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1.
In Vitro Cell Dev Biol Anim ; 60(5): 489-501, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38587578

RESUMO

Ror-family receptors, Ror1 and Ror2, are type I transmembrane proteins that possess an extracellular cysteine-rich domain, which is conserved throughout the Frizzled-family receptors and is a binding site for Wnt ligands. Both Ror1 and Ror2 function primarily as receptors or co-receptors for Wnt5a to activate the ß-catenin-independent, non-canonical Wnt signaling, thereby regulating cell polarity, migration, proliferation, and differentiation depending on the context. Ror1 and Ror2 are expressed highly in many tissues during embryogenesis but minimally or scarcely in adult tissues, with some exceptions. In contrast, Ror1 and Ror2 are expressed in many types of cancers, and their high expression often contributes to the progression of the disease. Therefore, Ror1 and Ror2 have been proposed as potential targets for the treatment of the malignancies. In this review, we provide an overview of the regulatory mechanisms of Ror1/Ror2 expression and discuss how Wnt5a-Ror1/Ror2 signaling is mediated and regulated by their interacting proteins.


Assuntos
Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Proteína Wnt-5a , Humanos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Proteína Wnt-5a/metabolismo , Proteína Wnt-5a/genética , Animais , Via de Sinalização Wnt , Transdução de Sinais , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia
2.
Biochem Biophys Res Commun ; 709: 149829, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38552553

RESUMO

The microRNA-200 (miR-200) family is a potent suppressor of epithelial-to-mesenchymal transition (EMT). While its role as a tumor suppressor has been well documented, recent studies suggested that it can promote cancer progression in several stages. In this study, we investigated whether the miR-200 family members play a role in the acquisition of a hybrid epithelial/mesenchymal (E/M) state, which is reported to be associated with cancer malignancy, in mesenchymal MDA-MB-231 cells. Our results demonstrated that the induction of miR-200c-141, a cluster of the miR-200 family member, can induce the expression of epithelial gene and cell-cell junction while mesenchymal markers are retained. Moreover, induction of miR-200c-141 promoted collective migration accompanied by the formation of F-actin cables anchored by adherens junction. These results suggest that the miR-200 family can induce a hybrid E/M state and endows with the ability of collective cell migration in mesenchymal cancer cells.


Assuntos
Células MDA-MB-231 , MicroRNAs , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Genes Supressores de Tumor , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica
3.
J Biol Chem ; 299(10): 105248, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37703992

RESUMO

Rho in filopodia (Rif), a member of the Rho family of small GTPases, induces filopodia formation primarily on the dorsal surface of cells; however, its function remains largely unclear. Here, we show that Rif interacts with Ror1, a receptor for Wnt5a that can also induce dorsal filopodia. Our immunohistochemical analysis revealed a high frequency of coexpression of Ror1 and Rif in lung adenocarcinoma. Lung adenocarcinoma cells cultured on Matrigel established front-rear polarity with massive filopodia on their front surfaces, where Ror1 and Rif were accumulated. Suppression of Ror1 or Rif expression inhibited cell proliferation, survival, and invasion, accompanied by the loss of filopodia and cell polarity in vitro, and prevented tumor growth in vivo. Furthermore, we found that Rif was required to activate Wnt5a-Ror1 signaling at the cell surface leading to phosphorylation of the Wnt signaling pathway hub protein Dvl2, which was further promoted by culturing the cells on Matrigel. Our findings reveal a novel function of Rif in mediating Wnt5a-Ror1-Dvl2 signaling, which is associated with the formation of polarized filopodia on 3D matrices in lung adenocarcinoma cells.

4.
J Biol Chem ; 298(7): 102090, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35654143

RESUMO

Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices and driving cell migration in complex 3D environments. Previous studies have indicated that microtubules (MTs) play a crucial role in elongation of invadopodia, but not their formation, probably by regulating delivery of membrane and secretory proteins within invadopodia. However, the identity of the responsible MT-based molecular motors and their regulation has been elusive. Here, we show that KIF1C, a member of kinesin-3 family, is localized to the tips of invadopodia and is required for their elongation and the invasion of cancer cells. We also found that c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, thereby enhancing its association with tyrosine phosphatase PTPD1, that in turn activates MT-binding ability of KIF1C, probably by relieving the autoinhibitory interaction between its motor and stalk domains. These findings shed new insights into how c-Src signaling is coupled to the MT-dependent dynamic nature of invadopodia and also advance our understanding of the mechanism of KIF1C activation through release of its autoinhibition.


