastrointestinal malignancy and predict patient survival is essential. HDAC1 has been reported to be closely associated with several types of cancer, but the precise role of HDAC1 in gastrointestinal cancer is not clear. Recently, quite a few studies have investigated the correlation between HDAC1 expression and clinical features or prognosis in multiple types of gastrointestinal malignancies, but the results were inconsistent. In this study, we systematically reviewed the association between HDAC1 and gastrointestinal malignancy using meta-analysis methods, and 28 eligible studies were analyzed. We found that the expression level of HDAC1 in gastrointestinal malignancies, especially in colorectal cancer (OR = 10.84, 95% CI = 5.33–22.07, P< 0.00001), was higher than that in noncancerous tissue, and HDAC1 expression was closely associated with some clinical features of gastrointestinal cancer patients, such as tumor stage (OR = 1.62, 95% CI = 1.28–2.05, P < 0.0001) and tumor grade (OR = 1.75, 95% CI = 1.03–2.95, P = 0.04). In addition, we also found that patients with low HDAC1 expression showed better overall survival than those with high HDAC1 expression in gastrointestinal malignancy, especially in gastric cancer (HR = 1.88, 95% CI = 1.14–3.12, P = 0.01). Our results strongly suggest that HDAC1 may serve as a good diagnostic and prognostic marker for gastrointestinal malignancy.

// Lei Chang 1 and Ruixia Guo 1 1 Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China Correspondence to: Lei Chang, email: nancy_lei7985@163.com Keywords: cervix cancer, radiotherapy, chemotherapy, efficacy, network meta-analysis Received: November 24, 2016 Accepted: February 15, 2017 Published: April 20, 2017 ABSTRACT Background: Cervix cancer was the second most common cancer in female. However, there was no network meta-analysis (NMA) comparing the efficacy of the multiple chemotherapeutic interventions combined with radiation therapy in patients after operation. Methods: Randomized controlled trials were retrieved from PubMed, Embase and Cochrane Library. Overall survival (OS), recurrence-free survival (RFS), incidence of recurrence and distant metastasis were the main outcomes, particularly 5-year OS and PFS were considered as primary outcomes. Furthermore, the hazard ratio (HR) or odds ratio (OR) and their 95% credible intervals (CrIs) were extracted. The surface under cumulative ranking curve (SUCRA) was also used in this NMA. Results: A total of 39 eligible trials with 8,952 patients were included and 22 common chemotherapies were evaluated in this meta-analysis. For OS, cisplatin+fluorouracil+hydroxyurea, fluorouracil+mitomycin C, cisplatin and cisplatin+fluorouracil were better than placebo. As for RFS, cisplatin+fluorouracil, fluorouracil+mitomycin C, and cisplatin alone had the significant superiority compared with placebo. In terms of incidence of recurrence, the optimal drug combination was cisplatin+ifosfamide (0.93) based on SUCRA. Moreover, epirubicin (OR = 0.28, 95% CrI: 0.08-0.91) was the only one had the distinguished potency in reducing the occurrence of distant metastasis with a SUCRA rank probability of 0.88. Conclusion: We recommended cisplatin+fluorouracil+hydroxyurea and cisplatin+docetaxel for their good efficacy in long term survival. Meanwhile, the combination of multiple drugs with different mechanisms worked better.

