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1.
PLoS One ; 14(12): e0226435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31869378

RESUMO

Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect normal hematopoiesis. The analysis of human AMLs has mostly been performed using end-point materials, such as cell lines and patient derived AMLs that also carry additional contributing mutations. The molecular effects of a single oncogenic hit, such as expression of the AML associated oncoprotein AML1-ETO on hematopoietic development and transformation into a (pre-) leukemic state still needs further investigation. Here we describe the development and characterization of an induced pluripotent stem cell (iPSC) system that allows in vitro differentiation towards different mature myeloid cell types such as monocytes and granulocytes. During in vitro differentiation we expressed the AML1-ETO fusion protein and examined the effects of the oncoprotein on differentiation and the underlying alterations in the gene program at 8 different time points. Our analysis revealed that AML1-ETO as a single oncogenic hit in a non-mutated background blocks granulocytic differentiation, deregulates the gene program via altering the acetylome of the differentiating granulocytic cells, and induces t(8;21) AML associated leukemic characteristics. Together, these results reveal that inducible oncogene expression during in vitro differentiation of iPS cells provides a valuable platform for analysis of aberrant regulation in disease.


Assuntos
Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Granulócitos/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Proteína 1 Parceira de Translocação de RUNX1/fisiologia , Transcriptoma , Proliferação de Células/genética , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Granulócitos/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucopoese/genética , Monócitos/fisiologia , Mielopoese/genética , Proteínas de Fusão Oncogênica/genética , Oncogenes/fisiologia , Proteína 1 Parceira de Translocação de RUNX1/genética , Transcriptoma/genética , Transfecção
2.
Oncogene ; 38(33): 6123-6141, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285549

RESUMO

Most N6-methyladenosine (m6A) associated regulatory proteins (i.e., m6A writer, eraser, and reader proteins) are involved in the pathogenesis of various cancers, mostly in m6A-dependent manners. As a component in the m6A 'writers', KIAA1429 is reported to be an RNA-binding protein and involved in the m6A modification, mRNA splicing and processing. Till now, the functions of KIAA1429 in tumorigenesis and related mechanism have not been reported. In the present study, we found KIAA1429 was highly expressed in breast cancer tissues, but frequently down-regulated in non-cancerous breast tissues. The overall survival of breast cancer patients with high-expression KIAA1429 was significantly shorter than those with low-expression KIAA1429. Then, we demonstrated that KIAA1429 was associated with breast cancer proliferation and metastasis in vivo and in vitro. The potential targeting genes of KIAA1429 in breast cancer were identified by RNA immunoprecipitation sequencing. One of these genes is cyclin-dependent kinase 1 (CDK1), which plays an oncogenic role in cancers. Furthermore, we confirmed that KIAA1429 played its oncogenic role in breast cancer by regulating CDK1 by an m6A-independent manner. 5'-fluorouracil was found to be very effective in reducing the expression of KIAA1429 and CDK1 in breast cancer. These findings indicated that KIAA1429 could promote breast cancer progression and was correlated with pathogenesis. It may represent a promising therapeutic strategy on breast cancer, especially in combination with CDK1 treatment.


Assuntos
Adenosina/análogos & derivados , Neoplasias da Mama/genética , Proteína Quinase CDC2/genética , Oncogenes/fisiologia , Proteínas de Ligação a RNA/fisiologia , Adenosina/metabolismo , Adenosina/fisiologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Quinase CDC2/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Proteínas de Ligação a RNA/genética , Células Tumorais Cultivadas
3.
Nutrients ; 11(5)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067776

RESUMO

The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.