Assuntos
Genes src , Cinesinas , Invasividade Neoplásica , Podossomos , Linhagem Celular Tumoral , Humanos , Cinesinas/genética , Microtúbulos/metabolismo , Fosforilação , Podossomos/metabolismo , Proteínas Tirosina Fosfatases não Receptoras , Tirosina/metabolismo
5.
Genes Cells ; 27(5): 368-375, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35261108

RESUMO

Accumulating evidence demonstrates that bone marrow (BM)-derived mesenchymal stem cells (MSCs) play critical roles in regulating progression of various types of cancer. We have previously shown that Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, and that CXCL16 secreted from MSCs then binds to its cognate receptor CXCR6 on the surface of an undifferentiated gastric cancer cell line MKN45 cells, eventually leading to proliferation and migration of MKN45 cells. However, it remains unclear about a possible involvement of another (other) cytokine(s) in regulating progression of gastric cancer. Here, we show that CXCL16-CXCR6 signaling is also activated in MSCs through cell-autonomous machinery, leading to upregulated expression of CCL5. We further show that CCR1 and CCR3, receptors of CCL5, are expressed on the surface of MKN45 cells, and that CCL5 secreted from MSCs promotes migration of MKN45 cells presumably via its binding to CCR1/CCR3. These data indicate that cell-autonomous CXCL16-CXCR6 signaling activated in MSCs upregulates expression of CCL5, and that subsequent activation of CCL5-CCR1/3 signaling in MKN45 cells through intercellular machinery can promote migration of MKN45 cells. Collectively, these findings postulate the presence of orchestrated chemokine signaling emanated from MSCs to regulate progression of undifferentiated gastric cancer cells.


Assuntos
Células-Tronco Mesenquimais , Neoplasias Gástricas , Linhagem Celular Tumoral , Quimiocina CXCL16/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo
6.
Oncol Rep ; 47(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34796907

RESUMO

Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring­like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU­Lu­MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU­Lu­MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription­quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU­Lu­MPPt3 CS and AD cells, respectively. Following KU­Lu­MPPt3 CS cell plating onto collagen­coated culture dishes, some cells exhibited a transformation of their morphology into KU­Lu­MPPt3 AD­like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU­Lu­MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU­Lu­MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU­Lu­MPPt3 cells.


Assuntos
Adenocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Humanos
7.
Congenit Anom (Kyoto) ; 61(6): 212-219, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34255394

RESUMO

External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling have been linked to Robinow syndrome, a genetic disorder in which male patients manifest a micropenis and defective urethral tube formation. Whereas Wnt5a is required for cell proliferation during embryonic external genitalia outgrowth, its role for urethral tube formation has yet to be understood. Here, we show that Wnt5a contributes to urethral tube formation as well as external genitalia outgrowth. Wnt5a is expressed in the embryonic external genitalia mesenchyme, and mesenchymal-specific conditional Wnt5a knockout mice resulted in hypospadias-like urethral defects. Early deletion of Wnt5a at E10.5 showed severe defects in both external genitalia outgrowth and urethral tube formation, along with reduced cell proliferation. The severe urethral tube defect persisted during later timing deletion of Wnt5a (E13.5). Further analyses revealed that loss of Wnt5a disrupted cell polarity and led to a reduction of the phosphorylated myosin light chain and the focal adhesion protein, vinculin. Altogether, these results suggest that Wnt5a coordinates cell proliferation and directed cell migration in a stage-dependent manner during male external genitalia development. Furthermore, Wnt5a may regulate cell polarity, focal adhesion formation, and cell contractility, leading to directed cell migration during male-type urethral formation in a manner that has not been reported in other organ fusion events.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Genitália/crescimento & desenvolvimento , Organogênese , Proteína Wnt-5a , Animais , Hipospadia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Proteína Wnt-5a/genética
8.
Oncol Rep ; 46(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34080643

RESUMO

Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)­positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV­related cancers. However, the function of Ror2 in HPV­positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV­negative and HPV­positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV­negative and HPV­positive OPSCC tissues. We then confirmed that HPV­positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV­negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G1/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV­positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV­related cancers.


Assuntos
Neoplasias de Cabeça e Pescoço/virologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Regulação para Cima , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Proteínas Repressoras/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo
9.
Cancer Sci ; 111(4): 1254-1265, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32012403

RESUMO

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.