// Soo Hyun Lee 1, 2, * , Jung-Sun Kim 3, * , Siyuan Zheng 4 , Jason T. Huse 2 , Joon Seol Bae 1 , Ji Won Lee 5 , Keon Hee Yoo 5 , Hong Hoe Koo 5 , Sungkyu Kyung 6 , Woong-Yang Park 1, 7 and Ki W. Sung 5 1 Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea 2 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 4 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 6 Department of Bioinformatics, Sungsil University, Seoul, Republic of Korea 7 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Woong-Yang Park, email: woongyang.park@samsung.com Ki W. Sung, email: kwsped@skku.edu Keywords: ARID1B, ALK, MYCN, neuroblastoma, sequencing Received: July 02, 2016 Accepted: April 11, 2017 Published: April 28, 2017 ABSTRACT Targeted panel sequencing was performed to determine molecular targets and biomarkers in 72 children with neuroblastoma. Frequent genetic alterations were detected in ALK (16.7%), BRCA1 (13.9%), ATM (12.5%), and PTCH1 (11.1%) in an 83-gene panel. Molecular targets for targeted therapy were identified in 16 of 72 patients (22.2%). Two-thirds of ALK mutations were known to increase sensitivity to ALK inhibitors. Sequence alterations in ARID1B were identified in 5 of 72 patients (6.9%). Four of five ARID1B alterations were detected in tumors of high-risk patients. Two of five patients with ARID1B alterations died of disease progression. Relapse-free survival was lower in patients with ARID1B alterations than in those without ( p = 0.01). In analysis confined to high-risk patients, 3-year overall survival was lower in patients with an ARID1B alteration (33.3 ± 27.2%) or MYCN amplification (30.0 ± 23.9%) than in those with neither ARID1B alteration nor MYCN amplification (90.5 ± 6.4%, p = 0.05). These results provide possibilities for targeted therapy and a new biomarker identifying a subgroup of neuroblastoma patients with poor prognosis.

Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.

// Jiqiao Shen 1, * , Jing Zhao 1, * , Tao Jiang 1, * , Xuefei Li 2 , Chao Zhao 2 , Chunxia Su 1 and Caicun Zhou 1 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, P.R. China 2 Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China * These authors contributed equally to this work Correspondence to: Chunxia Su, email: susu_mail@126.com Keywords: small cell lung cancer, circulating tumor cell, count Received: March 15, 2017 Accepted: March 31, 2017 Published: April 11, 2017 ABSTRACT To assess the predictive and prognostic significance of folate receptor (FR)-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) received first-line chemotherapy. Eligible patients with chemotherapy-naive, unresectable SCLC were enrolled and blood samples were collected. CTCs were enumerated using ligand-targeted polymerase chain reaction (LT-PCR) at baseline, after two cycles of chemotherapy regimen and on disease progression. In total, 80 patients were enrolled and 67 (83.8%) had positive CTC count at baseline (CTCs ≥ 8.7 FU/3mL). The baseline CTC counts in patients with partial response (PR) were significantly higher than those with progression disease (PD) ( P = 0.0365). An obvious reduction of CTC enumeration after two cycles of chemotherapy was significantly correlated with PR ( P = 0.0380), instead of SD ( P = 0.4934). Among positive CTC count group, patients with relative low CTC level had significantly longer progression-free survival (PFS) and overall survival (OS) than those with high CTC level (PFS: 9.1 vs 6.9 months, P = 0.0458; OS: 11.1 vs 8.6 months, P = 0.056). In multivariate analysis, distant metastases (HR = 1.466, P = 0.021) and relative low CTC level (HR = 0.656, P = 0.049) were the independent predictive factors for patients with SCLC received first-line chemotherapy. The present results demonstrated that baseline CTC counts could be the valuable predictive and prognostic biomarker for patients with SCLC received first-line chemotherapy. The reduction of CTC enumeration after two cycles of chemotherapy was a potential predictor of chemotherapeutic response in SCLC.

Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease that almost exclusively affects women. LAM cells migrate to the lungs, where they cause cystic destruction of lung parenchyma. Mutations in TSC1 or TSC2 lead to the activation of the mammalian target of rapamycin complex-1, a kinase that regulates growth factor-dependent protein translation, cell growth, and metabolism. Insulin-like growth factor binding protein 2 (IGFBP2) binds insulin, IGF1 and IGF2 in circulation, thereby modulating cell survival, migration, and invasion in neoplasms. In this study, we identified that IGFBP2 primarily localized in the nucleus of TSC2-null LAM patient-derived cells in vitro and in vivo. We also showed that nuclear accumulation of IGFBP2 is closely associated with estrogen receptor alpha (ERa) expression. Furthermore, estrogen treatment induced IGFBP2 nuclear translocation in TSC2-null LAM patient-derived cells. Importantly, depletion of IGFBP2 by siRNA reduced cell proliferation, enhanced apoptosis, and decreased migration and invasion of TSC2-null LAM patient-derived cells. More interestingly, depletion of IGFBP2 markedly decreased the phosphorylation of MAPK in LAM patient-derived TSC2-null cells. Collectively, these results suggest that IGFBP2 plays an important role in promoting tumorigenesis, through estrogen and ERalpha signaling pathway. Thus, targeting IGFBP2 may serve as a potential therapeutic strategy for women with LAM and other female gender specific neoplasms.

