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1.
Anticancer Res ; 41(10): 4821-4836, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593431

RESUMO

BACKGROUND/AIM: Our recent miRNA analyses revealed that miR-30a-5p has tumor-suppressive activity in pancreatic ductal adenocarcinoma (PDAC). Herein, we sought to identify tumor-suppressive genes controlled by miR-30a-5p, emphasizing on genes that are closely involved in the molecular pathogenesis of PDAC. We uncovered several novel findings regarding the pathogenesis of this disease. MATERIALS AND METHODS: In silico analyses were used to identify the putative target genes of miR-30a-5p and assess their expression levels. Direct regulation of RRM2 by miR-30a-5p and its oncogenic functions were evaluated in PDAC cell lines. Overexpression of RRM2 was demonstrated in clinical samples. RESULTS: A total of 24 putative targets were identified by in silico database analysis. High expression of 4 genes (CBFB, RRM2, AHNAK, and DCBLD1) was significantly associated with shorter survival of patients with PDAC. Functional assays demonstrated that knockdown of RRM2 attenuated the malignant phenotype of PDAC cells. CONCLUSION: The miR-30a-5p/RRM2 axis facilitated the malignant transformation of PDAC cells.


Assuntos
Carcinoma Ductal Pancreático/patologia , Genes Supressores de Tumor/fisiologia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Subunidade beta de Fator de Ligação ao Core/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Ribonucleosídeo Difosfato Redutase/genética , Ribonucleosídeo Difosfato Redutase/metabolismo , Análise de Sobrevida
2.
Nat Cell Biol ; 23(9): 978-991, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497368

RESUMO

The extracellular-signal-regulated kinases ERK1 and ERK2 (hereafter ERK1/2) represent the foremost mitogenic pathway in mammalian cells, and their dysregulation drives tumorigenesis and confers therapeutic resistance. ERK1/2 are known to be activated by MAPK/ERK kinase (MEK)-mediated phosphorylation. Here, we show that ERK1/2 are also modified by lysine-63 (K63)-linked polyubiquitin chains. We identify the tripartite motif-containing protein TRIM15 as a ubiquitin ligase and the tumour suppressor CYLD as a deubiquitinase of ERK1/2. TRIM15 and CYLD regulate ERK ubiquitination at defined lysine residues through mutually exclusive interactions as well as opposing activities. K63-linked polyubiquitination enhances ERK interaction with and activation by MEK. Downregulation of TRIM15 inhibits the growth of both drug-responsive and drug-resistant melanomas. Moreover, high TRIM15 expression and low CYLD expression are associated with poor prognosis of patients with melanoma. These findings define a role of K63-linked polyubiquitination in the ERK signalling pathway and suggest a potential target for cancer therapy.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Lisina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Poliubiquitina/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Genes Supressores de Tumor/fisiologia , Humanos , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Ubiquitina/metabolismo
3.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
4.
Cell Death Dis ; 12(6): 537, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035231

RESUMO

The chromobox (CBX) proteins mediate epigenetic gene silencing and have been implicated in the cancer development. By analyzing eight CBX family members in TCGA dataset, we found that chromobox 7 (CBX7) was the most strikingly downregulated CBX family member in urinary bladder cancer (UBC), as compared to normal tissues. Though dysregulation of CBX7 has been reported in multiple cancers, its specific role and clinical relevance in UBC remain unclear. Herein, we found that frequent downregulation of CBX7 in UBC specimens, which was due to its promoter hypermethylation, was correlated with poor prognosis. The ectopic expression of CBX7 suppressed UBC cell proliferation, migration, invasion, and cancer stemness, whereas CBX7 depletion promoted cancer cell aggressiveness. Importantly, CBX7 overexpression in UBC cells inhibited tumorigenicity, whereas CBX7 depletion promoted the tumor development, indicating its tumor-suppressive role in UBC. Using RNA-seq and chromosome immunoprecipitation (ChIP) assays, we identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of CBX7, which was negatively modulated by CBX7 in a PRC1-dependent manner and involved in stimulating ERK signaling. Consistently, AKR1B10 overexpression induced cancer cell aggressiveness, whereas suppression of AKR1B10 by siRNA or its small molecular inhibitor, oleanolic acid, reversed the CBX7 deficiency-induced cellular effects. AKR1B10 overexpression was negatively associated with CBX7 downregulation and predicted poor clinical outcomes in UBC patients. Taken together, our results indicate that CBX7 functions as a tumor suppressor to downregulate AKR1B10 and further inactivates ERK signaling. This CBX7/AKR1B10/ERK signaling axis may provide a new therapeutic strategy against UBC.


