RESUMEN
Lysyl oxidase-like 4 (LOXL4), a member of lysyl oxidase family, is a copper and lysine tyrosylquinone-dependent amine oxidase that serves the role of catalyzing the cross-linking of elastin and collagen in the extracellular matrix. Numerous studies have shown a significant association between LOXL4 expression levels and tumor proliferation, migration, invasion and patients' prognosis and overall survival in different types of tumors. Here we review their relationship and the molecular pathogenesis behind them, aiming to explore the possibilities of LOXL4 as a prognostic marker for diverse carcinomas and provide some indications for further research in this field.
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Carcinoma , Proteína-Lisina 6-Oxidasa , Humanos , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/metabolismo , Pronóstico , ColágenoRESUMEN
BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. METHODS: In a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes. RESULTS: Pathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages. CONCLUSIONS: Based on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread.
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Glomeruloesclerosis Focal y Segmentaria/genética , Laminina/genética , Proteína-Lisina 6-Oxidasa/genética , Edad de Inicio , Anciano , Membrana Basal/ultraestructura , Trastornos de los Cromosomas/genética , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Riñón/ultraestructura , Masculino , Persona de Mediana Edad , Mutación , Linaje , Secuenciación del ExomaRESUMEN
Accumulating evidence has revealed that various microRNAs are deregulated and involved in lung cancer development and metastasis. miR-210 is implicated in several cancer progression. However, the detailed biological function and role of miR-210 in lung adenocarcinoma remains unclear. Our current study was aimed to investigate the mechanism of miR-210 in lung adenocarcinoma progression. We observed that miR-210 was significantly upregulated in lung cancer cell lines (A549 and H1650) in comparison to BEAS-2B cells. In addition, we found that miR-210 was greatly elevated in lung adenocarcinoma tissues. Then, it was shown that overexpression of miR-210 was able to promote lung cancer cell proliferation and colony formation ability while inhibitors of miR-210 exhibited a reversed phenomenon. Subsequently, A549 and H1650 cell migration and invasion capacity were obviously restrained by miR-210 inhibition whereas induced by miR-210 mimics. Lysyl oxidase-like 4 (LOXL4), a member of the secreted copper-dependent amine oxidases has been found to be increased or decreased in different cancer types. Here, we confirmed that LOXL4 could serve as a downstream target of miR-210 and miR-210 promoted lung cancer progression via targeting LOXL4. In A549 and H1650 cells, knockdown of LOXL4 dramatically repressed lung cancer cell proliferation, migration, and invasion. In conclusion, our study implied that miR-210 might indicate a new perspective for lung cancer.
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Adenocarcinoma del Pulmón/genética , Proliferación Celular/genética , MicroARNs/genética , Proteína-Lisina 6-Oxidasa/genética , Células A549 , Adenocarcinoma del Pulmón/patología , Apoptosis/genética , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Invasividad Neoplásica/genética , Invasividad Neoplásica/patologíaRESUMEN
Aberrant microRNAs are widely identified in multiple cancers, including lung cancer. miR-135a-5p can function as a significant tumor regulator in diverse cancers via impacting multiple genes in oncogenic pathways. Nevertheless, the biological role of miR-135a-5p in lung cancer is poorly known. Here, we investigated its function in lung cancer. As exhibited, miR-135a-5p was elevated in lung cancer cells in contrast to BEAS-2B cells. Then, we inhibited miR-135a-5p expression by transfecting LV-anti-miR-135a-5p into lung cancer cells. As displayed, miR-135a-5p was obviously reduced in A549 and H1299 cells. Knockdown of miR-135a-5p repressed lung cancer cell growth and cell proliferation. Meanwhile, cell colony formation capacity was depressed, cell apoptosis was enhanced and cell cycle progression was blocked in G1 phase by inhibition of miR-135a-5p in vitro. Additionally, the migration and invasion of A549 and H1299 cells was strongly depressed by LV-anti-miR-135a-5p. For another, by using informatics analysis, lysyl oxidase-like 4 (LOXL4) was speculated as the downstream target of miR-135a-5p. We validated their direct correlation and moreover, overexpression of miR-135a-5p restrained LOXL4 levels in lung cancer cells. Subsequently, we proved that miR-135a-5p promoted lung cancer development via targeting LOXL4 by carrying out the in vivo assays. Taken these together, our study revealed miR-135a-5p might be indicated as a perspective for lung cancer via targeting LOXL4.