Assuntos
Butiratos/metabolismo , Microbioma Gastrointestinal , Regulação da Expressão Gênica/fisiologia , Oncogenes/fisiologia , Fibras na Dieta/metabolismo , Humanos
4.
J Biomed Sci ; 26(1): 35, 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31078138

RESUMO

Extracellular vesicle (EV)-mediated intercellular communication acts as a critical culprit in cancer development. The selective packaging of oncogenic molecules renders tumor-derived EVs capable of altering the tumor microenvironment and thereby modulating cancer developments that may contribute to drug resistance and cancer recurrence. Moreover, the molecular and functional characteristics of cancer through its development and posttreatment evolve over time. Tumor-derived EVs are profoundly involved in this process and can, therefore, provide valuable real-time information to reflect dynamic changes occurring within the body. Because they bear unique molecular profiles or signatures, tumor-derived EVs have been highlighted as valuable diagnostic and predictive biomarkers as well as novel therapeutic targets. In addition, the use of an advanced EV-based drug delivery system for cancer therapeutics has recently been emphasized in both basic and clinical studies. In this review, we highlight comprehensive aspects of tumor-derived EVs in oncogenic processes and their potential clinical applications.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares/fisiologia , Neoplasias/terapia , Oncogenes/fisiologia , Microambiente Tumoral , Comunicação Celular/fisiologia , Humanos
5.
Gene ; 704: 121-133, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980945

RESUMO

Cancer is caused by malfunctioning of genes that normally regulate cardinal processes including various nuclear functions, cell division and survival, cell surface to nucleus signaling cascades, etc. Cancer associated genes are often classified as oncogenes (OCGs) or tumor suppressor genes (TSGs) depending on whether they promote or suppress tumorigenesis, respectively. Such strict classification of cancer genes may however be an over-simplification. Several studies have highlighted a dual role for cancer genes, often impacting the same facet of tumorigenesis. Knowledge of a possible dichotomy of a cancer gene (particularly an OCG) is imperative when evaluating its possible utility as a therapeutic target. Though previous studies have extensively evaluated specific examples of cancer genes exhibiting a dual nature, efforts to unravel the molecular basis for such contrasting functions have been fewer. The current review is an attempt to delineate molecular events underlying the functional dichotomy of cancer genes at the DNA (mutations, gene fusions, etc.), RNA (alternative splicing, regulation through non-coding RNAs, etc.) and protein (isoforms, mis-localisation, post-translational modifications, proteolytic cleavage, etc.) levels.


Assuntos
Genes Supressores de Tumor/fisiologia , Neoplasias/genética , Oncogenes/fisiologia , Animais , Transformação Celular Neoplásica/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Mutação , Neoplasias/patologia
6.
Med Sci Monit ; 25: 888-892, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30739906

RESUMO

MYH9 was first discovered due to thrombocytopenia caused by MYH9 mutation-related abnormalities. In recent years, researchers have increasingly found that MYH9 plays an important role in cancer as a cytokine involved in cytoskeletal reorganization, cellular pseudopodia formation, and migration. MYH9 is closely related to the progress and poor prognosis of most solid tumors, and it is now accepted that MYH9 is a suppressor gene and plays an important role on the re-Rho pathway. Recent research has been limited to the study of tissues. However, it would be more direct and informative to be able to use hematology to assess tumor prognosis and changes in MYH9 levels and NMMHC-IIA. This article summarizes recent research on MYH9 and provides a reference for future clinical research.


Assuntos
Proteínas Motores Moleculares/metabolismo , Proteínas Motores Moleculares/fisiologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/fisiologia , Plaquetas , Genes Supressores de Tumor/fisiologia , Humanos , Proteínas Motores Moleculares/genética , Mutação , Cadeias Pesadas de Miosina/genética , Oncogenes/imunologia , Oncogenes/fisiologia , Trombocitopenia
7.
Biochem Biophys Res Commun ; 509(4): 966-972, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30654935

RESUMO

Autophagy is an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been demonstrated to be associated with many human diseases, including cancer. Alternative splicing of pre-mRNA is also an evolutionarily conserved regulatory mechanism of gene expression. Dysregulation of alternative splicing is increasingly linked to cancer. However, the association between these two cellular conserved processes is unclear. Splicing factors are critical players in the regulation of alternative splicing of pre-mRNA. We analyzed the expression of 28 splicing factors during hypoxia-induced autophagy in three oral squamous cell carcinoma (OSCC) cell lines. We discovered that oncogenes SRSF3 and SRSF1 are significantly downregulated in all three cell lines. Moreover, knockdown of SRSF3 increased autophagic activity, whereas overexpression of SRSF3 inhibited hypoxia-induced autophagy. Loss-of-function and gain-of-function assays also showed that SRSF3 inhibits the expression of p65 and FoxO1 and their downstream target gene BECN1, a key regulator of autophagy. Our results demonstrated that splicing factor SRSF3 is an autophagy suppressor.