Assuntos
Aldo-Ceto Redutases/genética , Complexo Repressor Polycomb 1/fisiologia , Neoplasias da Bexiga Urinária/patologia , Aldo-Ceto Redutases/metabolismo , Animais , Proliferação de Células/genética , Células Cultivadas , Progressão da Doença , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Complexo Repressor Polycomb 1/genética , Neoplasias da Bexiga Urinária/genética
5.
Cell Death Dis ; 12(5): 444, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947839

RESUMO

Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Transporte/metabolismo , Genes Supressores de Tumor/fisiologia , Feocromocitoma/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Humanos , Feocromocitoma/patologia , Transfecção
6.
Cell Death Dis ; 12(4): 351, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824269

RESUMO

Aberrant long-noncoding RNA (lncRNA) expression has been shown to be involved in the pathogenesis of endometrial cancer (EC). Herein, we report a novel tumor suppressor lncRNA SOCS2-AS1 in EC. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nuclear/cytoplasmic fractionation assays were used to detect the subcellular location. We found that SOCS2-AS1 was downregulated in EC tissues. Its reduced expression was correlated with advanced clinical stage and poor prognosis. Forced expression of SOCS2-AS1 suppressed EC cell proliferation and induced cell-cycle arrest and apoptosis. SOCS2-AS1-binding proteins were detected using RNA pull-down assay and mass spectrometry. Mechanistically, SOCS2-AS1 bound to Aurora kinase A (AURKA) and increased its degradation through the ubiquitin-proteasome pathway. In conclusion, SOCS2-AS1 may thus serve as a prognostic predictor and a biomarker for AURKA-inhibitor treatment in EC patients.


Assuntos
Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação para Baixo , Feminino , Genes Supressores de Tumor/fisiologia , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
7.
Cell Death Dis ; 12(4): 370, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824311

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15-20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.


Assuntos
Processamento Alternativo/genética , Proliferação de Células/fisiologia , Ciclina D1/metabolismo , Fatores de Transcrição NFI/metabolismo , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Mama/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Recidiva Local de Neoplasia/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
Cancer Chemother Pharmacol ; 88(2): 223-233, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33907880

RESUMO

PURPOSE: Limited value is achieved in systemic chemotherapy for oral squamous cell carcinoma (OSCC), due to cancer cell resistance against cytotoxic agents. Tumor suppressor activities of selenium-binding protein 1 (SELENBP1) have been shown in multiple human cancers except for OSCC. The aim of this study is to clarify the biological functions and potential mechanism of SELENBP1 in OSCC. METHODS: SELENBP1 expression and its clinical significance in OSCC were analyzed from The Cancer Genome Atlas (TCGA) database. Quantitative polymerase chain reaction (qPCR) or western blot was applied to determine SELENBP1, NRF2 and KEAP1 mRNA or protein levels. Sulforhodamine B assay (SRB) was performed to examine the cytotoxic effects of 5-fluorouracil (5-FU) and cisplatin on OSCC cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the role of SELENBP1 in KEAP1 transcription. RESULTS: SELENBP1 downregulation is positively correlated with a poor prognosis for OSCC patients. SELENBP1 knockdown enhances resistance of OSCC cells to 5-FU and cisplatin, while SENENBP1 overexpression displays the opposite effects. Mechanistically, SELENBP1 reduces NRF2 protein levels by promoting its polyubiquitination and degradation. SELENBP1 induces KEAP1 transcription by binding to KEAP1 promoter. Downregulation of SELENBP1 is induced by miR-4786-3p binding to the 3' untranslated region (UTR) of SELENBP1. CONCLUSION: SENENBP1 is identified as a novel protective biomarker for OSCC patients. Targeting at the miR-4786-3p-SELENBP1-KEAP1-NRF2 signaling axis may enhance the efficacy of chemotherapy for OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Bucais/genética , Fator 2 Relacionado a NF-E2/genética , Proteínas de Ligação a Selênio/genética , Regiões 3' não Traduzidas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Fluoruracila/farmacologia , Genes Supressores de Tumor/fisiologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Transdução de Sinais/genética
9.
Life Sci ; 277: 119398, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831429

