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1.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199510

RESUMO

During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting ATAT1, which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both ATAT1-knockout and tunicamycin-treated cells, whereas ATAT1 overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of ATAT1 and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, ATAT1 and ER stress marker genes may be useful diagnostic markers in various breast cancer types.


Assuntos
Acetiltransferases/genética , Neoplasias da Mama/genética , Estresse do Retículo Endoplasmático/genética , Proteínas dos Microtúbulos/genética , Tunicamicina/farmacologia , Acetilação/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas dos Microtúbulos/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacos
2.
Anticancer Res ; 41(7): 3317-3326, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230127

RESUMO

BACKGROUND/AIM: We evaluated the impact of FosL1, a member of the activated protein-1 family, on the pathways leading to regional metastasis of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We examined the influence of small interfering RNA (siRNA) and short heparin RNA (shRNA) mediated knockdown of FosL1 on cell migration, invasion, and proliferation in vitro as well as on regional metastasis in vivo. The prognostic significance of FosL1 was also analyzed using the Kaplan- Meier plotter using data from an HNSCC patient database. RESULTS: Down-regulation of FosL1 inhibited cell migration, invasion, and proliferation in vitro, decreased the incidence of regional metastases, and prolonged the survival of mice in vivo. We also determined that HNSCC patients with higher expression levels of FosL1 had a significantly shorter survival time than those with low expression of FosL1. CONCLUSION: FosL1 plays a crucial role in promoting cell migration, invasion, and proliferation in HNSCC.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-fos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/genética , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
3.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230131

RESUMO

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Assuntos
Carcinogênese/genética , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética , Estômago/patologia , Neoplasias Gástricas/patologia
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(6): 854-861, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34238737

RESUMO

OBJECTIVE: To detect the expression of miR-4719 in breast cancer tissues and cells and explore its role in regulating invasion and migration of breast cancer cells. OBJECTIVE: qRT-PCR was used to detect the expression of miR-4719 and ARHGAP36 in 30 pairs of human breast cancer tissues and adjacent tissues, two breast cancer cell lines (BT549 and MDA-MB- 231) and normal breast cells (MCF-10A). Bioinformatic methods were utilized to analyze the relationship between miR-4719 expression and overall survival of breast cancer patients and predict the potential target gene miR- 4719. miR-4719 mimics, ARHGAP36 shRNA and ARHGAP36 plasmids were transfected into breast cancer cells to test the effects of miR-4719 overexpression, ARHGAP36 knockdown and ARHGAP36 overexpression on cell migration and invasion using wound healing assay and Transwell assay. A dual-luciferase reporter assay was used to verify the direct binding between miR-4719 and 3'-UTR of ARHGAP36. OBJECTIVE: Compared with those in adjacent tissues or normal breast cells, the expressions of miR-4719 were significantly decreased and the expression of ARHGAP36 was increased in breast cancer tissues (P < 0.001) and breast cancer cell lines (P < 0.01). A low expression of miR-4719 was correlated with a poorer overall survival of breast cancer patients (P < 0.05). Overexpression of miR-4719 and ARHGAP36 knockdown both significantly attenuated the invasion and migration abilities of breast cancer cells (P < 0.05). The expression of miR-4719 was inversely correlated to that of ARHGAP36 in breast cancer tissues (P < 0.01). Dual-luciferase reporter assay confirmed that ARHGAP36 was the target gene of miR-4719 (P < 0.01), and exogenous miR-4719 could significantly lower the expression of ARHGAP36 (P < 0.05). ARHGAP36 overexpression significantly reversed the inhibitory effects of miR-4719 mimics on migration and invasion of breast cancer cells (P < 0.05). OBJECTIVE: The expression of miR-4719 is aberrantly decreased in breast cancer tissues to promote migration and invasion of breast cancer cells by up-regulating ARHGAP36 expression.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica/genética
5.
Head Face Med ; 17(1): 20, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158059

