• antibody–drug conjugates (ADCs)
• cancer immunotherapy
• chimeric antigen receptor T cell (CAR-T)
• monoclonal antibodies (mAbs)
• receptor tyrosine kinase-like orphan receptors (ROR1 and ROR2)

• Humans
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Receptor Tyrosine Kinase-like Orphan Receptors/antagonists & inhibitors
• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• Receptor Tyrosine Kinase-like Orphan Receptors/immunology
• Neoplasms/therapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Immunotherapy/methods
• Animals
• Signal Transduction
• Molecular Targeted Therapy
• Wnt-5a Protein/metabolism

• 2019YFA0904400 National Key R&D Program of China
• 2023A1515010549 Natural Science Foundation of Guangdong Province
• FDCT/0009/2023/RIC Science and Technology Development Fund of Macau
• MYRG2022-00143-FHS University of Macau

• molecular mechanisms
• precision medicine
• renal cancer
• signaling pathways
• targeted therapy

• National Natural Science Foundation of China
• Natural Science Foundation of Jiangsu Province

• Apoptosis
• Metastasis
• PI3K/AKT/mTOR signaling
• Proliferation
• Receptor tyrosine kinase-like orphan receptor 2
• Triplet-negative breast cancer

• Humans
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/metabolism
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• TOR Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Drug Resistance, Neoplasm/genetics
• Female
• Signal Transduction
• Phosphatidylinositol 3-Kinases/metabolism
• Cell Line, Tumor
• Cell Movement
• Neoplasm Invasiveness
• Gene Expression Regulation, Neoplastic
• Doxorubicin/pharmacology

• Differentiation
• Hepatocellular carcinoma
• Immunohistochemistry
• ROR2
• Wnt signaling

• Humans
• Carcinoma, Hepatocellular/pathology
• Cell Differentiation
• Liver Neoplasms/pathology
• Prognosis
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Wnt Signaling Pathway

• JP23K15466 Japan Society for the Promotion of Science
• GSK Japan Research Grant 2017 GSK Japan Research Grant
• JP19fk0210018 Japan Agency for Medical Research and Development

• SRY-Box Transcription Factor 3 (SOX3)
• TOF
• congenital heart disease
• heat shock protein A6 (HSPA6)
• receptor tyrosine kinase-like orphan receptor (ROR2)
• β-Catenin

• Humans
• beta Catenin/genetics
• beta Catenin/metabolism
• Down-Regulation/genetics
• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• SOXB1 Transcription Factors/metabolism
• Tetralogy of Fallot/genetics
• Wnt Signaling Pathway/genetics

• 8170315 Data Center of Management Science, National Natural Science Foundation of China - Peking University
• 82071583 Data Center of Management Science, National Natural Science Foundation of China - Peking University
• Taishan Scholarship Program

• Cancer metastasis
• DVL
• Dishevelled
• FZD
• Frizzled
• Non-canonical WNT signaling
• Omodysplasia
• ROR
• Robinow syndrome
• Tissue morphogenesis
• WNT5A

• Wnt Proteins/genetics
• Wnt Proteins/metabolism
• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Wnt-5a Protein/genetics
• Wnt-5a Protein/metabolism
• Signal Transduction/physiology
• Morphogenesis
• Wnt Signaling Pathway

• R01 CA230742 NCI NIH HHS
• R01 CA250211 NCI NIH HHS
• R35 GM119574 NIGMS NIH HHS
• R35 GM144341 NIGMS NIH HHS

• EMT
• ERK
• Invasion
• Melanoma
• Migration
• ROR2
• Tumor necrosis

• 11963 Cancer Research UK
• MR/M019012/1 Medical Research Council
• BID-PICT-2011-1605 Agencia Nacional de Promoción Científica y Tecnológica
• BID-PICT-2015-0513 Agencia Nacional de Promoción Científica y Tecnológica

• Cancer
• Oncogene
• ROR2
• Tumor-suppressor gene

• Cancer
• Immunoconjugates
• Immunotherapy
• Monoclonal antibodies
• Tumor microenvironment