Assuntos
Quimiocina CXCL16/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Fator de Transcrição STAT3/genética , Neoplasias Gástricas/genética , Animais , Anticorpos Neutralizantes/farmacologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Quimiocina CXCL16/antagonistas & inibidores , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Ligação Proteica/genética , Receptores CXCR6/genética , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Proteína Wnt-5a/genética
10.
J Biochem ; 167(4): 347-355, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926018

RESUMO

Much attention has been paid on the mechanism of cancer invasion from the viewpoint of the behaviour of individual cancer cells. On the other hand, histopathological analyses of specimens from cancer patients and of cancer invasion model animals have revealed that cancer cells often exhibit collective invasion, characterized by sustained cell-to-cell adhesion and polarized invasion as cell clusters. Interestingly, it has recently become evident that during collective invasion of cancer cells, the cells localized at invasion front (leader cells) and the cells following them (follower cells) exhibit distinct cellular characteristics, and that there exist the cells expressing representative proteins related to both epithelial and mesenchymal properties simultaneously, designated as hybrid epithelial-to-mesenchymal transition (EMT)-induced cells, in cancer tissue. Furthermore, the findings that cells adopted in hybrid EMT state form clusters and show collective invasion in vitro emphasize an importance of hybrid EMT-induced cells in collective cancer invasion. In this article, we overview recent findings of the mechanism underlying collective invasion of cancer cells and discuss the possibility of controlling cancer invasion and metastasis by targeting this process.


Assuntos
Neoplasias/patologia , Animais , Transição Epitelial-Mesenquimal , Humanos , Neoplasias/metabolismo
11.
Cancer Sci ; 110(10): 3340-3349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342590

RESUMO

Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion-metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain. MET-knockout cells were prepared and reconstituted with WT-MET or V370D-MET. HGF stimulation induced MET dimerization and biological responses in cells reconstituted with WT-MET, but HGF did not induce MET dimerization and failed to induce biological responses in V370D-MET cells. The V370D mutation abrogated HGF-dependent drug resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). Compared with WT-MET cells, V370D-MET cells showed different activation patterns in receptor tyrosine kinases upon exposure to survival/growth-stressed conditions. Surface plasmon resonance analysis indicated that affinity between the extracellular region of V370D-MET and HGF was reduced compared with that for WT-MET. Further analysis of the association between V370D-MET and the separate domains of HGF indicated that the SP domain of HGF was unchanged, but its association with the NK4 domain of HGF was mostly lost in V370D-MET. These results indicate that the V370D mutation in the MET receptor impairs the functional association with HGF and is therefore a loss-of-function mutation. This mutation may change the dependence of cancer cell growth/survival on signaling molecules, which may promote cancer cell characteristics under certain conditions.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/genética , Animais , Células CHO , Linhagem Celular Tumoral , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Técnicas de Inativação de Genes , Humanos , Mutação com Perda de Função , Domínios Proteicos , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Proteínas Proto-Oncogênicas c-met/metabolismo , Ativação Transcricional
12.
Clin Calcium ; 29(3): 291-297, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30814373

RESUMO

Non-canonical Wnt signaling, including planar cell polarity and Ca2+ pathways, plays crucial roles in developmental processes, including morphogenesis and tissue-/organo-genesis, in animals. Ror2 receptor tyrosine kinase mediates non-canonical Wnt signaling by acting as a receptor for Wnt5a, which also inhibits canonical Wnt signaling. Dysregulation of Wnt5a-Ror2 signaling causes a wide range of developmental defects and cancer progression. Recently, Ror2-mediated non-canonical Wnt signaling has also been shown to induce formation of filopodia that facilitates transport of Wnt to neighboring cells, thereby activating canonical Wnt signaling there.


Assuntos
Cálcio/metabolismo , Polaridade Celular , Proteínas Wnt , Via de Sinalização Wnt , Proteína Wnt-5a/metabolismo , Animais , Humanos
13.
Genes Cells ; 24(4): 307-317, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30801848

RESUMO

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2-/- mutant mice. In contrast, Ror1-/- mutant mice are viable and show no limb phenotype. Ror1-/- ;Ror2-/- double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1hyp ) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a-/- single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2-/- mutants. Ror2-/- ;Wnt9a-/- double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1hyp/hyp ;Wnt9a-/- double mutants. In addition, Ror1hyp/hyp ;Wnt9a-/- double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.