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Progresión de la Enfermedad , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Proteína-Lisina 6-Oxidasa/metabolismo , Animales , Apoptosis/genética , Secuencia de Bases , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Invasividad Neoplásica , Proteína-Lisina 6-Oxidasa/genéticaRESUMEN
BACKGROUND: Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. METHODS: LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting. RESULTS: LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis. CONCLUSIONS: Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC.
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Aminoácido Oxidorreductasas/genética , Carcinoma Hepatocelular/genética , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Hepatocitos/metabolismo , Neoplasias Hepáticas/genética , Neovascularización Patológica/genética , Adulto , Anciano , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Aminoácido Oxidorreductasas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Exosomas/patología , Femenino , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Hepatocitos/patología , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/metabolismo , Neovascularización Patológica/mortalidad , Neovascularización Patológica/patología , Comunicación Paracrina , Proteína-Lisina 6-Oxidasa , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Análisis de Supervivencia , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismoRESUMEN
Background and Objective: Lysyl oxidase-like protein 4 (LOXL4) is a secreted copper-dependent amine oxidase involved in the assembly and maintenance of extracellular matrix (ECM), playing a critical role in ECM formation and repair. Tumor-stroma interactions and ECM dysregulation are closely associated with the mechanisms underlying tumor initiation and progression. LOXL4 is the latest identified member of the lysyl oxidase (LOX) protein family. Currently, there is limited and controversial research on the role of LOXL4 in human malignancies. Its specific regulatory pathways, mechanisms, and roles in the occurrence, development, and treatment of malignancies remain incompletely understood. This article aims to illustrate the primary protein structure and the function of LOXL4 protein, and the relationship between LOXL4 protein and the occurrence and development of human malignant tumors to provide a reference for further clinical research. Methods: We searched the English literature on LOXL4 in the occurrence and development of various malignant tumors in PubMed and Web of Science. The search keywords include "cancer" "LOXL4" "malignant tumor" "tumorigenesis and development", etc. Key Content and Findings: LOXL4 is up-regulated in human gastric cancer, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, esophageal carcinoma and colorectal cancer, but down-regulated in human bladder cancer and lung cancer and inhibits tumor growth. There are two conflicting reports of both upregulation and downregulation in hepatocellular carcinoma, suggesting that LOXL4 has a bidirectional effect of promoting or inhibiting cancer in different types of human malignant tumors. We further explore the application prospect of LOXL4 protein in the study of malignant tumors, laying a theoretical foundation for the clinical diagnosis, treatment and screening of prognostic markers of malignant tumors. Conclusions: LOXL4 exerts a bidirectional regulatory role, either inhibiting or promoting tumors depending on the type of cancer. We still need more research to further confirm the molecular mechanism of LOXL4 in cancer progression.
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Background: Non-small cell lung cancer (NSCLC) progression is mediated by changes in gene expression induced by microRNAs. However, the underlying mechanisms remain to be elucidated. In this study, we investigated the roles of miR-183-5p and its target gene in lung cancer development. Methods: Relative levels of miR-183-5p and lysyl oxidase-like 4 (LOXL4) expression in lung cancer cells or tissues were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence or Western blotting as appropriate. The binding of miR-183-5p to LOXL4 sequences was verified by a dual luciferase reporter assay, and cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) and Edu staining. The cell cycle stage and apoptosis were detected by flow cytometry, and Transwell assays were performed to evaluate cell migration and invasion capabilities. The tumorigenic capability of cancer cells was analyzed using a cancer cell line-based xenograft nude mouse model. Results: miR-183-5p expression was decreased in the lung cancer tissues and cell lines and was negatively correlated with elevated LOXL4 expression. Treatment with miR-183-5p mimics suppressed LOXL4 expression, while treatment with an miR-183-5p inhibitor promoted LOXL4 expression in A549 cells. miR-183-5p was found to directly bind to the 3' UTR of the LOXL4 gene in A549 cells. Overexpression of LOXL4 enhanced cell proliferation, cell cycle progression, migration, and invasion, but repressed their apoptosis, and activated extracellular matrix (ECM) and the epithelial mesenchymal transition (EMT) process in A549 cells, while LOXL4 knockdown produced the opposite effects. Treatment with an miR-183-5P inhibitor promoted the proliferation, cell cycle progression, migration, and invasion of A549 cells but suppressed their apoptosis, and activated the ECM and EMT process, while all these effects were abrogated by LOXL4 knockdown. The tumorigenic capability of A540 cells in nude mice was greatly impaired by treatment with miR-183-5p mimics. Conclusions: miR-183-5p repressed the proliferation, migration, invasion, ECM formation, and EMT processes, and promoted the apoptosis of lung cancer cells by targeting LOXL4 expression.