• Cancer stem cells
• Drug resistance
• Signal pathways
• Treatments

• clear cell renal cell carcinoma
• histology
• immunohistochemistry
• molecular subtype
• prognostic classification

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/genetics
• Carcinoma, Renal Cell/diagnosis
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/pathology
• Carcinoma, Renal Cell/surgery
• Female
• Forkhead Box Protein M1/genetics
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Kidney Neoplasms/diagnosis
• Kidney Neoplasms/genetics
• Kidney Neoplasms/pathology
• Kidney Neoplasms/surgery
• Male
• Middle Aged
• Necrosis
• Nephrectomy
• Neuropilin-1/genetics
• Predictive Value of Tests
• RGS Proteins/genetics
• Reproducibility of Results
• Retrospective Studies
• Transcriptome
• Treatment Outcome

• Japan Society for the Promotion of Science

• ROR2
• bladder cancer
• prognosis
• survival
• upper tract urothelial carcinoma

The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca²⁺ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

• CAR T cells
• ROR1
• ROR2
• WNT signaling
• cancer
• immunotherapy
• non-canonical
• targeted therapy

• Animals
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Receptor Tyrosine Kinase-like Orphan Receptors/chemistry
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Wnt Signaling Pathway

The receptor tyrosine kinase like orphan receptor 2 (ROR2) has been implicated in the pathogenesis of a variety of human cancers, including breast cancer. Here, we analyzed the clinical significance of ROR2 in breast cancer (BC) progression, and its function in the regulation of BC cell proliferation and growth. Analysis of ROR2 mRNA levels in 45 BC tissues and adjacent non-tumor tissues revealed that ROR2 expression was significantly increased in BC tissues, and that it correlated with tumor diameter. Kaplan-Meier disease-free survival (DFS) analysis demonstrated that BC patients with higher ROR2 expression had lower DFS. Knockdown of ROR2 suppressed in vitro proliferation of BC cells and promoted apoptosis, while ROR2 overexpression induced BC cell proliferation and suppressed apoptosis. Importantly, ROR2 suppression also reduced the tumor growth in mouse BC xenografts, indicating that ROR2 promotes BC tumorigenesis in vivo. In addition, our data revealed that ROR2 promotes proliferation of BC cells by activating the PI3K/AKT signaling pathway. Together, our results indicate that ROR2 acts as an oncogenic gene in breast cancer, and suggest that the ROR2/PI3K/AKT regulatory network contributes to breast cancer progression.

• PI3K/AKT signaling
• ROR2
• apoptosis
• breast cancer cell
• proliferation

• Extracellular matrix
• Extracellular proteolysis
• MMPs
• Renal cell carcinoma
• TIMPs
• Tumor invasion
• Tyrosine kinase

• X-ray crystallography
• affinity maturation
• antibody engineering
• antigen
• cancer therapy
• epitope mapping
• kringle domain
• receptor tyrosine kinase (RTK) ROR2

Bone marrow‐derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a‐Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co–cultured MKN45 gastric cancer cells via the CXCL16‐CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co–cultured MKN45 cells. We also show that MSC‐derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co–injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti–CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co–injected with MSC. These results suggest that CXCL16 produced through Ror2‐mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6‐STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.

• CXCL16
• Ror1
• STAT3
• bone marrow-derived mesenchymal stem cells
• gastric cancer

• Acyltransferases/antagonists & inhibitors
• Acyltransferases/metabolism
• Carcinoma, Renal Cell/drug therapy
• Carcinoma, Renal Cell/metabolism
• Carcinoma, Renal Cell/pathology
• Cell Line, Tumor
• Down-Regulation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/metabolism
• Kidney Neoplasms/pathology
• Membrane Proteins/antagonists & inhibitors
• Membrane Proteins/metabolism
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/metabolism
• Pyrazines/pharmacology
• Pyridines/pharmacology
• Wnt Signaling Pathway/drug effects

• Forkhead box O (FoxO)
• basic fibroblast growth factor (bFGF)
• cell cycle
• cell signaling
• gene transcription