RESUMO

BACKGROUND: Oral cavity cancer ranks the sixth most common malignancy worldwide, of which oral squamous cell carcinoma is the predominant type. This study aimed to investigate the function and the underlying mechanism of resistin like beta (RETNLB) in oral squamous cell carcinoma. METHODS: The data of oral squamous cell carcinoma samples from The Cancer Genome Atlas database was used to examine RETNLB expression and assess its correlation with the clinical outcomes. Biological functions of RETNLB on the growth, invasion and migration of cells were determined by cell counting kit 8, clonogenic growth, and Transwell assays. Gene set enrichment analysis was utilized to identify the important gene sets associated with RETNLB expression, which was further confirmed by western blot. RESULTS: We found that RETNLB was upregulated in oral squamous cell carcinoma tissues and cells. High expression of RETNLB was closely linked to age and pathological tumor, and significantly related to poor survival of oral squamous cell carcinoma patients. Further functional experiments showed that knockdown of RETNLB significantly reduced the viability, mobility and invasiveness of cells. Moreover, gene set enrichment analysis suggested that Toll-like receptor signaling pathway was significantly correlated with high RETNLB expression. Further western blot analysis verified that silencing RETNLB could notably suppress the protein levels of Toll-like receptor 2, Toll-like receptor 4 and phosphor- extracellular signal-regulated kinase. CONCLUSIONS: These results suggested that downregulation of RETNLB may restrain the progression of oral squamous cell carcinoma by inactivating TLR/2/4/ERK pathway.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinógenos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genética , Invasividade Neoplásica/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
6.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065633

RESUMO

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Antígenos CD/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Bases de Dados Genéticas , Molécula de Adesão da Célula Epitelial/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Queratina-20/metabolismo , Invasividade Neoplásica/genética , Oxaliplatina/farmacologia , Transporte Proteico , Vimentina/metabolismo , beta Catenina/metabolismo
7.
Anticancer Res ; 41(6): 2805-2815, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083270

RESUMO

BACKGROUND/AIM: Copper metabolism MURR1 domain-containing 5 (COMMD5) is mainly expressed in renal tubules (RTs), where it facilitates re-differentiation of injured RTs. We reported that COMMD5 regulates the expression of epidermal growth factor receptor by participating in its endocytic membrane trafficking, thus inhibiting tumor growth. Here we aimed to determine the role of COMMD5 in malignant phenotypes of renal cell carcinoma (RCC). MATERIALS AND METHODS: The associations between COMMD5 levels in RTs adjacent to RCC tumors in patients and their clinicopathologic characteristics were evaluated, and the effects of COMMD5 on cancer stemness in RCC cells were investigated. RESULTS: Low COMMD5 levels in RTs correlated with high tumorigenesis and poor patient outcomes. COMMD5 overexpression in RCC cells reduced the proportion of cancer stem cell-like cells and their malignant phenotypes, including proliferation, invasion and sphere formation. Secreted COMMD5 from RT cells also reduced malignant phenotypes. CONCLUSION: COMMD5 might suppress malignant phenotypes of RCC, thus inhibiting tumor development and improving patient prognosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Proteínas Nucleares/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/metabolismo , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Humanos , Masculino , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , RNA Interferente Pequeno/genética
8.
J Int Med Res ; 49(6): 3000605211014998, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34130530

RESUMO

OBJECTIVE: Colon cancer has high morbidity and mortality rates, and proliferation, invasion and migration play an important role in colon cancer progression. Here, the effects of inhibin subunit beta A (INHBA) on cell proliferation, invasion and migration were investigated. METHODS: The UALCAN database was used to assess INHBA expression in colon cancer tissues and predict the survival of patients with high and low INHBA expression. The relevant proteins were detected by RT-qPCR and western blot. Cell transfection was performed to overexpress or inhibit INHBA and versican (VCAN). The high correlation between INHBA and VCAN found through LinkedOmics and StarBase databases was verified by immunoprecipitation assays. Cell proliferation was detected by cell counting kit-8 and colony formation assays. Wound healing and Transwell assays were used to assess migration and invasion. RESULTS: INHBA expression was upregulated in colon cancer tissues and cells. INHBA inhibition impaired the proliferation, migration and invasion of these cells. In addition, we confirmed the correlation between INHBA and VCAN in colon cancer cells. Finally, we found that INHBA interference inhibited the aggressive behavior of colon cancer cells by downregulating VCAN. CONCLUSION: INHBA promotes the proliferation, migration and invasion of colon cancer cells through the upregulation of VCAN.