Assuntos
Autofagia/efeitos dos fármacos , Proteína Beclina-1/antagonistas & inibidores , Oncogenes/fisiologia , Fatores de Processamento de Serina-Arginina/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Proteína Forkhead Box O1/antagonistas & inibidores , Humanos , Processamento de RNA , Fator de Transcrição RelA/antagonistas & inibidores
8.
Biochim Biophys Acta Mol Basis Dis ; 1865(3): 599-610, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543854

RESUMO

RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, migration and ultimately augmenting LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to effective cancer therapeutics.


Assuntos
Carcinogênese/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/fisiologia , Ubiquitina Tiolesterase/fisiologia , Células Cultivadas , Células HCT116 , Células HEK293 , Células HT29 , Células HeLa , Humanos , Células K562 , Células MCF-7 , Oncogenes/fisiologia , Ligação Proteica , Processamento de Proteína Pós-Traducional/genética , Estabilidade Proteica , Proteólise , Proteínas de Ligação a RNA/genética , Ubiquitina Tiolesterase/genética , Ubiquitinação
9.
Oncol Res ; 27(2): 219-226, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29562954

RESUMO

Breast cancer (BC) is the most common malignant tumor in women. Recently, long noncoding RNAs (lncRNAs) have been proposed as critical regulators in biological processes, including tumorigenesis. FOXC2-AS1, a single antisense oligonucleotide RNA transcribed from the negative strand of forkhead box protein C2 (FOXC2), has been identified as an oncogene in osteosarcoma. In the present study, we investigated the prognosis value and biological role of FOXC2-AS1 in BC. Our findings revealed that FOXC2-AS1 was significantly increased in BC tissues and cell lines, and Kaplan-Meier survival analysis indicated that a high level of FOXC2-AS1 was associated with poor prognosis of BC patients. Loss of function revealed that silenced FOXC2-AS1 significantly suppressed the proliferation ability, and flow cytometric analysis illustrated the influence of FOXC2-AS1 on cell cycle and apoptosis rate. Finally, we found that cyclin D1, cyclin D2, and cyclin D3 were all partly positively modulated by FOXC2-AS1 in BC. Collectively, FOXC2-AS1 may serve as a promising prognostic biomarker and therapeutic target for BC patients.


Assuntos
Neoplasias da Mama/mortalidade , Fatores de Transcrição Forkhead/genética , Oligonucleotídeos Antissenso/metabolismo , Oncogenes/fisiologia , RNA Longo não Codificante/fisiologia , RNA não Traduzido/fisiologia , Apoptose , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos
10.
Biomed Pharmacother ; 110: 656-666, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30551118

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a most common kidney malignancy, with atypical symptoms in the early stage and poor outcome in the late stage. Recently, emerging evidence revealed that some miRNAs play an essential role in the tumorigenesis and progression of RCC. Therefore, the aim of this study is that understand the detailed molecular mechanism of miR-23a-3p in RCC and identify its potential clinical value. METHODS: In this study, RT-qPCR, wound scratch assay, cell proliferation assay, transwell assay and flow cytometry assay were performed to detect miR-23a-3p expression and its proliferation, migration and apoptosis in RCC. The bioinformatics analysis, RT-qPCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-23a-3p and its potential targets. Moreover, we analyzed the relationship between miR-23a-3p expression and clinicopathological variables or overall survival (OS) from 118 formalin-fixed paraffin-embedded RCC samples. RESULTS: miR-23a-3p is significantly up-regulated in RCC tissue samples, RCC cell lines and the TCGA database. Upregulating miR-23a-3p enhances, while silencing miR-23a-3p suppresses cell viability, proliferation and mobility in ACHN and 786-O cell lines. Besides, overexpression of miR-23a-3p inhibits the cell apoptosis. Then our study further reveals that miR-23a-3p regulates tumorigenesis by targeting Proline-Rich Nuclear Receptor Coactivator 2 (PNRC2). Also, the cox proportional hazard regression analysis indicates that low expression of miR-23a-3p patients has a remarkable longer OS. CONCLUSIONS: Our results reveals that miR-23a-3p may not only serve as a new biomarker for prognosis but also serve as a new therapeutic strategy in the RCC treatment.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , MicroRNAs/biossíntese , Oncogenes/fisiologia , Receptores Citoplasmáticos e Nucleares/biossíntese , Transativadores/biossíntese , Adulto , Idoso , Biomarcadores/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Taxa de Sobrevida/tendências , Transativadores/genética
12.
Eur Rev Med Pharmacol Sci ; 22(16): 5156-5164, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30178836