• Deglycosylation
• MMP-13
• Monoclonal antibody
• ROR2

• Cancer
• WNT receptor
• growth factor receptor
• non-canonical WNT
• pseudokinase
• receptor signalling
• receptor tyrosine kinase

• Animals
• Humans
• Ligands
• Neoplasms/metabolism
• Protein Domains
• Receptor Protein-Tyrosine Kinases/chemistry
• Receptor Protein-Tyrosine Kinases/metabolism
• Wnt Signaling Pathway

We have reported that the phosphatidylinositol-3 kinase (PI3K)/Akt/RhoA signaling pathway mediates Wnt5a-induced cell migration of osteosarcoma cells. However, the specific receptors responding to Wnt5a ligand remain poorly defined in osteosarcoma metastasis.

Wound healing assays were used to measure the migration rate of osteosarcoma cells transfected with shRNA or siRNA specific against ROR2 or indicated constructs. We evaluated the RhoA activation in osteosarcoma MG-63 and U2OS cells with RhoA activation assay. A panel of inhibitors of PI3K and Akt treated osteosarcoma cells and blocked kinase activity. Western blotting assays were employed to measure the expression and activation of Akt. Clonogenic assays were used to measure the cell proliferation of ROR2-knockdown or ROR2-overexpressed osteosarcoma cells.

Wnt5a-induced osteosarcoma cell migration was largely abolished by shRNA or siRNA specific against ROR2. Overexpression of RhoA-CA (GFP-RhoA-V14) was able to rescue the Wnt5a-induced cell migration blocked by ROR2 knockdown. The Wnt5a-induced activation of RhoA was mostly blocked by ROR2 knockdown, and elevated by ROR2 overexpression, respectively. Furthermore, we found that Wnt5a-induced cell migration was significantly retarded by RhoA-siRNA transfection or pretreatment of HS-173 (PI3Kα inhibitor), MK-2206 (Akt inhibitor), A-674563 (Akt1 inhibitor), or CCT128930 (Akt2 inhibitor). The activation of Akt was upregulated or downregulated by transfected with ROR2-Flag or ROR2-siRNA, respectively. Lastly, Wnt5a/ROR2 signaling does not alter the cell proliferation of MG-63 osteosarcoma cells.

Taken together, we demonstrate that ROR2 receptor responding to Wnt5a ligand activates PI3K/Akt/RhoA signaling and promotes the migration of osteosarcoma cells.

• Migration
• Osteosarcoma
• ROR2
• Wnt5a

The tyrosine kinase-like orphan receptor 2 (ROR2) has a wnt-mediated, pro-tumorigenic role in certain types of cancer. The present study was designed to assess the protein expression level of ROR2 and its putative ligand Wnt member 5a (Wnt5a), as well as the association with clinicopathological features in papillary thyroid carcinoma (PTC). A total of 58 patients were recruited, resulting in 58 human PTC tissue samples and their paired adjacent noncancerous tissue samples being obtained. The protein expression levels of ROR2 and Wnt5a were evaluated by immunohistochemistry and western blotting, and messenger RNA expression levels were determined by reverse transcription-quantitative polymerase chain reaction. ROR2 and Wnt5a protein and mRNA expression were significantly overexpressed in PTC tissues (P<0.05). The present study also revealed that ROR2 and Wnt5a were significantly associated with tumor stage and lymph node metastasis (P<0.05). There was a positive association between ROR2 and Wnt5a expression levels (r=0.857; P=0.007). In conclusion, ROR2 and Wnt5a may act as tumor suppressor genes in the development of PTC; overexpression of ROR2 and Wnt5a in PTC may be important for tumorigenesis and tumor development.