Assuntos
Fissura Palatina/genética , Epistasia Genética , Deformidades Congênitas dos Membros/genética , Mutação , Osteogênese/genética , Proteínas Wnt/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase
14.
Cancer Sci ; 110(4): 1306-1316, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30742741

RESUMO

Collective invasion is an important strategy of cancers of epithelial origin, including colorectal cancer (CRC), to infiltrate efficiently into local tissues as collective cell groups. Within the groups, cells at the invasive front, called leader cells, are highly polarized and motile, thereby providing the migratory traction that guides the follower cells. However, its underlying mechanisms remain unclear. We have previously shown that signaling emanating from the receptor tyrosine kinase Ror2 can promote invasion of human osteosarcoma cells and that intraflagellar transport 20 (IFT20) mediates its signaling to regulate Golgi structure and transport. Herein, we investigated the role of Ror2 and IFT20 in collective invasion of CRC cells, where Ror2 expression is either silenced or nonsilenced. We show by cell biological analyses that IFT20 promotes collective invasion of CRC cells, irrespective of expression and function of Ror2. Intraflagellar transport 20 is required for organization of Golgi-associated, stabilized microtubules, oriented toward the direction of invasion in leader cells. Our results also indicate that IFT20 promotes reorientation of the Golgi apparatus toward the front side of leader cells. Live cell imaging of the microtubule plus-end binding protein EB1 revealed that IFT20 is required for continuous polarized microtubule growth in leader cells. These results indicate that IFT20 plays an important role in collective invasion of CRC cells by regulating organization of Golgi-associated, stabilized microtubules and Golgi polarity in leader cells.


Assuntos
Proteínas de Transporte/metabolismo , Complexo de Golgi/metabolismo , Microtúbulos/metabolismo , Neoplasias/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , RNA Interferente Pequeno/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo
15.
Nat Commun ; 9(1): 2816, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026494

RESUMO

Tube morphogenesis is essential for internal-organ development, yet the mechanisms regulating tube shape remain unknown. Here, we show that different mechanisms regulate the length and diameter of the murine trachea. First, we found that trachea development progresses via sequential elongation and expansion processes. This starts with a synchronized radial polarization of smooth muscle (SM) progenitor cells with inward Golgi-apparatus displacement regulates tube elongation, controlled by mesenchymal Wnt5a-Ror2 signaling. This radial polarization directs SM progenitor cell migration toward the epithelium, and the resulting subepithelial morphogenesis supports tube elongation to the anteroposterior axis. This radial polarization also regulates esophageal elongation. Subsequently, cartilage development helps expand the tube diameter, which drives epithelial-cell reshaping to determine the optimal lumen shape for efficient respiration. These findings suggest a strategy in which straight-organ tubulogenesis is driven by subepithelial cell polarization and ring cartilage development.


Assuntos
Cartilagem/metabolismo , Esôfago/metabolismo , Morfogênese/genética , Músculo Liso/metabolismo , Miócitos de Músculo Liso/metabolismo , Traqueia/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Animais , Cartilagem/citologia , Cartilagem/crescimento & desenvolvimento , Diferenciação Celular , Polaridade Celular , Embrião de Mamíferos , Esôfago/citologia , Esôfago/crescimento & desenvolvimento , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Liso/citologia , Miócitos de Músculo Liso/citologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Traqueia/citologia , Traqueia/crescimento & desenvolvimento , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
16.
Genes Cells ; 23(7): 606-613, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845703

RESUMO

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis and closely related to exposure to asbestos. MPM is a heterogeneous tumor with three main histological subtypes, epithelioid, sarcomatoid, and biphasic types, among which sarcomatoid type shows the poorest prognosis. The Ror-family of receptor tyrosine kinases, Ror1 and Ror2, is expressed in various types of tumor cells at higher levels and affects their aggressiveness. However, it is currently unknown whether they are expressed in and involved in aggressiveness of MPM. Here, we show that Ror1 and Ror2 are expressed in clinical specimens and cell lines of MPM with different histological features. Studies using MPM cell lines indicate that expression of Ror2 is associated tightly with high invasiveness of MPM cells, whereas Ror1 can contribute to their invasion in the absence of Ror2. However, both Ror1 and Ror2 promote proliferation of MPM cells. We also show that promoted invasion and proliferation of MPM cells by Ror signaling can be mediated by the Rho-family of small GTPases, Rac1, and Cdc42. These findings elucidate the critical role of Ror signaling in promoting invasion and proliferation of MPM cells.