RESUMO

OBJECTIVE: Osteosarcoma is a malignant bone tumor with high incidence. The prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. Numerous studies have demonstrated that aberrant expressions of microRNAs are involved in cancer initiation and development. However, the potential role of miR-214 in osteosarcoma remains largely unrevealed. The current study investigated the relationship between the miR-214 and TNF receptor-associated factor 3 (TRAF3) in osteosarcoma tissues and cell lines. We also aimed to evaluate the potential roles of miR-214 on the occurrence and metastasis in osteosarcoma and verify its effect on the regulation of TRAF3. PATIENTS AND METHODS: The miR-214 expression and TRAF3 expression in osteosarcoma tissue samples and cell line were measured using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Followed by transfection assays, transwell assay was conducted to detect the migration and invasion abilities of osteosarcoma cells. Subsequently, Western blotting and luciferase reporter assay were performed in osteosarcoma cells to confirm the target of miR-214. RESULTS: The results showed that miR-214 expression levels were significantly increased not only in osteosarcoma tissues but also in osteosarcoma cell lines as compared with adjacent normal tissues and matched cell lines, respectively. On the contrary, the TRAF3 expression levels in osteosarcoma tissues and cell lines were frequently decreased compared to the control group. Moreover, TRAF3 was identified as a direct target of miR-214 and the inverse relationship between them was also observed in osteosarcoma tissues. Additionally, we found that miR-214 restoration could significantly promote osteosarcoma cell invasion and migration via targeting TRAF3. CONCLUSIONS: MicroRNA-214 functioned as an oncogene in osteosarcoma via targeting TRAF3, which may provide new insights into osteosarcoma prevention and treatment.


Assuntos
Neoplasias Ósseas/metabolismo , MicroRNAs/biossíntese , Oncogenes/fisiologia , Osteossarcoma/metabolismo , Fator 3 Associado a Receptor de TNF/biossíntese , Idoso , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Fator 3 Associado a Receptor de TNF/genética
13.
J Cell Biochem ; 119(11): 8737-8742, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30086210

RESUMO

MicroRNAs (miRNAs) are short non-coding single-stranded RNAs, which play significant roles in the regulation of a myriad of biological processes. Overwhelmingly increasing high-impact research has also deepened our understanding about the central role of miRNAs in cancer development, metastatic spread, and development of resistance against various drugs. Recent studies have identified miRNAs that regulate RNA expression/processing and posttranscriptional expression of important oncogenes and tumor suppressors. Rapidly emerging experimentally verified data have started to shed light on the significance of miRNAs as biomarkers for diagnostic, prognostic, and monitoring purposes. Next-generation sequencing and DNA microarray technologies have helped us tremendously in the identification of miRNA and mRNA signatures in different cancers and their subtypes on a genome-wide scale. It is being increasing realized that miRNAs have diametrically opposite roles in different cancers. miR-410 is context-dependently involved in positive and negative regulation of cancers. miR-410 negatively regulates BAK1, CETN3, and BRD7 to promote cancer. However, miR-410 effectively targetes c-MET, AGTR1, and SNAIL to suppress cancer. In this review, we will comprehensively summarize most recent evidence available related to the "split personality" of miR-410 in different cancers.