RESUMO

BACKGROUND: Recent studies have provided compelling evidence regarding the association of microRNAs (miRNAs) with the progression and development of tumors. Among the miRNAs, the dysregulation of miR-146b-3p expression has been reported in several cancers, however, its effect on colorectal cancer (CRC) remains unexplored. Many studies have suggested a close correlation between the transcription factor (TF)-miRNA signal and cancer. The present study explored the effects of TF-miR-146b-3p axis on CRC and elucidated its downstream regulatory molecule. MATERIALS AND METHODS: The expression levels of miR-146b-3p in CRC tissues and cell lines were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). The impact of miR-146b-3p on CRC cell proliferation, migration, and invasion were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell proliferation assay and transwell migration and invasion assay. Additionally, the impact of miR-146b-3p on CRC cell cycle and apoptosis was investigated using flow cytometry. The targets of miR-146b-3p, predicted by miRWalk database, were verified using a dual-luciferase reporter system. The expression levels of TFs were detected using qRT-PCR. The effects of miR-146b-3p and SP1 on FAM107A expression were assessed by performing qRT-PCR and western blotting. Chromatin Immunoprecipitation (ChIP) Assay was performed and JASPAR database was utilized to explore the regulatory relationship between the SP1 and miR-146b-3p. RESULTS: Increased expression of miR-146b-3p in CRC tissues and cell lines correlated with poor overall survival (OS). Upregulation of miR-146b-3p expression remarkably promoted the proliferation, migration, and invasion of CRC cells and suppressed their apoptosis. Furthermore, SP1 overexpression significantly elevated the miR-146b-3p expression, decreased the FAM107A expression, and promoted the G1/S transition. The miR-146b-3p overexpression also enhanced the effects of SP1 overexpression on CRC cell proliferation, migration, and invasion, whereas miR-146b-3p knockdown led to the opposite results. CONCLUSION: Mechanistically, miR-146b-3p functions as an oncogene by directly targeting FAM107A. Our results highlight the critical regulatory role played by SP1-induced miR-146b-3p expression in CRC development. Our results suggest that SP1/miR-146b-3p/FAM107A axis may be a potential therapeutic target for CRC.


Assuntos
MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição Sp1/metabolismo , Adulto , Idoso , Animais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Proteínas Nucleares/genética , Fator de Transcrição Sp1/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Ovarian Res ; 14(1): 23, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526047

RESUMO

BACKGROUND: Ovarian cancer is the leading lethal gynecological cancer and is generally diagnosed during late-stage presentation. In addition, patients with ovarian cancer still face a low 5-year survival rate. Thus, innovative molecular targeting agents are required to overcome this disease. The present study aimed to explore the function of miR-362-3p and the underlying molecular mechanisms influencing ovarian cancer progression. METHODS: The expression levels of miR-362-3p were determined using qRT-PCR. Gain-of-function and loss-of-function methods were used to detect the effects of miR-362-3p on cell proliferation, cell migration, and tumor metastasis in ovarian cancer. A luciferase reporter assay was performed to confirm the potential target of miR-362-3p, and a rescue experiment was employed to verify the effect of miR-362-3p on ovarian cancer by regulating its target gene. RESULTS: miR-362-3p was significantly downregulated in ovarian cancer tissues and cell lines. In vitro, our data showed that miR-362-3p suppressed cell proliferation and migration. In vivo, miR-362-3p inhibited ovarian cancer growth and metastasis. Mechanistically, SERBP1 was identified as a direct target and functional effector of miR-362-3p in ovarian cancer. Moreover, SERBP1 overexpression rescued the biological function of miR-362-3p. CONCLUSIONS: Our data reveal that miR-362-3p has an inhibitory effect on ovarian cancer. miR-362-3p inhibits the development and progression of ovarian cancer by directly binding its target gene SERBP1.


Assuntos
Genes Supressores de Tumor/fisiologia , MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , Proteínas de Ligação a RNA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Transfecção
11.
Biomed Pharmacother ; 137: 111351, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33550046

RESUMO

Circular RNAs (circRNAs) are a class of endogenous noncoding RNA, which were previously considered as a byproduct of RNA splicing error. Numerous studies have demonstrated the altered expression of circRNAs in organ tissues during pathological conditions and their involvements in disease pathogenesis and progression, including cancers. In colorectal cancer (CRC), multiple circRNAs have been identified and characterized as "oncogenic", given their involvements in the downregulation of tumor suppressor genes and induction of tumor initiation, progression, invasion, and metastasis. Additionally, other circRNAs have been identified in CRC and characterized as "tumor suppressive" based on their ability of inhibiting the expression of oncogenic genes and suppressing tumor growth and proliferation. circRNAs could serve as potential diagnostic and prognostic biomarkers, and therapeutic targets or vectors to be utilized in cancer therapies. This review briefly describes the dynamic changes of the tumor microenvironment inducing immunosuppression and tumorigenesis, and outlines the biogenesis and characteristics of circRNAs and recent findings indicating their roles and functions in the CRC tumor microenvironment. It also discusses strategies and technologies, which could be employed in the future to overcome current cancer therapy challenges associated with circRNAs.


Assuntos
Neoplasias Colorretais/genética , RNA Circular/fisiologia , Microambiente Tumoral/genética , Animais , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Humanos , Oncogenes/fisiologia , RNA Circular/biossíntese , RNA Circular/classificação
12.
Am J Otolaryngol ; 42(2): 102920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33454555

RESUMO

OBJECTIVE: Thyroid carcinoma is the most common endocrine tumor, and thyroid papillary carcinoma is the most common form. Although thyroid papillary carcinoma presents a good prognosis, some patients still exhibit recurrence or distant metastasis. miR-1301-3p has been found involved in the occurrence and development of some special tumors. Our study aims to investigate the miR-1301-3p expression in thyroid papillary carcinoma, to explore its biological function, and to provide a potential marker for diagnosis and treatment of thyroid papillary carcinoma. MATERIALS AND METHODS: The tissue samples from 70 patients with PTC (n = 35) and benign tumors (n = 35) were collected respectively. miR-1301-3p expression were detected by qPCR. Diagnostic value of miR-1301-3p was analyzed by ROC curve. CCK-8 assays and flow cytometry were performed to detect the effect of miR-1301-3p on TPC-1 function. PCNA expression of protein was detected by WB. RESULTS: Compared with the normal group, the expression of miR-1301-3p was obviously decreased in both benign group and PTC group. With the higher T and N grades, the lower expression of miR-1301-3p. ROC curve analysis showed that the diagnostic values of miR-1301-3p for benign tumor and PTC were 0.766 and 0.881, respectively. Vitro experiments showed that miR-1301-3p was decreased in TPC-1 cells, then, upregulated miR-1301-3p blocked the TPC-1 cell cycle in G1/S phase, and inhibited the proliferation. PCNA expression was significantly increased in TPC-1 cells and significantly decreased after upregulation of miR-1301-3p. CONCLUSION: The present study showed that the expression of miR-1301-3p in PTC was significantly decreased, which was related to T and N grade. Upregulation of miR-1301-3p could inhibit cell proliferation and cell migration. miR-1301-3p may serve as a potential biomarker for the early diagnosis and treatment of PTC.


Assuntos
Biomarcadores Tumorais/genética , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Adulto Jovem
13.
Cell Death Dis ; 12(1): 47, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414404

RESUMO

The tumor suppressor prostate apoptosis response-4 (Par-4) has recently turned 'twenty-five'. Beyond its indisputable role as an apoptosis inducer, an increasing and sometimes bewildering, new roles for Par-4 are being reported. These roles include its ability to regulate autophagy, senescence, and metastasis. This growing range of responses to Par-4 is reflected by our increasing understanding of the various mechanisms through which Par-4 can function. In this review, we summarize the existing knowledge on Par-4 tumor suppressive mechanisms, and discuss how the interaction of Par-4 with different regulators influence cell fate. This review also highlights the new secretory pathway that has emerged and the likely discussion on its clinical implications.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Genes Supressores de Tumor/fisiologia , Apoptose , Humanos , Transdução de Sinais
14.
Dig Dis Sci ; 66(2): 381-397, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32185664

RESUMO

Approximately 80% of the human genome harbors biochemical marks of active transcription that its majority transcribes to noncoding RNAs, namely long noncoding RNAs (lncRNAs). LncRNAs are heterogeneous RNA transcripts that regulate critical biological processes such as cell survival and death. They involve in the progression of different cancers by affecting transcriptional and post-transcriptional modifications as well as epigenetic control of numerous tumor suppressors and oncogenes. Recent findings show that aberrant expression of lncRNAs is associated with tumor initiation, progression, invasion, and overall survival of patients with gastrointestinal (GI) cancers. Some lncRNAs play as tumor suppressors in all GI cancers, but others play as tumor promoters. However, some other lncRNAs might function as a tumor suppressor in one GI cancer, but as a tumor promoter in another GI cancer type. This fact highlights possible context dependency of the expression patterns and roles of at least some lncRNAs in GI cancer development and progression. Here, we review the functional relation of lncRNAs involved in the development and progression of GI cancer by focusing on their roles as tumor suppressor and tumor promoter genes.


Assuntos
Carcinógenos , Neoplasias Gastrointestinais/genética , Genes Supressores de Tumor/fisiologia , Regiões Promotoras Genéticas/fisiologia , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinógenos/metabolismo , Neoplasias Gastrointestinais/metabolismo , Humanos , RNA Longo não Codificante/biossíntese
15.
Am J Pathol ; 191(1): 157-167, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129760

RESUMO

Colorectal cancer (CRC) is a leading nonfamilial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis are not fully understood. This study demonstrates that cell adhesion molecule transmembrane and immunoglobulin domain containing 1 (TMIGD1) are highly expressed in mouse and human normal intestinal epithelial cells. TMIGD1 knockout mice were developed, and the loss of TMIGD1 in mice was shown to result in the development of adenomas in small intestine and colon. In addition, the loss of TMIGD1 significantly impaired intestinal epithelium brush border membrane, junctional polarity, and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation and cell migration, arrests cell cycle at the G2/M phase, and induces expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, TMIGD1 is shown to be progressively down-regulated in sporadic human CRC, and its downregulation correlates with poor overall survival. The findings herein identify TMIGD1 as a novel tumor suppressor gene and provide new insights into the pathogenesis of colorectal cancer and a novel potential therapeutic target.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Neoplasias do Colo/metabolismo , Glicoproteínas de Membrana/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Genes Supressores de Tumor/fisiologia , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
16.
Cancer Res ; 81(4): 935-944, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323382

RESUMO

p53 is a short-lived protein with low basal levels under normal homeostasis conditions. However, upon DNA damage, levels of p53 dramatically increase for its activation. Although robust stabilization of p53 serves as a "trademark" for DNA damage responses, the requirement for such dramatic protein stabilization in tumor suppression has not been well addressed. Here we generated a mutant p53KQ mouse where all the C-terminal domain lysine residues were mutated to glutamines (K to Q mutations at K367, K369, K370, K378, K379, K383, and K384) to mimic constitutive acetylation of the p53 C-terminus. Because of p53 activation, p53KQ/KQ mice were perinatal lethal, yet this lethality was averted in p53KQ/- mice, which displayed normal postnatal development. Nevertheless, p53KQ/- mice died prematurely due to anemia and hematopoiesis failure. Further analyses indicated that expression of the acetylation-mimicking p53 mutant in vivo induces activation of p53 targets in various tissues without obviously increasing p53 levels. In the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model, expression of the acetylation-mimicking p53-mutant protein effectively suppressed K-Ras-induced PDAC development in the absence of robust p53 stabilization. Together, our results provide proof-of-principle evidence that p53-mediated transcriptional function and tumor suppression can be achieved independently of its robust stabilization and reveal an alternative approach to activate p53 function for therapeutic purposes. SIGNIFICANCE: Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.


Assuntos
Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Acetilação , Animais , Apoptose/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Células Cultivadas , Dano ao DNA/genética , Genes Supressores de Tumor/fisiologia , Lisina/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Processamento de Proteína Pós-Traducional/genética , Estabilidade Proteica , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/química
17.
J Cell Physiol ; 236(1): 273-283, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32583462

RESUMO

Lung cancer is one of the most common cancers and its incidence is rising around the world. Various studies suggest that miR-330 acts as a tumor-suppressor microRNA (miRNA) in different types of cancers, but precisely how has remained unclear. In this study, we investigate miR-330 expression in lung cancer patient samples, as well as in vitro, by studying how normalization of miR-330 expression affects lung cancer cellular phenotypes such as viability, apoptosis, proliferation, and migration. We establish that low miR-330 expression predicts poor lung cancer prognosis. Stable restoration of reduced miR-330 expression in lung cancer cells reduces cell viability, increases the fraction of apoptotic cells, causes G2/M cell cycle arrest, and inhibits cell migration. These findings are substantiated by increased mRNA and protein expression of markers for apoptosis via the intrinsic pathway, such as caspase 9, and decreased mRNA and protein expression of markers for cell migration, such as vimentin, C-X-C chemokine receptor type 4, and matrix metalloproteinase 9. We showed that reduced miR-330 expression predicts poor lung cancer survival and that stable restoration of miR-330 expression in lung cancer cells has a broad range of tumor-suppressive effects. This indicates that miR-330 is a promising candidate for miRNA replacement therapy for lung cancer patients.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Células A549 , Apoptose/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Neoplasias Pulmonares/patologia , RNA Mensageiro/genética
18.
Mol Med Rep ; 22(6): 5304-5312, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174027

RESUMO

Laryngeal squamous cell carcinoma (LSCC) is a common type of malignant tumor of the head and neck. An increasing number of studies have illustrated that long non­coding RNAs (lncRNAs) serve an important role in the occurrence and development of LSCC. Therefore, the present study aimed to investigate the expression changes and mechanism of lncRNA fer­1­like family member 4 (FER1L4) in the progression of LSCC. The expression levels of FER1L4 in LSCC cell lines (AMC­HN­8, Tu 686, M4E and M2E) and a normal cell line (HBE135­E6E7) were analyzed using reverse transcription­quantitative PCR. The FER1L4 overexpression plasmid (plasmid­FER1L4) was subsequently transfected into Tu 686 cells to upregulate the expression levels of FER1L4. Cell viability was detected using a Cell Counting Kit­8 assay, cell proliferation was analyzed using a colony formation assay, apoptosis was examined by flow cytometry, and cell migration and invasion were determined using wound healing and Transwell assays, respectively. In addition, the plasmid­FER1L4 cells were also treated with insulin­like growth factor 1 (IGF­1) to determine the effect of FER1L4 on the AKT/ERK signaling pathway, and the effect of the plasmid­FER1L4 on the expression levels of AKT/ERK signaling pathway­related proteins were analyzed using western blotting. The results of the present study revealed that FER1L4 expression levels were downregulated in AMC­HN­8 and Tu 686 cells. Notably, FER1L overexpression significantly reduced the cell viability, proliferation, migration and invasion of LSCC cells, while promoting apoptosis. Meanwhile, the plasmid­FER1L4 also significantly suppressed the phosphorylation levels of AKT and ERK. Further studies indicated that the aforementioned changes could be reversed by IGF­1, indicating FER1L4 may regulate the progression of LSCC cells by inhibiting the AKT/ERK signaling pathway. In conclusion, the present study provided a potential novel direction for the treatment of LSCC in the future and suggested that FER1L4 may be a new target in this field.


Assuntos
RNA Longo não Codificante/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Apoptose/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Laríngeas/genética , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética
19.
Cell Death Dis ; 11(10): 839, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037185

RESUMO

Polyamine biosynthesis is an essential metabolic pathway for cell growth and differentiation in non-small-cell lung cancer (NSCLC). Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer. The results of our previous study showed that FATS-mediated polyubiquitination of p53 promotes the activation of p53 in response to DNA damage; however, little is known about the role of FATS in metabolic reprogramming in NSCLC. In the present study, FATS was observed to be significantly downregulated in NSCLC tissues compared with paired adjacent normal tissues and was associated with the survival of NSCLC patients. We further showed that the presence of the tumour suppressor FATS in NSCLC cells led to apoptosis by inducing pro-death autophagy. In addition, FATS was shown to function as a suppressor of polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) at the protein and mRNA levels, which was partially dependent on oestrogen receptor (ER). Furthermore, FATS was observed to bind to ERß and translocate to the cytosol, leading to ODC degradation. The findings of our study demonstrate that FATS plays important roles in polyamine metabolism in NSCLC and provides a new perspective for NSCLC progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/genética , Receptor beta de Estrogênio/genética , Neoplasias Pulmonares/genética , Ciclo Celular/genética , Genes Supressores de Tumor/fisiologia , Humanos , RNA Mensageiro/metabolismo
20.
Cells ; 9(10)2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33076453

RESUMO

Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.


Assuntos
Neoplasias Encefálicas/genética , Genes Supressores de Tumor/fisiologia , Glioma/genética , Oncogenes/fisiologia , Receptores Notch/fisiologia , Transdução de Sinais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Homeostase , Humanos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais
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