Assuntos
Neoplasias do Colo , Versicanas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidades beta de Inibinas , Invasividade Neoplásica/genética , Regulação para Cima , Versicanas/genética
9.
Ann Clin Lab Sci ; 51(2): 163-173, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941555

RESUMO

OBJECTIVE: This work aimed to explore the effect of NTSR1 on oncogenesis and the potential clinical role of gastric adenocarcinoma (GAC). METHODS: Immunohistochemistry was used to assay NTSR1 and EGFR/HER2 expression. NTSR1 and MET were disrupted using shRNA. The role of 19 genes related to cancer phenotype signaling pathways was explored. The expression of genes was verified by Western blotting or quantitative real-time polymerase chain reaction. The interactions among genes were analyzed by STRING. RESULTS: There was a significant positive correlation between the expression of NTSR1 and EGFR/HER2. The proliferation and invasion rate of MKN-45 cells was significantly reduced by the NTSR1 shRNA. The expression of MET and EGFR/HER2 was downregulated by the NTSR1 shRNA. NTSR1 modulated the invasion ability of gastric cancer cells via MET. NTSR1 interacted with MET via PIK3CA. Combined knockout of NTSR1 and MET further reduced the PIK3CA mRNA level and the invasion ability of MKN-45 cells. CONCLUSIONS: NTSR1 plays an important role in the occurrence, invasion, and metastasis of GAC in a manner involving several other genes, such as MET and EGFR/HER2. Therefore, NTSR1 constitutes a potential therapeutic target for GAC via synthetic lethality, and assessment of NTSR1 signaling may be necessary when performing tyrosine kinase inhibitor therapy.


Assuntos
Receptores de Neurotensina/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , China , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/genética , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Neurotensina/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/patologia
11.
Cancer Med ; 10(10): 3413-3426, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932125

RESUMO

Metastasis to regional lymph nodes or distal organs predicts the progression of the disease and poor prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies demonstrated that BTB and CNC homology 1 (BACH1) participates in various types of tumor metastasis. However, the function of BACH1 in ESCC was rarely reported. The present study demonstrated that BACH1 protein was overexpressed in ESCC tissues compared with paired esophageal epithelial tissues according to immunohistochemical staining (IHC). Higher levels of BACH1 mRNA were associated with decreased overall survival (OS) and shorter disease-free survival (DFS) of ESCC patients based on an analysis of The Cancer Genome Atlas (TCGA) datasets. BACH1 significantly enhanced the migration and invasion of ESCC in vitro. Mechanistically, BACH1 promoted the epithelial-mesenchymal transition (EMT) by directly activating the transcription of CDH2, SNAI2, and VIM, as determined by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). BACH1 overexpression significantly enhanced CDH2 promoter activity according to the results of a luciferase assay. The results of subsequent experiments indicated that BACH1 enhanced the growth of tumor xenografts. The density of CD31+ blood vessels and the expression of vascular endothelial growth factor C (VEGFC) in tumor xenografts were significantly associated with BACH1 levels according to the results of IHC and immunofluorescence (IF) analyses performed in vivo. Moreover, ChIP-qPCR analysis demonstrated that the transcriptional activity of VEGFC was also upregulated by BACH1. Thus, BACH1 contributes to ESCC metastasis and tumorigenesis by partially facilitating the EMT and angiogenesis, and BACH1 may be a promising therapeutic target or molecular marker in ESCC.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Neovascularização Patológica/genética , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética , Regulação para Cima/genética , Fator C de Crescimento do Endotélio Vascular/genética
12.
Nat Commun ; 12(1): 2606, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972557

RESUMO

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Th17/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/imunologia , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Th17/imunologia , Proteína Supressora de Tumor p53/metabolismo
13.
Medicine (Baltimore) ; 100(20): e25827, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011046