Assuntos
Genes Supressores de Tumor/fisiologia , MicroRNAs/genética , Neoplasias/genética , Oncogenes/fisiologia , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/metabolismo , Neoplasias/metabolismo , Transdução de Sinais/genética
14.
Biomed Pharmacother ; 105: 1155-1163, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021352

RESUMO

BACKGROUND: MicroRNA(miRNA) plays a key regulatory role in various stages of tumorigenesis, including cell growth, cell cycle control, apoptosis avoidance, tissue invasion, and metastasis. Several microRNAs are involved in the development of renal cell carcinoma (RCC) and the malignant transformation process. However, the effects of miR-663a on RCC have rarely been reported. METHODS: In the present study, the expression of miR-663a was examined in RCC using matched normal kidney tissues and four cell lines (786-O, Caki-1, ACHN and HK-2). MicroRNA mimics were transiently transfected into RCC cells and the effects of over expression on proliferation, migration, invasion, and apoptosis was observed. In addition, the relationship between miR-663a expression in 42 formalin-fixed paraffin-embedded (FFPE) clear cell renal carcinoma (ccRCC) samples and clinical pathological variables and overall survival was investigated. We evaluated the prognostic value of miR-663a expression in ccRCC by experimental results. RESULTS: The results showed that the expression of miR-663a was up-regulated in RCC cells and tissues and miR-663a was associated with proliferation, migration, invasion, and apoptosis of RCC. Cox proportional hazard regression analysis showed that a high expression of miR-663a patients had a significantly shorter overall survival in univariate and multivariate analysis. Kaplan-Meier survival curves showed that a high expression of miR-663a patients had a significantly shorter overall survival. CONCLUSIONS: These results indicate that miR-663a can be used as an independent marker for the poor prognosis of ccRCC, and may also play an important role as a tumor oncogene in the occurrence and development of RCC.


Assuntos
Carcinogênese/metabolismo , Carcinoma de Células Renais/metabolismo , Movimento Celular/fisiologia , Neoplasias Renais/metabolismo , MicroRNAs/biossíntese , Oncogenes/fisiologia , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Carcinogênese/patologia , Carcinoma de Células Renais/diagnóstico , Feminino , Humanos , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico
15.
Zhonghua Zhong Liu Za Zhi ; 40(5): 321-324, 2018 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-29860756

RESUMO

The initiation of tumor is a complex process with multi-factor participation, particularly the activation of oncogenes and/or inactivation of tumor suppressor genes. Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. Additionally, as a metabolic process in cells, autophagy also contributes greatly to differentiation, metastasis and chemoresistance of tumor cells, and has become a central topic in recent years. The understanding of connection between lncRNAs and autophagy as well as their mechanisms underlying tumorigenesis, can provide new ideas for the diagnosis and treatment of tumors.


Assuntos
Autofagia/fisiologia , Neoplasias/fisiopatologia , RNA Longo não Codificante/fisiologia , Carcinogênese/genética , Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Oncogenes/fisiologia
16.
Oncogene ; 37(29): 4033-4045, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29706658

RESUMO

The actin crosslinking protein α-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor-interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-κB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage-independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-κB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1-NF-κB, with potential implications for targeting ACTN4 in the treatment of melanoma.


Assuntos
Actinina/metabolismo , Melanoma/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Masculino , Melanócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Oncogenes/fisiologia , Transdução de Sinais/fisiologia , Transcrição Genética/fisiologia , Ativação Transcricional/fisiologia
17.
Biosystems ; 167: 1-23, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29605248

RESUMO

Cancer or tumour growth has been addressed from a variety of mathematical modelling perspectives in the past. Examples are single variable growth models, reaction diffusion models, compartment models, individual cell-based models, clonal competition models, to name only a few. In this paper, we show that the so called Bertalanffy-type growth model is a macroscopic model variant that can be conceived as an optimal condensed modelling approach that to a high degree preserves complexity with respect to the aforementioned more complex modelling variants. The derivation of the Bertalanffy-type model is crucially based on features of metabolism. Therefore, this model contains a shape parameter that can be interpreted as a resource utilisation efficiency. This shape parameter reflects features that are usually captured in much more complex models. To be specific, the shape parameter is related to morphological structures of tumours, which in turn depend on metabolic conditions. We, furthermore, show that a single variable variant of the Bertalanffy-type model can straightforwardly be extended to a multiclonal competition model. Since competition is crucially based on available shared or clone-specific resources, the metabolism-based approach is an obvious candidate to capture clonal competition. Depending on the specific context, metabolic reprogramming or other oncogene driven changes either lead to a suppression of cancer cells or to an improved competition resulting in outgrowth of tumours. The parametrisation of the Bertalanffy-type growth model allows to account for this observed variety of cancer characteristics. The shape parameter, conceived as a classifier for healthy and oncogenic phenotypes, supplies a link to survival and evolutionary stability concepts discussed in demographic studies, such as opportunistic versus equilibrium strategies.