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INTRODUCTION: Lysyl oxidase-like 4 is an amine oxidase from the lysyl oxidase family that was previously shown to be overexpressed in head and neck cancer and upregulated in response to hypoxia. The possible role of lysyl oxidase-like 4 as a tumor marker in advanced stage larynx cancer was investigated. OBJECTIVE: To investigate the expression of lysyl Oxidase-Like 4 protein in advanced stage laryngeal cancer and elucidate its possible role as a tumor marker, predictor of treatment response and prognosticator. METHODS: Diagnostic specimens of 72 patients treated for stage III-IV laryngeal squamous cell carcinoma were evaluated for lysyl oxidase-like 4 expression by immunohistochemistry. RESULTS: Lysyl oxidase-like 4 expression was correlated with advanced tumor stage (pâ¯=â¯0.041) and better differentiation (pâ¯=â¯0.025) but was independent of tumor diameter (pâ¯=â¯0.456). Response to induction chemotherapy or the need for salvage laryngectomy were not affected by lysyl oxidase-like 4 expression (pâ¯=â¯0.999, pâ¯=â¯0.070 respectively). Increased lysyl oxidase-like 4 expression was associated with better 2 year overall survival in both univariate (pâ¯=â¯0.036) and multivariate analyses (pâ¯=â¯0.014). CONCLUSION: Lysyl oxidase-like 4 expression emerges with advancing stages, is lost with worsening differentiation, and may have tumor suppressive properties in larynx cancer.
Asunto(s)
Neoplasias Laríngeas , Proteína-Lisina 6-Oxidasa , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Biomarcadores de Tumor/metabolismo , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/metabolismo , Laringectomía , Estadificación de Neoplasias , Proteína-Lisina 6-Oxidasa/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismoRESUMEN
Laryngeal squamous cell carcinoma (LSCC) is an aggressive malignancy with highly mortality rate. Long non-coding RNA (lncRNA) AGAP2-AS1 is an identified oncogene in several types of cancers. However, the role of AGAP2-AS1 in LSCC remains unclear. The expression levels of AGAP2-AS1 in LSCC tissues and cell lines were measured using qRT-PCR. AGAP2-AS1 was knocked down in LSCC cells through transfection with siRNA-AGAP2-AS1. Cell proliferation and invasion were detected using MTT and transwell assays. Dual-luciferase reporter gene assay was performed to confirm the interaction with AGAP2-AS1 and downstream genes. Our results showed that AGAP2-AS1 expression was remarkably increased in human LSCC tissues and cell lines. Knockdown of AGAP2-AS1 significantly inhibited the proliferation and invasion of LSCC cells. In addition, AGAP2-AS1 sponged miR-193a-3p and regulated its expression in LSCC cells. Inhibition of miR-193a-3p reversed the effects of AGAP2-AS1 knockdown on LSCC cells. Furthermore, Lysyl oxidase-like 4 (LOXL4) was a target gene of miR-193a-3p and the role of miR-193a-3p was mediated by LOXL4. In conclusion, these findings suggest that knockdown of AGAP2-AS1 inhibited the proliferation and invasion of LSCC cells through regulating the miR-193a-3p/LOXL4 axis.
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Neoplasias de Cabeza y Cuello , MicroARNs , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
Background: Lung cancer is the leading cause of cancer-associated mortality worldwide, and most lung cancers are classified as non-small cell lung cancer (NSCLC). MiR-328 influence the progression of multiple tumors, but the role of miR-328-5p in NSCLC has not been elucidated. The aim of this study was to illuminate the oncogenic role and potential molecular mechanisms of the miR-328-5p and lysyl oxidase like 4 (LOXL4) in NSCLC. Methods: Expression of miR-328-5p was detected by real-time quantitative polymerase chain reaction (qRT-PCR) in tumor and non-tumor adjacent tissues. After Lentivirus-miR-328-5p was employed to intervene this miRNA in NSCLC cell lines, RT-qPCR was used to detect the expression levels of miR-328-5p. Cell Counting Kit-8 (CCK-8), cell colony formation, flow cytometry, wound healing, Transwell assays were used to determine the malignant phenotypes of NSCLC cells. Nude mice models of subcutaneous tumors were established to observe the effect of miR-328-5p on tumorigenesis. Targeting the 3'UTR of LOXL4 by miR-328-5p was verified by integrated analysis including transcriptome sequencing, dual-luciferase and western-blot assays. Results: High miR-328-5p level was observed in NSCLC cells from The Cancer Genome Atlas (TCGA) database and tumor tissues collected from NSCLC patients. Overexpressed miR-328-5p promoted NSCLC cell proliferation, survival, and migration, and promoted tumor growth in vivo. Knockdown of miR-328-5p suppressed tumorigenic activities. Transcriptome sequencing analysis revealed that LOXL4 was downregulated by miR-328-5p, which was confirmed by dual-luciferase reporter and western-blot assays. Conclusions: miR-328-5p showed targeted regulation of LOXL4 to promote cell proliferation and migration in NSCLC.
