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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...
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...
April 16, 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
Lisa Ida, Tomoya Yamaguchi, Kiyoshi Yanagisawa, Taisuke Kajino, Yukako Shimada, Motoshi Suzuki, Takashi Takahashi
We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a transcriptional target of the NKX2-1/TTF-1 lineage-survival oncogene in lung adenocarcinoma. ROR1 consequently sustains a favorable balance between pro-survival phosphatidylinositol 3-kinase-protein kinase B and pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1)-p38MAPK signaling. In contrast to recent advances in understanding how ROR1 sustains pro-survival signaling, the mechanism of ROR1 repression of pro-apoptotic signaling remains rather elusive...
February 2016: Cancer Science
Mohammad Hojjat-Farsangi, Mahmood Jeddi-Tehrani, Amir Hossein Daneshmanesh, Fariba Mozaffari, Ali Moshfegh, Lotta Hansson, Seyed Mohsen Razavi, Ramazan Ali Sharifian, Hodjattallah Rabbani, Anders Österborg, Håkan Mellstedt, Fazel Shokri
BACKGROUND: ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients. MATERIALS AND METHODS: Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay...
2015: PloS One
Claire Henry, Estelle Llamosas, Alexandra Knipprath-Meszaros, Andreas Schoetzau, Ellen Obermann, Maya Fuenfschilling, Rosemarie Caduff, Daniel Fink, Neville Hacker, Robyn Ward, Viola Heinzelmann-Schwarz, Caroline Ford
AIM: In recent years, the Wnt signalling pathway has been implicated in epithelial ovarian cancer and its members have potential as diagnostic, prognostic and therapeutic targets. Here we investigated the role of two Wnt receptor tyrosine kinases (RTKs), ROR1 and ROR2, and their putative ligand, Wnt5a, in ovarian cancer. METHODS: Immunohistochemistry for ROR2 was performed in a large patient cohort, including benign controls, borderline tumours and epithelial ovarian cancer...
November 24, 2015: Oncotarget
Natalia Brenda Fernández, Daniela Lorenzo, María Elisa Picco, Gastón Barbero, Leonardo Sebastián Dergan-Dylon, María Paula Marks, Hernán García-Rivello, Liliana Gimenez, Vivian Labovsky, Luca Grumolato, Pablo Lopez-Bergami
The Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is primarily expressed by neural crest cells during embryogenesis. Following a complete downregulation after birth, ROR1 was shown to re-express in various types of cancers. Little is known about ROR1 expression and function in melanoma. Here we show that ROR1 is aberrantly expressed in both melanoma cell lines and tumors and that its expression associates with poor Post-Recurrence Survival of melanoma. Using gain- and loss-of-function approaches we found that ROR1 enhances both anchorage-dependent and -independent growth of melanoma cells...
November 2016: Molecular Carcinogenesis
Abbas Ali Imani Fooladi, Hamideh Mahmoodzadeh Hosseini, Jafar Amani
BACKGROUND: Today, Lack of efficient therapeutic strategy for breast cancer (the most common cause of death in women) is one of the momentous problematic topics for all health care committees. Designing new specific vaccine, based on antigens located on the surface of cancer cells can be useful. Over expression of ROR1, lacked of HER2/neu, and hormone receptors on cell surface in the breast cancer, introduce this protein as an appropriate candidate for designing cancer vaccine. OBJECTIVES: We hypothesized the extracellular domain of receptor tyrosine kinase like orphan receptor 1 (ROR-1) along with a super antigen such as staphylococcal enterotoxin B could be a potent vaccine for drug resistant breast cancer...
May 2015: Iranian Journal of Cancer Prevention
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