SNORD47 is a member of the C/D box small nucleolar RNAs, which have been implicated in cancer development. We intended to investigate the therapeutic potential of SNORD47 in glioma. We found that the expression of SNORD47 was downregulated in glioma tissues samples and inversely associated with advanced tumor stage (WHO grade IV). Kaplan-Meier survival analysis revealed that glioma patients with high SNORD47 expression had longer overall survival than those with low SNORD47 expression. SNORD47 suppressed the proliferation of glioma cells and induced G2 phase arrest. In addition, upregulation of SNORD47 suppressed invasion and epithelial-mesenchymal transition in glioma cells, and combination treatment with lenti-SNORD47 could augment the anti-tumor effect of temozolomide. These results showed that SNORD47 acted as a tumor suppressor in glioma, and provided the potential anti-tumor function in glioma treatment.

// Yongbin Zheng 1 , Chao Yang 1 , Shilun Tong 1 , Yu Ding 1 , Wenhong Deng 1 , Dan Song 1 , Kuang Xiao 1 1 Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China Correspondence to: Yongbin Zheng, email: zhengyongbinhb@163.com Keywords: colorectal cancer, variation, genetic, TINCR, lncRNA Received: January 05, 2017 Accepted: February 13, 2017 Published: March 24, 2017 ABSTRACT Colorectal cancer (CRC) accounts for the leading causes of cancer-related morbidity and mortality. However, a large part of heritable factors are warranted to be explored. Long non-coding RNAs (lncRNAs) serve critical roles in cancer development and progression. Herein, we explored effect of genetic variants of Tissue differentiation-inducing non-protein coding RNA (TINCR), a key lncRNA required for somatic tissue differentiation and tumor progression, on risk and progression of CRC. Three tagSNPs, including rs2288947, rs8105637, and rs12610531, were evaluated in in a two-stage, case-control study. Two SNPs, rs2288947 and rs8105637, were significantly associated with susceptibility of CRC in both stages. When pooled together, the allele G was significantly associated with 23% decreased risk of CRC (OR=0.77; 95% CI=0.67-0.88; P value = 1.2×10 -4 )for SNP rs2288947. While for SNP rs8105637, the allele A was significantly associated with 22% increased risk of CRC (OR=1.22; 95% CI=1.09-1.37; P value = 6.2×10 -4 ). The two SNPs were also statistically associated with occurrence of lymph node metastasis of CRC. The carriers of allele G are less likely to get lymph node metastasis (OR=0.77; 95% CI=0.63-0.94; P value = 0.011) for rs2288947, and the carriers of allele A are more likely to get lymph node metastasis (OR=1.22; 95% CI=1.03-1.43; P value = 0.019) for rs8105637. These results suggest that lncRNA TINCR polymorphisms may be implicated in the development and progression of CRC.

