RESUMEN
Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.
Asunto(s)
Podosomas , Neoplasias Gástricas , Línea Celular Tumoral , Cortactina/genética , Cortactina/metabolismo , Humanos , Invasividad Neoplásica , Monoéster Fosfórico Hidrolasas/metabolismo , Podosomas/metabolismo , Podosomas/patología , Receptores de Superficie Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.Significance: Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. Cancer Res; 78(11); 3041-53. ©2018 AACR.
Asunto(s)
MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/genética , Quinasas Quinasa Quinasa PAM/genética , Sistema de Señalización de MAP Quinasas/genética , Canales de Potasio de Rectificación Interna/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias Gástricas/genética , Animales , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Humanos , MAP Quinasa Quinasa Quinasa 2 , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Transducción de Señal/genética , Neoplasias Gástricas/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación/genéticaRESUMEN
Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in invasion and metastasis of some cancers, but the role of FPR2 in gastric cancer (GC) has not yet been elucidated. In this study, we found that the levels of FPR2 expression in GC were positively correlated with invasion depth, lymph node metastasis and negatively correlated with the patients' overall survival. Multivariate analysis indicated that FPR2 expression was an independent prognostic marker for GC patients. FPR2-knockdown significantly abrogated the migration and invasion stimulated by Hp(2-20) and Ac(2-26), two well-characterized ligands for FPR2 in GC cells. FPR2 deletion also reduced the tumorigenic and metastatic capabilities of GC cells in vivo. Mechanistically, stimulation with FPR2 ligands resulted in down-regulation of E-cadherin and up-regulation of vimentin, which were reversed by FPR2 knock-down, implying the involvement of epithelial-mesenchymal transition (EMT). Moreover, the activation of FPR2 was accompanied with ERK1/2 phosphorylation, which could be attenuated by FPR2 silencing or treatment with MEK inhibitor, PD98059. Altogether, our results demonstrate that FPR2 is functionally involved in invasion and metastasis, and potentially acts as a novel prognostic marker as well as a potential therapeutic target in human GC.
Asunto(s)
Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia/diagnóstico , Receptores de Formil Péptido/genética , Receptores de Lipoxina/genética , Neoplasias Gástricas/diagnóstico , Anciano , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Femenino , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Clasificación del Tumor , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Fosforilación , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Formil Péptido/antagonistas & inhibidores , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/antagonistas & inhibidores , Receptores de Lipoxina/metabolismo , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Vimentina/genética , Vimentina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Invasion and metastasis are major malignant characteristics of human gastric cancer (GC), but the underlying molecular mechanisms are poorly understood. Recent studies have shown that scinderin (SCIN), an actin severing and capping protein that regulates the actin cytoskeleton, is involved in the proliferation and migration of certain cancer cells. Accordingly, this study aimed to investigate the potential role of SCIN in the invasion and metastasis of human GC cells and to evaluate its prognostic value for GC patients. We found that high levels of SCIN expression in GC tumors were correlated with poor overall survival of patients. Silencing of SCIN effectively suppressed the migratory and invasive capabilities of human GC cells in vitro and tumorigenicity and metastasis in vivo. Furthermore, knockdown of SCIN markedly inhibited the formation of filopodia, decreasing GC cell migration and the expression of Cdc42, an important regulator of filopodia by GC cells. These findings suggest that SCIN may be a novel prognostic marker and a potential therapeutic target in human GC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Movimiento Celular , Gelsolina/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Femenino , Gelsolina/genética , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Ratones Endogámicos BALB C , Ratones Desnudos , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Trasplante de Neoplasias , Seudópodos/metabolismo , Seudópodos/patología , Interferencia de ARN , Factores de Riesgo , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Factores de Tiempo , Transfección , Regulación hacia Arriba , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Runt-related transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but has also been implicated in the progression of certain human cancer. This study aimed to elucidate the role of RUNX2 in the invasive and metastatic potentials of human gastric cancer (GC) and the underlying mechanisms. We found that the levels of RUNX2 expression in gastric cancer tissues were correlated with the differentiation degrees, invasion depth and lymph node metastasis. COX regression analysis indicated that RUNX2 was an independent prognostic indicator for GC patients. RUNX2 significantly increased the migration and invasion ability of GC cells in vitro and enhanced the invasion and metastatic potential of GC cells in an orthotopic GC model of nude mice. Mechanistically, RUNX2 directly bound to the promoter region of the gene coding for the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with AMD3100, a CXCR4 inhibitor, attenuated RUNX2-promoted invasion and metastasis. These results demonstrate that RUNX2 promotes the invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Gástricas/patología , Animales , Apoptosis/efectos de los fármacos , Bencilaminas , Biomarcadores de Tumor/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Ciclamas , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Piwi genes have an important role in stem cell development, gametogenesis and RNA interference in diverse organisms. So far, most of the studies have focused on the function of Piwis in vertebrates, but their function during spermiogenesis in invertebrates still remains largely unclear. In order to investigate the function of Piwis during spermiogenesis in the crab Portunus trituberculatus, we use RT-PCR and RACE to identify three Piwi complete cDNA sequences from the total RNA of the testis in P. trituberculatus. The deduced amino acid sequences of P. trituberculatus Piwi-1, Piwi-2 and Piwi-3 showed that each contains a well-conserved PAZ domain and PIWI domain. RT-PCR analyzed the tissue expression pattern of P. trituberculatus Piwi-1, Piwi-2 and Piwi-3 in the testis, heart, muscle, hepatopancreas and gill. All of the Piwis are found in germ cells of adult testis in P. trituberculatus by in situ hybridization, suggesting that these genes may play function during spermiogenesis in this species.