Assuntos
Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mesotelioma Maligno , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/fisiologia , Transdução de Sinais
17.
Cell Struct Funct ; 42(2): 159-167, 2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-29070775

RESUMO

The submandibular gland (SMG) is one of the major salivary glands that play important roles for variety of physiological functions, such as digestion of foods, prevention of infection, and lubrication of the mouth. Dysfunction of the SMG, often associated with a salivary inflammation, adversely influences a person's quality of life. However, the mechanism underlying inflammation-driven dysfunction of the SMG is largely unknown. Here, we used a mouse model in which the main excretory duct of the SMG is ligated unilaterally to induce inflammation of the gland and examined the expression of Wnt5a, Ror1 and Ror2 genes, encoding Wnt5a ligand and its cognate receptors, which have been implicated in tissue damage or inflammatory responses in variety of tissues. We show that expression levels of Ror1, Ror2, and Wnt5a are increased in the ligated SMG undergoing interstitial fibrosis, which is accompanied by robust expression of fibrosis-associated genes, such as TGF-ß1, TNF-α, IL-1ß, and MMP-2. Increased immunostaining signal of Ror2 was detected in the fibrotic tissues with abundant accumulation of fibroblasts and collagen fibers in the ligated SMG, suggesting that Ror2-mediated signaling might be activated in response to tissue damage and associated with progression of fibrosis in the SMG.Key words: submandibular gland, Ror2, Wnt5a, fibrosis, inflammation.


Assuntos
Fibrose/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Glândula Submandibular/metabolismo , Animais , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/patologia , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/análise , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Glândula Submandibular/patologia
18.
Sci Signal ; 10(494)2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851822

RESUMO

Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation. Mice with an osteoclast-specific deficiency in Ror2 (Ror2ΔOcl/ΔOcl) had increased bone mass. Osteoclasts derived from these mice exhibited impaired bone resorption and actin ring formation, defects that were rescued by overexpression of constitutively active RhoA. These osteoclasts also exhibited reduced interaction between c-Src and Pkn3 and reduced c-Src kinase activity. Similar to Ror2ΔOcl/ΔOcl mice, mice with a global deficiency of Pkn3 (Pkn3-/-) had increased bone mass. The proline-rich region and kinase domain of Pkn3 were required to restore the bone-resorbing activity of osteoclasts derived from Pkn3-/- mice. Thus, Pkn3 promotes bone resorption downstream of Wnt5a-Ror2-Rho signaling, and this pathway may be a therapeutic target for bone diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease.


Assuntos
Reabsorção Óssea/metabolismo , Proteínas dos Microfilamentos/metabolismo , Osteoclastos/metabolismo , Proteína Quinase C/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteína Wnt-5a/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Actinas/metabolismo , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Reabsorção Óssea/patologia , Proteína Tirosina Quinase CSK , Modelos Animais de Doenças , Quinase 2 de Adesão Focal/genética , Quinase 2 de Adesão Focal/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Osteoporose/metabolismo , Osteoporose/patologia , Doenças Periodontais/metabolismo , Doenças Periodontais/patologia , Fosforilação , Proteína Quinase C/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Proteína Wnt-5a/genética , Proteínas rho de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP , Quinases da Família src/genética , Quinases da Família src/metabolismo
19.
J Biochem ; 162(1): 1-10, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28338985

RESUMO

Proper organization of microtubule (MT) arrays is essential for numerous cellular functions, including intracellular transport and cell migration. Although the centrosome generally serves as the primary MT-organizing centre in proliferating animal cells, MTs are also organized at the Golgi apparatus in a wide range of cell types to regulate Golgi ribbon formation that is required for polarized cell migration. Furthermore, differentiated epithelial cells and neurons possess organized non-centrosomal MTs predominantly at the apical cortical regions and the axonal and dendritic neurites, respectively, to establish and maintain their highly polarized morphology. Unlike radial arrays of centrosomal MTs, non-centrosomal MTs are organized into non-radial asymmetric network, which facilitates polarized transport and cell polarization. In this review, we will focus on recent advances in our understanding of the regulatory mechanisms and cellular functions of non-centrosomal MTs.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Microtúbulos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Movimento Celular , Centrossomo/metabolismo , Complexo de Golgi/metabolismo , Humanos
20.
Sci Rep ; 7(1): 1, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28127051

RESUMO

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.


Assuntos
Proteínas de Transporte/metabolismo , Complexo de Golgi/metabolismo , Invasividade Neoplásica/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Movimento Celular , Humanos , Células-Tronco Mesenquimais/ultraestrutura , Microtúbulos/metabolismo , Podossomos/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais
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