RESUMO

ABSTRACT: Neuroblastoma is an embryonal tumor of the autonomic nervous system with poor prognosis in children. In present study, we demonstrated the relationship of miRNA-34a-5p in the regulating of the Wnt/ß-catenin signaling pathway by targeting SRY-related HMG-box (SOX4)Reverse transcription-quantitative PCR was used to detect the expression levels of miRNA-34a-5p and SoX4. Western blotting was performed to assess the protein expression levels of SoX4, Wnt, MMP9, Bax, and Bcl-2. The proliferation, apoptosis, migration and invasion of neuroblastoma cells were determined using MTT, flow cytometry and Transwell assays.In this study, we sought to investigate the role of miRNA-34a-5p on neuroblastoma and the possible molecular mechanism. We had performed in-vitro and in-vivo experiments to evaluate the effects of miRNA-34a-5p on neuroblastoma cell proliferation and invasion by altering its expression level via cell transfection. On the basis of our study, miRNA-34a-5p showed decreased expression levels in neuroblastoma. Subsequently, we manipulated miRNA-34a-5p expression through cell transfection and observed abnormal expression of ß-catenin as well as the downstream targets of the Wnt/ß-catenin pathway in neuroblastoma cells. With all these evidences, we determined that miRNA-34a-5p regulated Wnt/ß-catenin pathway by targeting SOX4.In conclusion, our study demonstrates that miRNA-34a-5p can inhibit the over-activation of the Wnt/ß-catenin signaling pathway via targeting SOX4 and further regulate proliferation, invasion of neuroblastoma cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neuroblastoma/genética , Fatores de Transcrição SOXC/genética , Via de Sinalização Wnt/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Invasividade Neoplásica/genética , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Fatores de Transcrição SOXC/metabolismo , beta Catenina/metabolismo
14.
Anticancer Res ; 41(5): 2441-2449, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952469

RESUMO

BACKGROUND/AIM: The regulation of gene expression by miRNAs plays an important role in cancer progression. Here, we investigated the role of miR-3663-3p in gastric cancer. PATIENTS AND METHODS: The relationship between miR-3663-3p expression, clinicopathological features and prognosis were retrospectively analyzed in 80 gastric cancer patients. RESULTS: miR-3663-3p expression was significantly lower in gastric cancer tissue than adjacent non-cancerous tissue (p=0.002). Recurrence free survival was significantly lower in patients with low miR-3663-3p expression (p=0.016). Low miR-3663-3p expression was also an independent predictive factor for recurrence (p=0.029). Overexpression of miR-3663-3p in gastric cancer cell lines significantly suppressed cell proliferation, migration/invasion, and induced G0/G1 arrest (p<0.01). Furthermore, overexpression of miR-3663-3p decreased Cyclin D1 mRNA and protein, and reduced the phosphorylation of Retinoblastoma (Rb) protein. CONCLUSION: miR-3663-3p is a clinically useful predictor of gastric cancer recurrence. It exhibits tumor suppressive features through limited entry into the cell cycle in a Cyclin D1-Rb dependent manner.


Assuntos
Ciclina D1/genética , MicroRNAs/genética , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligases/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , Neoplasias Gástricas/patologia
15.
Life Sci ; 277: 119569, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961855