• Wnt member 5a
• papillary thyroid carcinoma
• tumor
• tyrosine kinase-like orphan receptor 2

• NF-κB (NF-KB)
• Ror1 receptor kinase
• cell proliferation
• cell signaling
• gene regulation
• gene transcription
• muscle regeneration
• satellite cells (SCs)

The present study investigated the prognostic significance of Wnt family member 5a (Wnt5a) and receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression in laryngeal squamous cell carcinoma (LSCC). The protein expression levels of Wnt5a and Ror2 were analyzed in specimens from 137 patients with LSCC, using immunohistochemical staining of tissue microarrays and pairs of LSCC and adjacent tissue samples, and examined the associations between the two markers and various clinicopathological parameters. The Wnt5a and Ror2 expression levels were significantly higher in LSCC tissues than in normal tissue samples (Wnt5a, P=0.015; Ror2, P=0.039), and were significantly associated with high tumor stage (P<0.001), lymph node metastasis (Wnt5a, P=0.029; Ror2, P=0.018), and with each other (P=0.002). Patients with LSCC with high Wnt5a or Ror2 expression had poorer prognosis compared with those with low Wnt5a (P=0.022) or Ror2 (P=0.038) expression. Thus, Wnt5a and Ror2 may affect LSCC development, and are potential biomarkers in LSCC.

• Wnt family member 5a
• immunohistochemistry
• laryngeal squamous cell carcinoma
• prognosis
• receptor tyrosine kinase-like orphan receptor 2

• Epithelial–mesenchymal transition
• metastasis
• non-canonical Wnt signaling pathway
• ovarian cancer
• receptor tyrosine kinase–like orphan receptor 2 tyrosine kinase

• Cell motility
• Epithelial–mesenchymal transition (EMT)
• Matrix metalloproteinase-2 (MMP-2)
• Metastasis
• Oral squamous cell carcinoma (OSCC)
• Prognosis
• Ror2
• Tongue squamous cell carcinoma
• Wnt5a
• ΔNp63

Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiation and chemotherapy. Current therapies for RCC patients are inefficient due to the lack of diagnostic and therapeutic markers. The expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. In the present study, we investigated the receptor tyrosine kinase-like orphan receptor 2 (Ror2), a new tumor-associated kinase, in RCC primary tumors and cell lines. Knockdown of Ror2 expression in RCC cells with specific shRNA significantly reduced cell proliferation and induced apoptosis. Using in vitro migration and Matrigel invasion assays, we found that cell migration and invasive ability were also significantly inhibited. In RCC, Ror2 expression correlated with expression of genes involved at the cell cycle and migration, including PCNA, CDK1, TWIST, and MMP-2. Furthermore, in vivo xenograft studies in nude mice revealed that administration of a Ror2 shRNA plasmid significantly inhibited tumor growth. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.

• Wnt signaling
• gastric carcinoma
• proliferation
• receptor tyrosine kinase-like orphan receptor 2

• Antibodies
• Colorectal cancer
• Immunohistochemistry
• ROR2

Wnt5A, which is a member of the non-transforming Wnt protein family, is implicated in inflammatory processes. It is also highly expressed by ovarian cancer cells. ROR2, which is a member of the Ror-family of receptor tyrosine kinases, acts as a receptor or co-receptor for Wnt5A. The Wnt5A–ROR2 signaling pathway plays essential roles in the migration and invasion of several types of tumor cell and influences their cell polarity. We investigated the modulation of Wnt5A–ROR2 by inflammatory mediators and its involvement in the migration of the human ovarian cancer cell line SKOV-3.

SKOV-3 cells were treated with LPS (lipopolysaccharide), LTA (lipoteichoic acid) and recombinant human IL-6 alone or in combination with STAT3 inhibitor (S1155S31-201) or NF-kB inhibitor (BAY11-7082) for 4, 8, 12, 24 and 48 h. The Wnt5A and ROR2 expression levels were determined at the gene and protein levels. Cells were transfected with specific siRNA against Wnt5A in the absence or presence of human anti-ROR2 antibody and cell migration was assessed using transwells.