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It has been shown that thoracic aortic aneurysm and dissection (TAAD) could be a Mendelian trait caused by a single gene mutation. The LOX gene mutation leads to the development of human TAAD. The LOXL4 gene is a member of the lysyl oxidase gene family. We identified seven variants in the LOXL4 gene in 219 unrelated patients with TAAD by whole-exome sequencing (WES). To further investigate whether LOXL4 is a candidate causative gene for human TAAD, a LOXL4 knockout mouse was generated, and the mutant mice were treated by subcutaneous infusion of angiotensin II. We found that abrogation of LOXL4 did not induce a more severe thoracic or abdominal aortic aneurysm compared with the wild-type C57BL/6J mice. Our results suggest that LOXL4 may not play a major role in the development of angiotensin II-induced aortic aneurysm. The functional study using this animal model system is important for the evaluation of candidate genes of TAAD identified by WES.
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Angiotensina II/efectos adversos , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Torácica/patología , Secuenciación del Exoma/métodos , Proteína-Lisina 6-Oxidasa/genética , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Torácica/inducido químicamente , Aneurisma de la Aorta Torácica/genética , China , Modelos Animales de Enfermedad , Mutación del Sistema de Lectura , Técnicas de Inactivación de Genes , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Índice de Severidad de la EnfermedadRESUMEN
Enhancer of Zeste Homolog 2 (EZH2), a key epigenetic regulator, is involved in breast cancer progression and metastasis. LOXL4 is increasingly recognized as an important player in cancer progression. To date, how EZH2 regulates LOXL4 in the progression of breast cancer remains unclear. Methods: We evaluated the association between LOX family proteins and EZH2 in invasive breast carcinoma through the starBase v2.0 analysis, and its correlation with breast tumorigenesis using the Oncomine dataset. We then applied miRcode data combined with gene expression omnibus (GEO) data to screen candidate miRNAs mediating the regulation of LOXL4 by EZH2. We explored the regulatory mechanism of EZH2, miR-29b/miR-30d, and LOXL4 in breast cancer cells by qRT-PCR, Western blotting, cell proliferation, colony formation, and wound healing assays, xenograft experiments, dual-luciferase reporter assay, and chromatin immunoprecipitation. All statistical tests were two-sided. Results: Inhibition of EZH2 or LOXL4, or miR-29b/miR-30d overexpression, decreased breast cancer cell proliferation, migration, and metastasis in vitro and in vivo. LOXL4 was identified as a direct target of miR-29b and miR-30d. EZH2 inhibition enhanced miR-30d and miR-29b transcription via promoter binding activity, leading to the reduced expression of LOXL4. Immunohistochemical analysis of human breast cancer specimens and flow cytometry analysis of tumor-infiltrating macrophages in mice showed a positive association of EZH2 with LOXL4 expression and macrophage infiltration. Conclusions: Our findings identified EZH2-miR-29b/miR-30d-LOXL4 signaling pathway was involved in breast tumorigenesis, and suggested that the epigenetic modulation represents a potential therapeutic target for breast cancer by controlling macrophage activation.