Assuntos
Carcinogênese/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Carga Tumoral/fisiologia , Carcinogênese/genética , Humanos , Neoplasias/genética , Oncogenes/fisiologia
18.
Neoplasia ; 20(5): 533-542, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29649779

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers and it usually develops from a background of liver fibrosis or inflammation. The crosstalk between tumor cells and stromal cells plays an important and stimulating role during tumor progression. Previously we found in a krasV12-induced zebrafish HCC model that oncogenic hepatocytes activate hepatic stellate cells (HSCs) by up-regulation of serotonin and activate neutrophils and macrophages by up-regulation of cortisol. In the present study, we found a novel signaling transduction mechanism between oncogenic hepatocytes and HSCs. After krasV12 induction, fibrinogen was up-regulated in oncogenic hepatocytes. We reasoned that fibrinogen may bind to integrin αvß5 on HSCs to activate HSCs. Consistent with this notion, pharmaceutical treatment using an antagonist of integrin αvß5, cilengitide, significantly blocked HSC activation and function, accompanied by attenuated proliferation of oncogenic hepatocytes and progression of liver fibrosis. On the contrary, adenosine 5'-diphosphate, an agonist of αvß5, activated HSCs significantly that further stimulated the tumor progression and liver fibrosis. Interestingly, in human liver disease samples, we detected an increased level of fibrinogen during tumor progression which indicated the potential role of fibrinogen signaling in HCC progression. Thus, we concluded a novel interaction between oncogenic hepatocytes and HSCs through the fibrinogen related pathway in both the zebrafish HCC model and human liver disease samples.


Assuntos
Carcinogênese/metabolismo , Fibrinogênio/metabolismo , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores de Vitronectina/metabolismo , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Progressão da Doença , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Oncogenes/fisiologia , Transdução de Sinais/fisiologia , Peixe-Zebra/metabolismo
19.
Int J Mol Sci ; 19(3)2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29547527

RESUMO

The fundamental function of ribonucleic acids is to transfer genetic information from DNA to protein during translation process, however, this is not the only way connecting active RNA sequences with essential biological processes. Up until now, many RNA subclasses of different size, structure, and biological function were identified. Among them, there are non-coding single-stranded microRNAs (miRNAs). This subclass comprises RNAs of 19-25 nucleotides in length that modulate the activity of well-defined coding RNAs and play a crucial role in many physiological and pathological processes. miRNA genes are located both in exons, introns, and also within non-translated regions. Several miRNAs that are transcribed from the adjacent miRNA genes are called cluster. One of the largest ones is miR-17-92 cluster known as OncomiR-1 due to its strong link to oncogenesis. Six miRNAs from the OncomiR-1 have been shown to play important roles in various physiological cellular processes but also through inhibition of cell death in many cancer-relevant processes. Due to the origin and similarity of the sequence, miR-17-92 cluster and paralogs, miR-106b-25 and miR-106a-363 clusters were defined. Here we discuss the oncogenic function of those miRNA subgroups found in many types of cancers, including brain tumors.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , MicroRNAs/fisiologia , Oncogenes/fisiologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , Família Multigênica , Neuroblastoma/genética , Oncogenes/genética
20.
Oncogene ; 37(16): 2122-2136, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29391601

RESUMO

Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lyn, which results in an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptotic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells.


Assuntos
Apoptose/genética , Proteína 11 Semelhante a Bcl-2/fisiologia , Quinases da Família src/fisiologia , Animais , Proteína 11 Semelhante a Bcl-2/antagonistas & inibidores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/genética , Células HEK293 , Células HeLa , Humanos , Células K562 , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oncogenes/fisiologia , Transdução de Sinais/genética , Quinases da Família src/genética
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