Asunto(s)
Braquiuros/genética , Espermatogénesis/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular/métodos , ADN Complementario/genética , Datos de Secuencia Molecular , Filogenia , Estructura Terciaria de Proteína/genética , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
Metallothioneins (MTs) possess a unique molecular structure that provides metal-binding and redox capabilities. These capabilities include the maintenance of metal equilibria that protect against heavy metals (especially cadmium) and oxidative damage. Past studies have focused on the function of MTs in vertebrates. However, the functions of MTs during spermiogenesis in invertebrates remain unclear. In order to investigate the function of MTs during spermiogenesis in Portunus trituberculatus, we used RT-PCR and RACE to identify two MT complete cDNA sequences in the total RNA from the P. trituberculatus testis. The 450 bp MT-1 cDNA consists of a 77 bp 5' untranslated region, a 196 bp 3' untranslated region, and a 177 bp open reading frame that encodes 58 amino acids including 19 cysteines. The 581 bp MT-2 cDNA consists of 73 bp 5' untranslated region, a 328 bp 3' untranslated region, and a 180 bp open reading frame that encodes 59 amino acids including 18 cysteines. MT-1 and MT-2 of P. trituberculatus more closely resemble invertebrate (especially crab) MT homologues than vertebrate MT homologues as indicated by protein alignment comparisons and phylogenetic tree analysis. MT-1 and MT-2 were detected in the heart, testis, muscle, hepatopancreas, and gill of P. trituberculatus by tissue expression analysis. In addition, MT-1 and MT-2 are present during the entire process of spermiogenesis in P. trituberculatus as indicated by H&E staining and in situ hybridization. MT-1 and MT-2 expression levels significantly increase after cadmium (Cd) exposure as measured by real-time quantitative PCR analysis. Therefore, we suggest that MT-1 and MT-2 perform important functions in spermiogenesis and testis detoxification in P. trituberculatus.
Asunto(s)
Braquiuros/fisiología , Cadmio/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Metalotioneína/metabolismo , Testículo/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Braquiuros/clasificación , Braquiuros/genética , Braquiuros/metabolismo , Masculino , Metalotioneína/genética , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Espermatogénesis/efectos de los fármacos , Espermatogénesis/genética , Testículo/metabolismoRESUMEN
OBJECTIVE: To compare the effect of abdominal acupuncture and Chinese medicine on pain relieving in pelvic cavity in patients with endometriosis. METHODS: Fifty-eight cases were randomly divided into 2 groups. Thirty cases were in abdominal acupuncture group and 28 cases in Chinese medicine group. Abdominal acupuncture points such as Zhongwan (CV 12), Xiawan (CV 10) and Qihai (CV 6), etc. were adopted for the abdominal acupuncture group, and Tianqi Tongjing Capsule (radix notoginseng capsule for dysmenorrhea) was taken by the Chinese medicine group. After a 3-month treatment, the scores of McGill pain questionaire, level of serum CA125, average value of the radial line of endometrial cyst of ovary and the sum of 3 radial lines of the uterus of patients with adenomyosis as the complication of both groups were observed before and after treatment. RESULTS: The McGill estimation of 6 items for both groups improved obviously after treatment (all P < 0.01, except numbers of selected deseriptors in Chinese medicine group). The differences of the result of McGill estimation of 6 items after treatment had statistical significance, the scores in the abdominal acupuncture group were obviously better than those in the Chinese medicine group (all P < 0.01). The differences of CA125 levels within one group or between 2 groups had statistical significance (P < 0.01, P < 0.05). The difference of the radial lines of patients with endometrial cyst of ovary within one group or between 2 groups after treatment had not statistical significance (all P > 0.05). For the value of 3 radial lines of the uterus of patients with adenomyosis within one group before and after treatment, only the difference in the abdominal acupuncture group had statistical significance (P < 0.01). The differences before and after treatment in the Chinese medicine group and the difference between 2 groups after treatment had no statistical significance (all P > 0.05). CONCLUSION: Effect of abdominal acupuncture on relieving pain of pelvic cavity caused by endometriosis, reducing the level of serum CA125 is obverious than Tianqi Tongjing Capsule (radix notoginseng capsule for dysmenorrhea). However, the effects on reducing the size of the ovarian endometrial cyst and the size of uterus with adenomyosis are not significant. Therefore, it is concluded that abdominal acupuncture is a better choice for endometriosis with pain as the chief complaints.