// Ran Liu 1, * , Huiting Wei 2, * , Peng Gao 3 , Hu Yu 4 , Ke Wang 4 , Zheng Fu 2 , Baohui Ju 5 , Meng Zhao 4 , Shangwen Dong 6 , Zhijun Li 6 , Yifeng He 7 , Yuting Huang 4 and Zhi Yao 2 1 Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China 2 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300071, China 3 University of the District of Columbia, Washington D.C., 20008, United States 4 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300040, China 5 Second Hospital of Tianjin Medical University, Tianjin, 300211, China 6 Tianjin Medical University General Hospital, Tianjin, 300052, China 7 Department of Gynecology and Obstetrics, Renji Hospital, Shanghai, 200127, China * These authors have contributed equally to this work Correspondence to: Zhi Yao, email: yaozhi@tijmu.edu.cn Yuting Huang, email: hyacinth0256228@hotmail.com Keywords: ovarian cancer, CD47, macrophage, phagocytosis, monoclonal antibody Received: January 20, 2017 Accepted: February 22, 2017 Published: March 24, 2017 ABSTRACT Targeting CD47 efficiently enhances macrophage phagocytosis in both physiological and pathological conditions. Anti-CD47 antibodies have been shown to inhibit the progression of several types of cancer. However, the mechanism of anti-CD47 monoclonal antibody (mAb) treatment remains controversial. In this study, we confirmed that CD47 protein is highly expressed in ovarian cancer, and is correlated with poor clinical characteristics and prognosis. CD47 knockdown in the ovarian cancer cell line, SK-OV-3, promoted phagocytosis by macrophages in vitro and inhibited tumor growth in vivo . These data combined suggest that CD47 inhibition is a potential strategy for cancer treatment. Using an anti-CD47 mAb, we found that CD47 inhibition in both SK-OV-3 cells and primary cancer cells was able to recapitulate our knockdown results and led to an increase in the number of infiltrating macrophages. In addition, the CD133 + tumor initiating cells expressed a high level of CD47, and anti-CD47 mAb treatment was able to trigger the phagocytosis of this cell population. In conclusion, our results indicate that CD47 inhibits macrophage phagocytosis of ovarian cancer cells, and down-regulation of CD47 or inhibiting CD47 by mAb was able to reverse the negative effect. Thus, CD47 antibody therapy may be a promising strategy to treat ovarian cancer.

B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients’ clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.

// Mandy Menzel 1 , Hamid Akbarshahi 1 , Ellen Tufvesson 2 , Carl Persson 3 , Leif Bjermer 2 , Lena Uller 1 1 Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden 2 Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden 3 Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden Correspondence to: Lena Uller, email: Lena.Uller@med.lu.se Keywords: asthma, rhinovirus, azithromycin, MDA5, IFNβ Received: February 08, 2017 Accepted: March 12, 2017 Published: March 18, 2017 ABSTRACT Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulus-induced asthma exacerbations. Azithromycin dose-dependently augmented viral-induced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of MDA5 but not RIG-I in azithromycin’s IFN-inducing effects in vitro . In vivo azithromycin induced IFNβ protein, restoring a reduced lung IFN response exclusively in allergic exacerbating mice. This was associated with induction of interferon-stimulated genes and MDA5, but not RIG-I. We suggest that clinically relevant concentrations of azithromycin produce MDA5-dependent, anti-viral, IFN-inducing effects in bronchial epithelium distinctly from asthmatic donors. Similarly, azithromycin induced MDA5-associated IFN in virally stimulated lungs in vivo exclusively in allergic mice. Effects of azithromycin and MDA5-active drugs on viral-induced exacerbations deserve further research.

// Zaixiang Tang 1, 2, 3, 4 , Qinghua Zeng 5 , Yan Li 4 , Xinyan Zhang 4 , Jinlu Ma 5, 6 , Mark J. Suto 5 , Bo Xu 5 , Nengjun Yi 4 1 Department of Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou 215123, China 2 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, 215123, China 3 Center for Genetic Epidemiology and Genomics, Medical College of Soochow University, Suzhou, 215123, China 4 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA 5 Drug Discovery Division, Southern Research Institute, Birmingham, AL 35294, USA 6 Department of Radiation Oncology, The First Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, 710061, China Correspondence to: Nengjun Yi, email: nyi@uab.edu Bo Xu, email: bxu@southernresearch.org , bxu@uab.edu Keywords: gene signature, radio-sensitivity, radiotherapy, survival prediction, sarcoma Received: September 27, 2016 Accepted: January 24, 2017 Published: March 15, 2017 ABSTRACT Adjuvant radiotherapy is an important clinical treatment option for the majority of sarcomas. The motivation of current study is to identify a gene signature and to predict radiosensitive patients who are most likely to benefit from radiotherapy. Using the public available data of soft tissue sarcoma from The Cancer Genome Atlas, we developed a cross-validation procedure for identifying a gene signature and predicting radiosensitive patients through. The result showed that the predicted radiosensitive patients who received radiotherapy had a significantly better survival with a reduced rate of new tumor event and disease progression. Strata analysis showed that the predicted radiosensitive patients had significantly better survival under radiotherapy independent of histologic types. A hierarchical cluster analysis was used to validate the gene signature, and the results showed the predicted sensitivity for each patient well matched the results from cluster analysis. Together, we demonstrate a radiosensitive molecular signature that can be potentially used for identifying radiosensitive patients with sarcoma.