There was a strong downregulation of Wnt5A expression in the presence of STAT3 or NF-kB inhibitors. Cell stimulation with LTA or IL-6 for 8 h led to significantly increased levels of Wnt5A (5- and 3-fold higher, respectively). LPS, LTA or IL-6 treatment significantly increased ROR2 expression (2-fold after 48 h). LPS- or LTA-induced Wnt5A or ROR2 expression was abrogated in the presence of STAT3 inhibitor (p < 0.001). IL-6-induced Wnt5A expression was abrogated by both STAT3 and NF-kB inhibitors (p < 0.001). Although not significant, IL-6-induced ROR2 expression showed a modest decrease when STAT3 inhibitor was used. Moreover, cell migration was decreased by 80 % in siRNA Wnt5A-transfected cells in the presence of anti-human ROR2 antibody (p < 0.001).

This study revealed for the first time that inflammatory mediators modulate Wnt5A and ROR2 through NF-kB and STAT3 transcription factors and this may play a role in ovarian cancer cell migration. The results described here provide new insight into the role of the Wnt5A–ROR2 complex in ovarian cancer progression in relation to inflammation.

• Inflammation
• Migration
• NF-kB/STAT3 signaling pathways
• Ovarian cancer
• ROR2
• Wnt5A

We investigated the expression of receptor tyrosine kinase-like orphan receptor (ROR) 2 and Wnt5a and their prognostic significance in non-small cell lung cancer (NSCLC). Tissue microarray-based immunohistochemical analysis was performed to determine the expression of ROR2 and Wnt5a in 219 patients. mRNA expression of ROR2 and Wnt5a was examined in 20 pairs of NSCLC and matched adjacent normal tissues by real-time PCR. Compared with non-tumorous tissues, both mRNA expression and protein product of ROR2 and Wnt5a genes were significantly increased in NSCLC. c² analysis revealed that high ROR2 or Wnt5a expression in NSCLC was significantly associated with advanced TNM stage. High expression of both ROR2 and Wnt5a was also related to advanced TNM stage. Multivariate analyses suggested that ROR2, Wnt5a and TNM stage were independent prognostic factors in NSCLC. Our clinical findings suggest that high ROR2 or Wnt5a expression is associated with poor prognosis in NSCLC, and combined detection of ROR2 and Wnt5a is helpful in predicting the prognosis of NSCLC.

• RTK-like orphan receptor 2 (ROR2)
• Wnt5a
• immunohistochemistry
• non-small cell lung cancer
• prognosis

• CD44
• ITGA6
• Kidney cancer
• Twist2

Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers.

• Wnt signaling pathway
• development
• renal cell carcinoma
• therapeutic target

• CD44
• ITGA6
• Twist2
• kidney cancer

Wnt-5a is a member of the WNT family of secreted lipoglycoproteins, whose expression increases during development; moreover, Wnt-5a plays a key role in synaptic structure and function in the adult nervous system. However, the mechanism underlying these effects is still elusive. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the gene expression of their targets through hybridization with complementary sequences in the 3′ UTR, thereby inhibiting the translation of the target proteins. Several evidences indicate that the miRNAs are actively involved in the regulation of neuronal function.

In the present study, we examined whether Wnt-5a modulates the levels of miRNAs in hippocampal neurons. Using PCR arrays, we identified a set of miRNAs that respond to Wnt-5a treatment. One of the most affected miRNAs was miR-101b, which targets cyclooxygenase-2 (COX2), an inducible enzyme that converts arachidonic acid to prostanoids, and has been involved in the injury/inflammatory response, and more recently in neuronal plasticity. Consistent with the Wnt-5a regulation of miR-101b, this Wnt ligand regulates COX2 expression in a time-dependent manner in cultured hippocampal neurons.

The biological processes induced by Wnt-5a in hippocampal neurons, involve the regulation of several miRNAs including miR-101b, which has the capacity to regulate several targets, including COX-2 in the central nervous system.

