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J Yu, L Chen, B Cui, Christina Wu, M Y Choi, Y Chen, L Zhang, L Z Rassenti, G F Widhopf Ii, T J Kipps
Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Xiao-Ying Zhang, Pei-Ying Zhang
Receptor tyrosine kinases (RTKs) are cell surface glycoproteins with enzymatic activity involved in the regulation of various important functions. In all-important physiological functions including differentiation, cell-cell interactions, survival, proliferation, metabolism, migration and signaling these receptors are the key players of regulation. Additionally, mutations of RTKs or their overexpression have been described in many human cancers and are being explored as a novel avenue for a new therapeutic approach...
November 2016: Oncology Letters
Ashwini Balakrishnan, Tracy Goodpaster, Julie Randolph-Habecker, Benjamin G Hoffstrom, Florencia G Jalikis, Lisa K Koch, Carolina Berger, Paula L Kosasih, Anusha Rajan, Daniel Sommermeyer, Peggy Porter, Stanley R Riddell
PURPOSE: This study examines cell-surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most non-mutated tumor antigens, however prior studies suggest that ROR1 is absent on most normal tissues. EXPERIMENTAL DESIGN: Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell-surface ROR1 by immunohistochemistry (IHC) in FFPE tissues...
November 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yu-Zhu Zheng, Rui Ma, Jian-Kang Zhou, Cheng-Lin Guo, Yong-Sheng Wang, Zheng-Guang Li, Lun-Xu Liu, Yong Peng
Currently, there is no reliable biomarker to clinically predict the prognosis of lung adenocarcinoma (ADC). The receptor-tyrosine-kinase like orphan receptor 1 (ROR1) is reported to be overexpressed and associated with poor prognosis in several tumors. This study aimed to examine the expression of ROR1 and evaluate its prognostic significance in human lung ADC patients. In this present study, Western blot analysis and immunohistochemistry were performed to characterize expression of ROR1 protein in lung ADC patients...
November 10, 2016: Scientific Reports
Bing Cui, Emanuela M Ghia, Liguang Chen, Laura Z Rassenti, Christopher DeBoever, George F Widhopf, Jian Yu, Donna S Neuberg, William G Wierda, Kanti R Rai, Neil E Kay, Jennifer R Brown, Jeffrey A Jones, John G Gribben, Kelly A Frazer, Thomas J Kipps
ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1(Neg)), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1(Pos)). Transcriptome analyses revealed that ROR1(Neg) cases generally could be distinguished from those that were ROR1(Pos) in unsupervised gene-expression clustering analysis...
December 22, 2016: Blood
Nora Bengoa-Vergniory, Irantzu Gorroño-Etxebarria, Inmaculada López-Sánchez, Michele Marra, Pierluigi Di Chiaro, Robert Kypta
Wnt proteins preferentially activate either β-catenin-dependent or β-catenin-independent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a β-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a...
October 5, 2016: Molecular Neurobiology
Na Zhang, Guangyi Jin, Zhenchao Jin, Bing Liu, Boya Peng, Ningning Gao, Yunlong Hu, Li Tang
Objective To investigate the synergistic anti-breast cancer effect of Toll-like receptor 7 agonist T7-ethacrynic acid conjugate (T7-EA) in combination with receptor-tyrosine-kinase-like orphan receptor 1 (ROR1). Methods ROR1 cytotoxic T lymphocyte (CTL) epitope was predicted using Syfpeithi online software. Mouse spleen lymphocytes and bone marrow dendritic cells (DCs) were separately stimulated with 4 μmol/L T7-EA and 4 μmol/L ROR1 alone or in combination. ELISA assay was used to measure the levels of interferon-γ (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α)...