RESUMO

AIMS: Long noncoding RNA (LncRNA) urothelial cancer associated 1 (UCA1) was dysregulated in colorectal cancers (CRC) and promoted tumor progression of CRC. The aims of this study are to further investigate the underlying mechanism. MAIN METHODS: Short hairpin RNAs (shRNAs) were applied for gene knockdown. microRNA mimic and pcDNA-UCA1 plasmids were transfected for miR-495 and UCA1 overexpression, respectively. MTT was applied to determine cell viability and sensitivity of 5-fluorouracil (FU). Transwell assays were performed to evaluate cell migration/invasion. Angiogenesis was evaluated by tube formation. Western blotting and quantitative PCR were utilized for protein and mRNA detection, respectively. The interaction of UCA1, miR-495 and SP1/SP3 were explored by dual-luciferase assay. RNA pulldown was adopted to determine the UCA1/miR-495 interaction. KEY FINDINGS: UCA1 was significantly upregulated in CRC tissues. UCA1 enhanced cell proliferation, migration/invasion, angiogenesis, epithelial-mesenchymal transition, and resistance to 5-FU in CRC cell lines. MiR-495 was inversely correlated to the expression of UCA1. The results indicated that UCA1 sponged miR-495, leading to the disinhibition of SP1/SP3 expression. SP1/SP3 induced the expression of DNA methyltransferases and, in turn, contributed to UCA1 mediated tumor-promoting actions. Reduction of SP1/SP3 exerted anti-cancer effects, which can be reversed by forced expression of UCA1. SIGNIFICANCE: UCA1-miR-495-SP1/SP3 axis is dysregulated in CRC and contributed to malignant phenotypes of CRC. UCA1-SP1/SP3 may form a positive feedback loop in CRC.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp3/genética , Fator de Transcrição Sp3/metabolismo
16.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946718

RESUMO

Cancer is a multifactorial disease that affects millions of people every year and is one of the most common causes of death in the world. The high mortality rate is very often linked to late diagnosis; in fact, nowadays there are a lack of efficient and specific markers for the early diagnosis and prognosis of cancer. In recent years, the discovery of new diagnostic markers, including microRNAs (miRNAs), has been an important turning point for cancer research. miRNAs are small, endogenous, non-coding RNAs that regulate gene expression. Compelling evidence has showed that many miRNAs are aberrantly expressed in human carcinomas and can act with either tumor-promoting or tumor-suppressing functions. miR-19a is one of the most investigated miRNAs, whose dysregulated expression is involved in different types of tumors and has been potentially associated with the prognosis of cancer patients. The aim of this review is to investigate the role of miR-19a in cancer, highlighting its involvement in cell proliferation, cell growth, cell death, tissue invasion and migration, as well as in angiogenesis. On these bases, miR-19a could prove to be truly useful as a potential diagnostic, prognostic, and therapeutic marker.


Assuntos
MicroRNAs/genética , Neoplasias/diagnóstico , Neoplasias/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Detecção Precoce de Câncer/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Masculino , Modelos Genéticos , Invasividade Neoplásica/genética , Neoplasias/patologia , Oncogenes , Prognóstico
17.
Gene ; 791: 145718, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33991650

RESUMO

The incidence rates of colorectal cancer have been increasing in the last decades, yet the overall survival rate is still not ideal. There is a need to further investigate detailed mechanism for colorectal cancer tumorigenesis. The biological function of protein arginine methyltransferases 3 (PRMT3) is seldom studied in tumorigenesis. Here, we attempted to elucidate the link between PRMT3 and tumorigenesis in colorectal cancer. Results revealed that PRMT3 was upregulated in colorectal cancer. Besides, PRMT3 overexpression promoted colorectal cancer cell proliferation, migration, and invasion. Regarding mechanism for colorectal cancer tumorigenesis, PRMT3 stabilized C-MYC and the pro-tumorigenesis function of PRMT3 was dependent on C-MYC. Clinically, these findings might provide a novel therapeutical treatment strategy for colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Metilação , Invasividade Neoplásica/genética , Proteína-Arginina N-Metiltransferases/fisiologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Ribossômicas/metabolismo
18.
Biochem Biophys Res Commun ; 556: 106-113, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839405