Neural crest cells are a highly migratory pluripotent cell population that generates a wide array of different cell types and failure in their migration can result in severe birth defects and malformation syndromes. Neural crest migration is controlled by various means including chemotaxis, repellent guidance cues and cell-cell interaction. Non-canonical Wnt PCP (planar cell polarity) signaling has previously been shown to control cell-contact mediated neural crest cell guidance. PTK7 (protein tyrosine kinase 7) is a transmembrane pseudokinase and a known regulator of Wnt/PCP signaling, which is expressed in Xenopus neural crest cells and required for their migration. PTK7 functions as a Wnt co-receptor; however, it remains unclear by which means PTK7 affects neural crest migration. Expressing fluorescently labeled proteins in Xenopus neural crest cells we find that PTK7 co-localizes with the Ror2 Wnt-receptor. Further, co-immunoprecipitation experiments demonstrate that PTK7 interacts with Ror2. The PTK7/Ror2 interaction is likely relevant for neural crest migration, because Ror2 expression can rescue the PTK7 loss of function migration defect. Live cell imaging of explanted neural crest cells shows that PTK7 loss of function affects the formation of cell protrusions as well as cell motility. Co-expression of Ror2 can rescue these defects. In vivo analysis demonstrates that a kinase dead Ror2 mutant cannot rescue PTK7 loss of function. Thus, our data suggest that Ror2 can substitute for PTK7 and that the signaling function of its kinase domain is required for this effect.

• Animals
• Cell Movement
• Neural Crest/cytology
• Neural Crest/embryology
• Neural Crest/metabolism
• Protein Binding
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Wnt Signaling Pathway
• Xenopus
• Xenopus Proteins/genetics
• Xenopus Proteins/metabolism

Primary thyroid lymphoma (PTL) is a rare malignant thyroid tumor; its pathogenesis is closely related to chronic lymphocytic thyroiditis. The different pathological subtypes and stages of PTL have distinct clinical characteristics and prognosis, but the specific reasons are not clear. Wnt5a is a representative protein of non-canonical Wnt signaling. It plays an important role in many different types of tumors. This study is to explore the changes of Wnt5a and its receptor Ror2 in PTL development process and the clinical significance of their represent. We collected 22 PTL patient tumor specimens and clinical data. We observed the expression of Wnt5a and Ror2 in PTL tumor tissues by immunohistochemistry. Wnt5a was expressed positively in 12 (54.5 %) cases, and Ror2 was expressed positively in 18 (81.8 %) cases. The expression of Wnt5a had a significant difference in different pathological subtypes of PTL (P < 0.05). Wnt5a and Ror2 expression were associated with local invasion and clinical stage, respectively (P < 0.05), and had no significant correlation with age, gender, and tumor size. Although, no significant difference in overall survival was found between positive and negative groups of Wnt5a (P = 0.416) or Ror2 (P = 0.256), respectively. We still consider that Wnt5a and Ror2 play a complex and subtle role in the pathogenesis and progression of PTL and may become potential biomarkers and therapeutic targets of PTL.

• Immunohistochemistry
• Primary thyroid lymphoma
• Ror2
• Wnt5a

• cell cycle progression
• colony formation
• osteosarcoma
• proliferation
• receptor tyrosine kinase-like orphan receptor 2

RTK-like orphan receptor 2 (ROR2) is overexpressed in several cancers and has tumorigenic activity. However, the expression of ROR2 and its functional and prognostic significance have yet to be evaluated in pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time polymerase chain reaction was used to characterize the expression of ROR2 mRNA in PDAC, corresponding peritumoral tissues, and PDAC cell lines. Immunohistochemical analysis with tissue microarrays was used to evaluate ROR2 expression in PDAC and to investigate the relationship of this expression to clinicopathological factors and prognosis. The expression of ROR2 mRNA and protein was significantly higher in PDAC than in normal pancreatic tissues. High cytoplasmic ROR2 expression in cancer cells was significantly associated with a primary tumor, distant metastasis, and TNM stage, and high stromal ROR2 expression was significantly associated with regional lymph node metastasis and TNM stage. The Kaplan–Meier method and Cox regression analyses showed that high ROR2 expression in tumor cytoplasm or stromal cells was significantly associated with malignant attributes and reduced survival in PDAC. We present strong evidence that ROR2 could be used as an indicator of poor prognosis and could represent a novel therapeutic target for PDAC.