July 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
C E Henry, E Llamosas, A Djordjevic, N F Hacker, C E Ford
Ovarian cancer survival remains poor despite recent advances in our understanding of genetic profiles. Unfortunately, the majority of ovarian cancer patients have recurrent disease after chemotherapy and lack other treatment options. Wnt signalling has been extensively implicated in cancer progression and chemoresistance. Therefore, we investigated the previously described Wnt receptors ROR1 and ROR2 as regulators of epithelial-to-mesenchymal transition (EMT) in a clinically relevant cell line model. The parental A2780- and cisplatin-resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance...
May 30, 2016: Oncogenesis
Yang Zeng, Yoshika Kurokawa, Tin-Tin Win-Shwe, Qin Zeng, Seishiro Hirano, Zhenya Zhang, Hideko Sone
Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH2) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers...
2016: Journal of Toxicological Sciences
Oscar Diaz-Horta, Clemer Abad, Levent Sennaroglu, Joseph Foster, Alexandra DeSmidt, Guney Bademci, Suna Tokgoz-Yilmaz, Duygu Duman, F Basak Cengiz, M'hamed Grati, Suat Fitoz, Xue Z Liu, Amjad Farooq, Faiqa Imtiaz, Benjamin B Currall, Cynthia Casson Morton, Michiru Nishita, Yasuhiro Minami, Zhongmin Lu, Katherina Walz, Mustafa Tekin
Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Lixing Yang, Mi-Sook Lee, Hengyu Lu, Doo-Yi Oh, Yeon Jeong Kim, Donghyun Park, Gahee Park, Xiaojia Ren, Christopher A Bristow, Psalm S Haseley, Soohyun Lee, Angeliki Pantazi, Raju Kucherlapati, Woong-Yang Park, Kenneth L Scott, Yoon-La Choi, Peter J Park
Although exome sequencing data are generated primarily to detect single-nucleotide variants and indels, they can also be used to identify a subset of genomic rearrangements whose breakpoints are located in or near exons. Using >4,600 tumor and normal pairs across 15 cancer types, we identified over 9,000 high confidence somatic rearrangements, including a large number of gene fusions. We find that the 5' fusion partners of functional fusions are often housekeeping genes, whereas the 3' fusion partners are enriched in tyrosine kinases...
May 5, 2016: American Journal of Human Genetics
Wenqi Ma, Xin He, Hongli Zhang, Ting Liu, Xiaolei Feng, Qi Zhou
OBJECTIVE: To investigate the expression of receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) and its role in cell growth in human colorectal carcinoma (CRC). METHODS: Real-time quantitative PCR (qRT-PCR) and immunohistochemistry (IHC) were used to detect the expression of ROR1 in CRC (n=60) and matched tumor-adjacent tissues. The relationship between the expression of ROR1 and clinical features was analyzed by Pearson chi-square test. siRNA was used to down-regulate the expression of ROR1 in SW480 cells in vitro...
May 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Abdul Salam Khan, Mohammad Hojjat-Farsangi, Amir Hossein Daneshmanesh, Lotta Hansson, Parviz Kokhaei, Anders Österborg, Håkan Mellstedt, Ali Moshfegh
Dishevelled (DVL) proteins are components of the Wnt signalling pathways, and increased expression is associated with various malignancies. Information on DVLs in chronic lymphatic leukaemia (CLL) is limited. The aim of the present study was to investigate the role of DVLs in CLL cells and association with Wnt pathways downstream of ROR1. DVL1, 2 and 3 were exclusively expressed in CLL cells as compared to normal peripheral blood mononuclear cells (PBMCs). The expression of DVL1 and DVL3 proteins was significantly more pronounced in progressive than in non-progressive disease (p < 0...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Mitsuyo Matsumoto, Keiichi Kondo, Takuma Shiraki, Andrey Brydun, Ryo Funayama, Keiko Nakayama, Nobuo Yaegashi, Hideki Katagiri, Kazuhiko Igarashi
The transcription repressor BTB and CNC homology 1 (BACH1) represses genes involved in heme metabolism and oxidative stress response. BACH1 also suppresses the p53-dependent cellar senescence in primary mouse embryonic fibroblasts (MEFs). To investigate the role of BACH1 in MEF other than its known functions, we carried out a genomewide mapping of binding site for BACH1 and its heterodimer partner MAFK in immortalized MEFs (iMEFs) using chromatin immunoprecipitation and next-generation sequencing technology (ChIP-sequence)...