// Song Park 1, * , Yonghun Sung 1, * , Jain Jeong 1 , Minjee Choi 1 , Jinhee Lee 1 , Wookbong Kwon 1 , Soyoung Jang 1 , Si Jun Park 1 , Hyeng-Soo Kim 1 , Mee-Hyun Lee 3 , Dong Joon Kim 3 , Kangdong Liu 3 , Sung-Hyun Kim 2, 3 , Zigang Dong 3 , Zae Young Ryoo 1 , Myoung Ok Kim 4 1 School of Life Science, BK21 Plus KNU Creative Bio Research Group, College of Natural Sciences, Kyungpook National University, Buk-ku, Daegu 41566, Republic of Korea 2 Institute of Life Science and Biotechnology, Kyungpook National University, Buk-ku, Daegu 41566, Republic of Korea 3 China-US(Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China 4 The School of Animal BT Science, Kyungpook National University, Sangju-si, Gyeongsangbuk-do 37224, Republic of Korea * These authors contributed equally to this work Correspondence to: Myoung Ok Kim, email: ok4325@knu.ac.kr Zae Young Ryoo, email: jaewoong64@hanmail.net Keywords: hMAGEA2, breast cancer, triple-negative breast cancer, metastasis, Akt Received: December 14, 2016 Accepted: March 06, 2017 Published: March 14, 2017 ABSTRACT Breast cancer is the most abundant cancer worldwide and a severe problem for women. Notably, breast cancer has a high mortality rate, mainly because of tumor progression and metastasis. Triple-negative breast cancer (TNBC) is highly progressive and lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Therefore, there are no established therapeutic targets against TNBC. In this study, we investigated whether the expression of human melanoma-associated antigen A2 (MAGEA2) is associated with TNBC. We found that hMAGEA2 is significantly overexpressed in human TNBC tissues; we also observed oncogenic properties using TNBC cell lines (MDA-MB-231 and MDA-MB-468). The overexpression of hMAGEA2 in MDA-MB-231 cell line showed dramatically increased cellular proliferation, colony formation, invasion, and xenograft tumor formation and growth. Conversely, knockdown of hMAEGA2 in MDA-MB-468 cell line suppressed cellular proliferation, colony formation, and xenograft tumor formation. Additionally, we showed that hMAGEA2 regulated the activation of Akt and Erk1/2 signaling pathways. These data indicate that hMAGEA2 is important for progression of TNBC and may serve as a novel molecular therapeutic target.

// Heng Zhang 1, 2 , Limei Liu 1 , Chungang Liu 1 , Jinhong Pan 2 , Gensheng Lu 2 , Zhansong Zhou 2 , Zhiwen Chen 2 , Cheng Qian 1 1 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 2 Department of Urology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China Correspondence to: Cheng Qian, email: cqian3184@163.com Zhiwen Chen, email: zhiwen@tmmu.edu.cn Keywords: Notch3, urothelial cancer, cisplatin, histone deacetylase, chemoresistance Received: March 14, 2016 Accepted: December 12, 2016 Published: March 13, 2017 ABSTRACT Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo . In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin. Furthermore, suberoylanilide hydroxamic acid (SAHA, a histone deacetylase [HDAC] inhibitor) induced acetylation of NOTCH3, downregulated Notch 3 , prevented urothelial cancer cell proliferation, and induced cell cycle arrest. Taken together, these data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer.