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1.
Cancer Res ; 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031573

RESUMO

Breast cancer (BC) is the most common malignancy in women worldwide. However, the mechanisms underlying BC energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long non-coding RNA (lncRNA), HOXC-AS3, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of HOXC-AS3 in BC was identified by in published microarray and RNA-seq datasets, then confirmed by RT-qPCR in fresh BC tissues. Glucose deprivation induced HOXC-AS3 overexpression in a dose- and time-dependent manner in BC cells. Gain- and loss-of-function experiments in vitro and in vivo showed that HOXC-AS3 triggers energy metabolism reprogramming. ChIRP-mass spectrometry and UMI RIP-seq identified binding motifs of HOXC-AS3 with SIRT6. HOXC-AS3 selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, HOXC-AS3 binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. Additionally, HOXC-AS3, SP1, and miR-1224-5p formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-HOXC-AS3-motif-RNAs effectively blocked the function of HOXC-AS3, ultimately suppressing BC progression. These results reveal a critical role for HOXC-AS3 in regulating the metabolic reprogramming of BC cells under metabolic stress. Use of an anti-HOXC-AS3-motif RNA mixture may be a promising strategy to suppress BC progression.

2.
Cancer Lett ; 524: 82-90, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34626692

RESUMO

Long non-coding RNAs (lncRNAs) play important roles in cancer development and progression; however, their contributions to gastric cancer metastasis remain largely unknown. By lncRNA microarray screening, our study showed that 453 lncRNAs are dysregulated in gastric cancer tissues with or without lymph node metastasis, of which lnc-LEMGC ranks as one of the most significantly downregulated lncRNAs. Lnc-LEMGC inhibited cell migration and invasion both in vitro and in vivo, by combining with protein DNA-PKcs. Importantly, nucleotides 1300-1800 of lnc-LEMGC prevented DNA-PKcs phosphorylation of serine 2056 and partially abrogated the effects of downstream effectors, ErbB1, SRC and protein tyrosine kinase 2 (FAK), in the epidermal growth factor receptor (EGFR) pathway. The results of this study extend our knowledge of lncRNA's molecular mechanisms, in which lnc-LEMGC functions by directly suppressing the phosphorylation of its combined protein DNA-PKcs and inactivating the DNA-PKcs downstream EGFR signaling.


Assuntos
Receptores ErbB/genética , Quinase 1 de Adesão Focal/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Quinases da Família src/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Neoplasias Gástricas/patologia
3.
Oncogene ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34754080

RESUMO

Breast cancer (BC) is the most common cancer in women worldwide, and the exploration of aberrantly expressed genes might clarify tumorigenesis and help uncover new therapeutic strategies for BC. Although RGMA was recently recognized as a tumor suppressor gene, its detailed biological function and regulation in BC remain unclear. Herein, we found that RGMA was downregulated in BC tissues compared with non-tumorous breast tissues, particularly in metastatic BC samples, and that patients with low RGMA expression manifested a poorer prognosis. Furthermore, DNMT1 and DNMT3A were found to be recruited to the RGMA promoter and induced aberrant hypermethylation, resulting in downregulation of RGMA expression in BC. In contrast, RGMA overexpression suppressed BC cell proliferation and colony-formation capabilities and increased BC cell apoptosis. Furthermore, RGMA knockdown accelerated BC cell proliferation and suppressed cellular apoptosis in vitro and in vivo. Reversal of RGMA promoter methylation with 5-Aza-CdR restored RGMA expression and blocked tumor growth. Overall, DNMT1- and DNMT3A-mediated RGMA promoter hypermethylation led to downregulation of RGMA expression, and low RGMA expression contributed to BC growth via activation of the FAK/Src/PI3K/AKT-signaling pathway. Our data thus suggested that RGMA might be a promising therapeutic target in BC.

4.
Cell Death Differ ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608273

RESUMO

Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

5.
Oncogene ; 40(14): 2524-2538, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33674746

RESUMO

Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and ß-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.


Assuntos
Quinase 1 de Adesão Focal/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Transdução de Sinais , Neoplasias Gástricas/patologia
6.
Mol Oncol ; 14(10): 2629-2645, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32767629

RESUMO

Gastric cancer (GC) is one of the most common cancers around the world. Searching for specific gene expression changes during the development of GC could help identify potential therapy targets. We previously showed that the histone code reader SPIN1 may act as an oncogene in breast cancer. At present, the biological function and regulation of SPIN1 in GC remain unclear. Here, we demonstrate that SPIN1 is upregulated in GC tissues, compared with nontumorous gastric tissues. Increased expression of SPIN1 is closely associated with poor prognosis for patients with GC. Increased SPIN1 expression enhances GC cell proliferation, migration, and invasion and promotes cell cycle progression. Mechanically, SPIN1 sustains GC cell proliferation via activation of the MDM2-p21-E2F1 signaling pathway by binding to H3K4me3 of the MDM2 promoter region. Interestingly, E2F1 could directly bind to the SPIN1 promoter and activate its transcription, thus forming a positive feedback loop. Our data suggest that SPIN1 plays an important role in the development of GC and could be used as a promising prognostic biomarker and therapeutic target for GC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator de Transcrição E2F1/metabolismo , Retroalimentação Fisiológica , Proteínas Associadas aos Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Animais , Apoptose/genética , Carcinogênese/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transdução de Sinais , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/genética
7.
Front Oncol ; 10: 1062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719745

RESUMO

Invasion and metastasis of gastric cancer after curative resection remain the most common lethal outcomes. However, our current understanding of the molecular mechanism underlying gastric cancer metastasis is far from complete. Herein, we identified TOR signaling pathway regulator (TIPRL) as a novel metastasis suppressor in gastric cancer through genome-wide gene expression profiling analysis using mRNA microarray. Decreased TIPRL expression was detected in clinical gastric cancer specimens, and low TIPRL expression was correlated with more-advanced TNM stage, distant metastasis, and poor clinical outcome. Moreover, TIPRL was identified as a direct target of miR-216a-5p and miR-383-5p. Functional study revealed that re-expression of TIPRL in gastric cancer cell lines suppressed their migratory and invasive capacities, whereas inverse effects were observed in TIPRL-deficient models. Mechanistically, TIPRL downstream effectors and signaling pathways were investigated using mRNA microarray. Gene expression profiling revealed that TIPRL could not modulate the downstream genes at transcriptional levels, thereby implying that the regulation might occur at the post-transcriptional levels. We further demonstrated that TIPRL induced phosphorylation/activation of AMPK, which in turn attenuated phosphorylation of mTOR, p70S6K, and 4E-BP1, thereby leading to inactivation of mTOR signaling and subsequent suppression of cell migration/invasion in gastric cancer. Taken together, TIPRL acts as a novel metastasis suppressor in gastric cancer, at least in part, through regulating AMPK/mTOR signaling, likely representing a promising target for new therapies in gastric cancer.

8.
Front Oncol ; 10: 633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509569

RESUMO

Gastric cancer is one of the most common cancers in the world, and long non-coding RNAs (lncRNAs) play a crucial role in proliferation, metastasis, and invasion of gastric cancer. However, there are very few researches focusing on the effects of lncRNAs on metastatic gastric cancer. In this research, we identify one kind of lncRNA, called AK025387, which is highly expressed in metastatic gastric cancer samples compared with non-metastatic gastric cancer samples. The expression of AK025387 is significantly positively correlated with lymph node metastasis. The in situ hybridization demonstrates that AK025387 is located in both nucleus and cytoplasm, but mostly in cytoplasm. AK025387 promotes gastric cancer cells migratory and invasive ability, but it inhibits apoptosis in vitro. Furthermore, AK025387 regulates Raf-1, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), and extracellular signal-regulated kinase (ERK) and is involved in mitogen-activated protein kinase (MAPK) signaling pathway to perform its biological functions. We conclude that AK025387 is highly expressed in metastatic gastric cancer, and its biological functions suggest the potential of AK025387 to be a biomarker of metastatic gastric cancer.

9.
Br J Cancer ; 122(12): 1825-1836, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32336754

RESUMO

BACKGROUND: Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) played important regulatory roles in many cancer types. However, the role of lncRNAs in gastric cancer (GC) progression remains unclear. METHODS: RT-qPCR assay was performed to detect the expression of HNF1A-AS1 in gastric cancer tissues and the non-tumourous gastric mucosa. Overexpression and RNA interference approaches were used to investigate the effects of HNF1A-AS1 on GC cells. Insight into competitive endogenous RNA (ceRNA) mechanisms was gained via bioinformatics analysis, luciferase assays and an RNA-binding protein immunoprecipitation (RIP) assay, RNA-FISH co-localisation analysis combined with microRNA (miRNA)-pulldown assay. RESULTS: This study displayed that revealed expression of HNF1A-AS1 was associated with positive lymph node metastasis in GC. Moreover, HNF1A-AS1 significantly promoted gastric cancer invasion, metastasis, angiogenesis and lymphangiogenesis in vitro and in vivo. In addition, HNF1A-AS1 was demonstrated to function as a ceRNA for miR-30b-3p. HNF1A-AS1 abolished the function of the miRNA-30b-3p and resulted in the derepression of its target, PIK3CD, which is a core oncogene involved in the progression of GC. CONCLUSION: This study demonstrated that HNF1A-AS1 worked as a ceRNA and promoted PI3K/AKT signalling pathway-mediated GC metastasis by sponging miR-30b-3p, offering novel insights of the metastasis mechanism in GC.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Idoso , Animais , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/fisiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
10.
Neurobiol Learn Mem ; 169: 107155, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904547

RESUMO

Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aß expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aß production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aß in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aß production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aß production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aß production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aß production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Diabetes Mellitus Experimental/metabolismo , Grelina/metabolismo , Neurônios/metabolismo , Proteína Fosfatase 1/metabolismo , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/psicologia , Grelina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Quinase I-kappa B/metabolismo , Masculino , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/administração & dosagem , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Regulação para Cima
11.
Clin Breast Cancer ; 20(2): e113-e126, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31899158

RESUMO

BACKGROUND: Breast cancer is the most common cause of cancer-related death in women worldwide. MicroRNA (miRNA) ectopic expression has been reported to be involved in the regulation of gene expression in breast cancer. We screened several differentially expressed miRNAs associated with breast cancer chemoresistance, growth, and metastasis using a miRNA microarray. Increased expression of miR-4472 has been associated with larger breast tumors and chemoresistance. However, the biologic function of miR-4472 and its molecular mechanisms in cancer progression have not yet been reported. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction was used to measure the expression of miR-4472 in breast cancer tissue and cell lines. The biologic functions of miR-4472 and its target gene were explored using Transwell, cell proliferation, and flow cytometry assays. Bioinformatics tools, dual-luciferase reporter assays, and Western blot were used to identify the target genes of miR-4472. Western blot was used to explain the participation of miR-4472 and target gene in epithelial-to-mesenchymal transition. RESULTS: miR-4472 was significantly upregulated in highly metastatic breast cancer tissues, and its expression was positively associated with larger tumor size and advanced pTNM stage. miR-4472 promoted breast cancer cell metastasis and growth. Repulsive guidance molecule A (RGMA) was a direct target gene of miR-4472. RGMA was identified as a suppressor in cancer metastasis. miR-4472 downregulated expression of RGMA and promoted epithelial-to-mesenchymal transition by suppressing E-cadherin and initiating vimentin, ß-catenin, and Slug. CONCLUSIONS: miR-4472 contributes to the progression of breast cancer by regulating RGMA expression and inducing epithelial-to-mesenchymal transition, indicating that miR-4472/RGMA might serve as a therapeutic target for breast cancer.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Ligadas por GPI/genética , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Regulação para Cima
12.
Front Oncol ; 9: 1210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781505

RESUMO

Breast cancer is the most common female malignancy worldwide, however its molecular pathogenesis still needs in-depth investigation. Here we first revealed that the olfactory receptor family 2, subfamily T, member 6 (OR2T6) was significantly over-expressed in breast cancer tissues compared with normal breast tissues. OR2T6 expression was tightly correlated with higher TNM staging, positive lymph node metastasis, and associated with poorer patients' overall and disease-free survival. And OR2T6 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines in vitro (MCF-7 and MDA-MD-231). Mechanically, it promoted the expression of mesenchymal markers (Vimentin, N-cadherin, and ß-catenin) while inhibited E-cadherin expression, suggesting that OR2T6 played a key role in the regulation of epithelial-mesenchymal transition (EMT) process. Moreover, the human gene expression microarray clarified that MAPK/ERK pathway could be initiated by OR2T6 at mRNA level, which was further confirmed at protein level by western blot analysis. Thus, we concluded that OR2T6, as a novel oncogene, contributed to the progression of breast carcinoma by the initiation of EMT and MAPK/ERK pathway.

13.
J Exp Clin Cancer Res ; 38(1): 124, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30871606

RESUMO

BACKGROUND: Gastric cancer is the second most common cause of cancer-related mortality; thus, the mechanisms underlying tumor metastasis and growth in gastric cancer need to be extensively explored. METHODS: Differentially expressed genes were examined in gastric cancer samples with lymph node metastasis (LNM) and without LNM using mRNA microarray and RT-qPCR. The effects of G antigen 7B (GAGE7B) on the metastasis, growth, and angiogenesis of gastric cancer were investigated in vitro and in vivo. GAGE7B protein expression was detected by immunohistochemical (IHC) analysis. Microarray, RT-qPCR, and western blot assays were performed to detect downstream target genes of GAGE7B. Dual-luciferase reporter and western blot assays were used to identify miRNAs that could negatively regulate GAGE7B. RESULTS: GAGE7B was significantly overexpressed in samples with LNM. High expression levels of GAGE7B were associated with advanced clinical stage and poor patient survival. GAGE7B dramatically enhanced the metastasis, growth, and angiogenesis ability of gastric cancer. GAGE7B was further demonstrated to promote the progression of gastric cancer by activating the p38δ/pMAPKAPK2/pHSP27 pathway. However, the GAGE7B-induced p38δ/pMAPKAPK2/pHSP27 pathway was inactivated by miR-30c, as the expression levels of both GAGE7B and p38δ were found to be directly suppressed by miR-30c. Intriguingly, GAGE7B was found to be a ceRNA for p38δ, as it activated the p38δ/pMAPKAPK2/pHSP27 pathway by competitively binding miR-30c. CONCLUSIONS: GAGE7B may serve as a prognostic indicator in gastric cancer. GAGE7B significantly promotes gastric cancer progression by upregulating the p38δ/pMAPKAPK2/pHSP27 pathway, but it is negatively regulated by miR-30c. GAGE7B and miR-30c may be potential therapeutic targets in gastric cancer.


Assuntos
Antígenos de Neoplasias/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Proteínas de Choque Térmico , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteína Quinase 13 Ativada por Mitógeno/genética , Chaperonas Moleculares , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fosforilação , Prognóstico , Transdução de Sinais , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transfecção
14.
Cancer Res ; 78(20): 5877-5890, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30185552

RESUMO

Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease.Significance: This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. Cancer Res; 78(20); 5877-90. ©2018 AACR.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Antissenso/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/metabolismo , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina E/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
15.
Oncotarget ; 8(52): 89631-89642, 2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29163776

RESUMO

Chemoresistance represents a major obstacle to effective therapy for breast cancer. Emerging evidences associated aberrantly expressed miRNAs with tumor development and chemoresistance. MiR-1268b has never been studied in any cancers before, and its roles in mediating tumor progression and drug resistance are still unclear. Selected from miRNA microarray and confirmed by real-time quantitative PCR (RT-qPCR), miR-1268b was found to be significantly upregulated in drug sensitive and ERBB2 negative tissues, as well as in breast cancer patients with low clinical stage. And miR-1268b had a higher expression in chemosensitive breast cancer cell lines, compared with the chemoresistant cell line. Moreover, the results revealed that miR-1268b induced breast cancer cell apoptosis and increased cell chemosensitivity. ERBB2 was demonstrated to be the target gene of miR-1268b by dual-luciferase reporter assays, western blot, and immunocytochemistry. Furthermore, PI3KCA, AKT, BCL2 in the ERBB2-PI3K-AKT signaling pathway were found to be downstream effectors of miR-1268b. In conclusion, miR-1268b increased chemosensitivity, at least in part, via modulation of PI3K-AKT pathway by targeting ERBB2. MiR-1268b may serve as a potential therapeutic target for patients with breast cancers.

16.
Tumour Biol ; 39(4): 1010428317697551, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28381163

RESUMO

The protocadherin 7 is a member of the protocadherin family that expressed aberrantly in many types of human cancers. However, its expression, function, and underlying mechanisms are little known in gastric cancer. In this study, we detected protocadherin 7 expression in gastric cancer tissues and non-tumorous gastric mucosa tissues by real-time quantitative polymerase chain reaction and immunohistochemistry. The association of protocadherin 7 expression with the clinicopathological characteristics and the prognosis was subsequently analyzed. MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)) and transwell assays were performed to assess the effect of protocadherin 7 on proliferation, migration, and invasion in gastric cancer cell lines. Moreover, real-time quantitative polymerase chain reaction and western blot were used to detect the expression of epithelial-mesenchymal transition markers. Protocadherin 7 expression was decreased gradiently from normal tissue to gastric cancer, especially in gastric cancer tissue with lymph node metastasis. Low expression of protocadherin 7 was significantly associated with Lauren's classification ( p = 0.0005), lymph node metastases ( p = 0.0002), and tumor node metastasis stage ( p = 0.0221), as well as poor prognosis ( p < 0.05). Furthermore, down-regulation of protocadherin 7 in gastric cancer cell lines significantly increased their migration and invasion abilities (both p < 0.05), while it had no influence on the gastric cancer cell proliferation ( p > 0.05). Additionally, our results demonstrated that E-cadherin expression was down-regulated in gastric cancer cells with protocadherin 7 depletion. Our data indicated that protocadherin 7 may play important roles in the invasion and metastasis of gastric cancer, and protocadherin 7 could suppress cell migration and invasion through E-cadherin inhibition. Protocadherin 7 can serve as a novel biomarker for diagnostic and prognosis in patients with gastric cancer.


Assuntos
Caderinas/fisiologia , Movimento Celular , Neoplasias Gástricas/patologia , Adulto , Idoso , Antígenos CD , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico
17.
J Mol Neurosci ; 62(1): 1-10, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28401370

RESUMO

Diabetes mellitus (DM) has been regarded as an important risk factor for Alzheimer's disease (AD), and diabetic patients and animals have shown cognitive dysfunction. More research has shown that the amyloid-ß (Aß), which is a hallmark of AD, was found deposited in the hippocampus of diabetic rats. This Aß accumulation is regulated by the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP-1). However, the expression of RAGE and LRP-1 in diabetic rats is not very clear. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether the expression of RAGE and LRP-1 is related to Aß1-42 deposition at the hippocampus, prefrontal lobe, and amygdala in DM. We found that diabetic rats had longer escape latency and less frequency of entrance into the target zone than that of the control group (P < 0.05) in the Morris water maze (MWM) test. The Aß1-42 expression in the hippocampus and prefrontal lobe significantly increased in the DM group compared to the control group (P < 0.05). RAGE increased (P < 0.05), while LRP-1 decreased (P < 0.05) in the hippocampus tissue and prefrontal lobe tissue of DM rats. The Aß1-42 deposition was correlated with RAGE positively (P < 0.05), but with LRP-1 negatively (P < 0.05). Further, the expression levels of Aß1-42, RAGE, and LRP-1 were not changed in the amygdala between the diabetic rats and the control group. These findings indicated that upregulating RAGE and/or downregulating LRP-1 at the hippocampus and the prefrontal lobe contributed to the Aß1-42 accumulation and then further promoted the cognitive impairment of diabetic rats.


Assuntos
Tonsila do Cerebelo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipocampo/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Cognição , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/genética
18.
Int J Mol Med ; 39(4): 927-935, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28259959

RESUMO

Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that is overexpressed in various types of human cancers and has an important function in cancer progression. However, there is a paucity of data available regarding the biological effects of TMPRSS4 on breast cancer (BC) cells and the underlying mechanisms. In this study, expression of TMPRSS4 in BC tissues was detected by immunohistochemistry. The relationship between TMPRSS4 expression and clinicopathological characteristics as well as prognosis was evaluated. The effects of TMPRSS4 on cell proliferation, migration and invasion were investigated in BC cell lines in vitro. Additionally, RT-qPCR and western blot analysis were used to determine the expressions of epithelial-mesenchymal transition (EMT) biomarkers and TMPRSS4 in BC cell lines. We found that TMPRSS4 was overexpressed in BC tissues and its expression level was closely correlated with tumor size, histological grade, lymph node metastasis, clinical stage as well as poor survival (all P<0.05) and could be recognized as an independent prognostic factor for BC patients. Overexpression of TMPRSS4 promoted the proliferation, migration and invasion of BC cells in vitro. Moreover, TMPRSS4 knockdown significantly enhanced the expression of E-cadherin and claudin-1 and inhibited the expression of vimentin and Slug, indicating suppression of EMT. Our results suggest that TMPRSS4 plays a crucial role in the progression of BC. Moreover, TMPRSS4 overexpression promoted the proliferation, invasion and migration of BC cells by possibly inducing EMT. To conclude, TMPRSS4 may be a potential therapeutic target for cancer treatment.


Assuntos
Neoplasias da Mama/enzimologia , Proliferação de Células , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Serina Endopeptidases/biossíntese , Adulto , Neoplasias da Mama/patologia , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Invasividade Neoplásica
19.
Hepatol Res ; 46(8): 784-93, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26609665

RESUMO

AIM: Hepatocarcinogenesis is a multistep process from cirrhosis through low-grade dysplastic nodule, high-grade dysplastic nodule to hepatocellular carcinoma. Differential diagnosis between high-grade dysplastic nodules and early hepatocellular carcinomas is particularly difficult. The present study aims to identify a novel biological marker for differential diagnosis of the two lesions. METHODS: The expression level of an miRNA pair, miRNA-96-5p and 3p, was assessed by reverse transcription polymerase chain reaction in hepatic tissues. RESULTS: We showed that mature miRNA-96-5p and passenger strand miRNA-96-3p were differentially expressed in multistep hepatocarcinogenesis. miRNA-96-5p was significantly upregulated from cirrhosis, dysplastic nodules to hepatocellular carcinoma. However, significance of determination of miRNA-96-5p expression level for differential diagnosis between high-grade dysplastic nodule and hepatocellular carcinoma is limited. In contrast, the expression of miRNA-96-3p was detectable in cirrhosis and dysplastic nodules. Also, it was completely undetectable in the majority of hepatocellular carcinomas (30/34, 88.2%). The sensitivity and specificity of miRNA-96-3p negative expression for differential diagnosis of hepatocellular carcinomas from high-grade dysplastic nodules were 88.2% and 84.2%, respectively. In addition, a more specific diagnosis could be carried out by combining miRNA-96-3p with glypican 3, with the specificity of 100%. CONCLUSION: These findings demonstrated that miRNA-96-3p is a helpful diagnostic biomarker in differential diagnosis between high-grade dysplastic nodules and well-differentiated small hepatocellular carcinomas, especially in combination with glypican 3.

20.
Oncotarget ; 6(35): 37458-70, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26460960

RESUMO

Vascular Endothelial Growth Factor C (VEGF-C) has critical roles in angiogenesis in human cancers; however, the underlying mechanisms regulating VEGF-C expression remain largely unknown. In the present study, VEGF-C protein expression and the density of blood vessels or lymphatic vessels were determined by immunohistochemistry in 103 cases of gastric cancer tissues. Suppression of VEGF-C by miR-27b, miR-101 and miR-128 was investigated by luciferase assays, Western blot and ELISA. The miRNAs expression levels were detected in human gastric cancers by real-time quantitative PCR. Cell proliferation, migration and invasion assays were performed to assess the effect of miRNAs on gastric cancer cells and human umbilical vascular endothelial cells (HUVECs). Our data showed that high VEGF-C expression was significantly associated with increased tumor size, advanced TNM classification and clinical stage, higher microvessel density (MVD) and lymphatic density (LVD), as well as poor survival in patients with gastric cancer. Furthermore, VEGF-C was found to be a direct target gene of miR-27b, miR-101, and miR-128. The expression levels of the three miRNAs were inversely correlated with MVD. Overexpression of miR-27b, miR-101, or miR-128 suppressed migration, proliferation activity, and tube formation in HUVECs by repressing VEGF-C secretion in gastric cancer cells. We conclude that miR-27b, miR-101 and miR-128 inhibit angiogenesis by down-regulating VEGF-C expression in gastric cancers.


Assuntos
MicroRNAs/metabolismo , Neovascularização Patológica , Neoplasias Gástricas/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Feminino , Gastrectomia , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Estimativa de Kaplan-Meier , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Masculino , MicroRNAs/genética , Microvasos/metabolismo , Microvasos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Fatores de Tempo , Transfecção , Resultado do Tratamento , Carga Tumoral , Fator C de Crescimento do Endotélio Vascular/genética
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