June 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Eun-Hwa Jung, Han-Na Lee, Gi-Yeon Han, Min-Jung Kim, Chan-Wha Kim
Glioblastoma is the most malignant of brain tumours and is difficult to cure because of interruption of drug delivery by the blood-brain barrier system, its high metastatic capacity and the existence of cancer stem cells (CSCs). Although CSCs are present as a small population in malignant tumours, CSCs have been studied as they are responsible for causing recurrence, metastasis and resistance to chemotherapy and radiotherapy for cancer. CSCs have self-renewal characteristics like normal stem cells. The aim of this study was to investigate whether receptor tyrosine kinase-like orphan receptor 1 (ROR1) is involved in stem cell maintenance and malignant properties in human glioblastoma...
April 2016: Cell Biochemistry and Function
Hui-Ping Chien, Shir-Hwa Ueng, Shin-Cheh Chen, Yu-Sun Chang, Yung-Chang Lin, Yun-Feng Lo, Hsien-Kun Chang, Wen-Yu Chuang, Yi-Ting Huang, Yun-Chung Cheung, Shih-Che Shen, Chuen Hsueh
Overexpression of receptor tyrosine kinase-like orphan receptor (ROR1) in a variety of human malignancies is associated with aggressive behaviour. Therapeutic agents targeting ROR1 have shown promising results in vivo and in vitro studies. In breast cancer, high-level expression of ROR1 mRNA is associated with high-grade tumours and metastasis. We investigated the prevalence and prognostic significance of ROR1 expression in triple negative breast cancer (TNBC). ROR1 was immunohistochemically stained on full-face sections of 210 TNBC patient samples...
May 2016: Virchows Archiv: An International Journal of Pathology
Annalen Bleckmann, Lena-Christin Conradi, Kerstin Menck, Nadine Annette Schmick, Antonia Schubert, Eva Rietkötter, Jetcy Arackal, Peter Middel, Alexandra Schambony, Torsten Liersch, Kia Homayounfar, Tim Beißbarth, Florian Klemm, Claudia Binder, Tobias Pukrop
Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study...
April 2016: Clinical & Experimental Metastasis
Xiaoyuan Qi, Yuka Okinaka, Michiru Nishita, Yasuhiro Minami
Spatiotemporally regulated interaction between the metanephric mesenchyme (MM) and Wolffian duct (WD) is essential for the induction of a single ureteric bud (UB). The MM then interacts with the tip of the UB to induce outgrowth and branching of the UB, which in turn promotes growth of the adjacent MM. The Ror family receptor tyrosine kinases, Ror1 and Ror2, have been shown to act as receptors for Wnt5a to mediate noncanonical Wnt signaling. Previous studies have shown that Ror2-mutant mice exhibit ectopic formation of the UB, due to abnormal juxtaposition of the MM to the WD...
April 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) sustains prosurvival signalling directly downstream of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinoma. Here we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1...
2016: Nature Communications
Jian Yu, Liguang Chen, Bing Cui, George F Widhopf, Zhouxin Shen, Rongrong Wu, Ling Zhang, Suping Zhang, Steven P Briggs, Thomas J Kipps
Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. We found that Wnt5a enhanced proliferation and migration of chronic lymphocytic leukemia (CLL) cells and that these effects were blocked by the humanized anti-ROR1 mAb cirmtuzumab (UC-961). Treatment of CLL cells with Wnt5a induced ROR1 to oligomerize with ROR2 and recruit guanine exchange factors (GEFs), which activated Rac1 and RhoA; siRNA-mediated silencing of either ROR1 or ROR2 or treatment with UC-961 inhibited these effects...
February 2016: Journal of Clinical Investigation
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