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Neoplasias de la Mama/patología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , MicroARNs/genética , Proteína-Lisina 6-Oxidasa/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/genética , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Proteína-Lisina 6-Oxidasa/metabolismo , Microambiente TumoralRESUMEN
Intestinal infection by Cryptosporidium parvum causes significant alterations in the gene expression profile in host epithelial cells. Previous studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of human intestinal cryptosporidiosis, we report here that trans-suppression of the cadherin 3 (CDH3) and lysyl oxidase like 4 (LOXL4) genes in human intestinal epithelial cells following C. parvum infection involves host delivery of the Cdg7_FLc_1000 RNA, a C. parvum RNA that has been previously demonstrated to be delivered into the nuclei of infected host cells. Downregulation of CDH3 and LOXL4 genes was detected in host epithelial cells following C. parvum infection or in cells expressing the parasite Cdg7_FLc_1000 RNA. Knockdown of Cdg7_FLc_1000 attenuated the trans-suppression of CDH3 and LOXL4 genes in host cells induced by infection. Interestingly, Cdg7_FLc_1000 was detected to be recruited to the promoter regions of both CDH3 and LOXL4 gene loci in host cells following C. parvum infection. Host delivery of Cdg7_FLc_1000 promoted the PH domain zinc finger protein 1 (PRDM1)-mediated H3K9 methylation associated with trans-suppression in the CDH3 gene locus, but not the LOXL4 gene. Therefore, our data suggest that host delivery of Cdg7_FLc_1000 causes CDH3 trans-suppression in human intestinal epithelial cells following C. parvum infection through PRDM1-mediated H3K9 methylation in the CDH3 gene locus, whereas Cdg7_FLc_1000 induces trans-suppression of the host LOXL4 gene through H3K9/H3K27 methylation-independent mechanisms.
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Transporte Activo de Núcleo Celular/fisiología , Aminoácido Oxidorreductasas/metabolismo , Cadherinas/metabolismo , Cryptosporidium parvum/fisiología , Proteínas Protozoarias/farmacología , ARN Protozoario/metabolismo , Aminoácido Oxidorreductasas/genética , Cadherinas/genética , Línea Celular , Cryptosporidium parvum/genética , Regulación hacia Abajo , Células Epiteliales/metabolismo , Células Epiteliales/parasitología , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Proteína-Lisina 6-Oxidasa , Proteínas Protozoarias/metabolismoRESUMEN
Abstract Introduction: Lysyl oxidase-like 4 is an amine oxidase from the lysyl oxidase family that was previously shown to be overexpressed in head and neck cancer and upregulated in response to hypoxia. The possible role of lysyl oxidase-like 4 as a tumor marker in advanced stage larynx cancer was investigated. Objective: To investigate the expression of lysyl Oxidase-Like 4 protein in advanced stage laryngeal cancer and elucidate its possible role as a tumor marker, predictor of treatment response and prognosticator. Methods: Diagnostic specimens of 72 patients treated for stage III-IV laryngeal squamous cell carcinoma were evaluated for lysyl oxidase-like 4 expression by immunohistochemistry. Results: Lysyl oxidase-like 4 expression was correlated with advanced tumor stage (p = 0.041) and better differentiation (p = 0.025) but was independent of tumor diameter (p = 0.456). Response to induction chemotherapy or the need for salvage laryngectomy were not affected by lysyl oxidase-like 4 expression (p = 0.999, p = 0.070 respectively). Increased lysyl oxidase-like 4 expression was associated with better 2 year overall survival in both univariate (p = 0.036) and multivariate analyses (p = 0.014). Conclusion: Lysyl oxidase-like 4 expression emerges with advancing stages, is lost with worsening differentiation, and may have tumor suppressive properties in larynx cancer.
Resumo Introdução: A proteína tipo-lisil oxidase-4 é uma amina oxidase da família lisil oxidase cuja superexpressão em câncer de cabeça e pescoço e up-regulação em resposta à hipóxia foram previamente demonstradas. O possível papel da proteína tipo-lisil oxidase-4 como um marcador tumoral no câncer de laringe em estágio avançado foi investigado. Objetivos: Investigar a expressão da proteína tipo-lisil oxidase-4 no câncer de laringe em estágio avançado e elucidar seu possível papel como marcador tumoral, preditor da resposta ao tratamento e do prognóstico. Método: Amostras diagnósticas de 72 pacientes tratados para carcinoma espinocelular da laringe em estágio III-IV foram avaliadas quanto à expressão da proteína tipo-lisil oxidase-4 por imuno-histoquímica. Resultados: A expressão de proteína tipo-lisil oxidase-4 foi correlacionada com o estágio avançado do tumor (p = 0,041) e melhor diferenciação (p = 0,025), mas foi independente do diâmetro do tumor (p = 0,456). A resposta à quimioterapia de indução ou a necessidade de laringectomia de resgate não foram afetadas pela expressão da proteína tipo-lisil oxidase-4 (p = 0,999, p = 0,070 respectivamente). O aumento da expressão da proteína tipo-lisil oxidase-4 foi associado a melhor sobrevida global de 2 anos nas análises univariada (p = 0,036) e multivariada (p = 0,014). Conclusão: A expressão da proteína tipo-lisil oxidase-4 surge com o avanço dos estágios e desaparece com pioria da diferenciação e pode ter propriedades supressoras de tumor no câncer de laringe.
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Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.