RESUMO

Among all lung cancer cases, lung adenocarcinoma (LAC) represents nearly 40% and remains the leading cause of cancer deaths worldwide. Although the combination therapy of surgical treatment with radiotherapy, chemotherapy, and immunotherapy, has been used to treat LAC, unfortunately, high recurrence rates and poor survival remain. Therefore, novel prognostic markers and new targets for molecular targeted therapy in LAC is urgently needed. Fork-head box R2 (FOXR2) plays a key role in a wide range of cellular processes, including cellular proliferation, invasion, differentiation, and apoptosis, and it has been reported to be implicated in progression of LAC, thus inhibition of FOXR2 may be a novel targeting therapy for lung cancer. This current study found that E3 ligase PJA1 regulates ubiquitin-mediated degradation of FOXR2 and predicts good outcome of patients with LAC. In addition, it was showed force expression of PJA1 significantly inhibited LAC cells invasion and induced apoptosis in vitro through inactivating Wnt/ß-catenin signaling pathway. In short, our findings reveal that PJA1 could be a potential diagnostic and prognostic biomarkers and the PJA1- FOXR2 axis could be served as a promising target for LAC therapy.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Apoptose , Fatores de Transcrição Forkhead/metabolismo , Invasividade Neoplásica , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Animais , Apoptose/genética , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/química , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Prognóstico , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Via de Sinalização Wnt , beta Catenina/metabolismo
19.
Cancer Med ; 10(10): 3358-3372, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33838016

RESUMO

Recent studies have identified microRNAs (miRNAs) as a compelling novel class of biomarker in colorectal cancer (CRC) development and metastasis. Here, we demonstrated that the level of plasma exosomal miR-140-3p in CRC patients was lower than that in healthy controls. The decreased miR-140-3p level was also observed in CRC patients with liver metastasis. The expression of miR-140-3p in CRC tissues were significantly lower than that in matched normal tissues. Functionally, miR-140-3p overexpression suppressed proliferation, migration, invasion, and ß-catenin nuclear translocation, as well as promoted apoptosis in LoVo cells, while inhibition of miR-140-3p reversed these cellular processes in HCT 116 cells. Notably, BCL9 and BCL2 were recognized as direct targets of miR-140-3p. BCL9 knockdown abrogated miR-140-3p inhibitor-induced effects on HCT 116 cells with decreased proliferation, migration, and invasion. BCL2 knockdown increased apoptosis of miR-140-3p inhibitor-transfected HCT 116 cells. In vivo experiments revealed that miR-140-3p overexpression inhibited tumor growth in LoVo xenograft model and diminished metastatic nodules in nude mice liver. Taken together, this work supports that miR-140-3p exerts as a tumor suppressor in CRC progression via targeting BCL9 and BCL2, and suggests miR-140-3p-BCL9/BCL2 axis may be applied in miRNA-based therapy and prognostication of CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , beta Catenina/genética
20.
J Int Med Res ; 49(4): 3000605211009802, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33909533

RESUMO

OBJECTIVE: Semaphorin 3C (Sema3C) may regulate tumor metastasis and prognosis. We determined the biological roles of Sema3C in the hepatic metastasis of gastric adenocarcinoma and evaluated its clinical significance as a potential biomarker. METHODS: Sema3C expression in gastric cancer (GC) cell lines and tissues was measured using RT-qPCR and western blotting. Moreover, Sema3C functions were analyzed using Transwell assays and in vitro metastasis assays in gain- and loss-of-function experiments. Furthermore, the impact of Sema3C on the prognosis of 80 randomly selected patients with GC was investigated by immunohistochemistry. Additionally, the expression of epithelial-mesenchymal transition (EMT) indicators was verified by immunohistochemistry in GC tissues. RESULTS: Sema3C expression was significantly upregulated in highly metastatic GC cell lines and tissues. Additionally, Sema3C promoted invasion, migration and hepatic metastasis in GC cells. Moreover, Sema3C expression was positively correlated with clinicopathological features in GC and paired hepatic metastatic tissues, and Sema3C expression was an independent prognostic factor. Finally, Sema3C expression was associated with node metastasis, hepatic metastasis and EMT marker expression. CONCLUSIONS: Sema3C may play roles in regulating the EMT and metastasis of gastric adenocarcinoma, highlighting its potential use as a prognostic factor for hepatic metastasis and poor prognosis in gastric adenocarcinoma.


Assuntos
Adenocarcinoma , Neoplasias Hepáticas , Semaforinas , Neoplasias Gástricas , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Invasividade Neoplásica/genética , Metástase Neoplásica , Prognóstico , Semaforinas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética
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