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1.
Plant Physiol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685645

RESUMO

Members of the mitochondrial transcription terminator factor (mTERF) family, originally identified in vertebrate mitochondria, are involved in the termination of organellular transcription. In plants, mTERF proteins are mainly localized in chloroplasts and mitochondria. In Arabidopsis thaliana, mTERF8/pTAC15 was identified in the plastid-encoded RNA polymerase (PEP) complex, the major RNA polymerase of chloroplasts. In this work, we demonstrate that mTERF8 is associated with the PEP complex. An mTERF8 knockout line displayed a wild type-like phenotype under standard growth conditions, but showed impaired efficiency of photosystem II electron flow. Transcription of most chloroplast genes was not substantially affected in the mterf8 mutant; however, the level of the psbJ transcript from the psbEFLJ polycistron was increased. RNA blot analysis showed that a larger transcript accumulates in mterf8 than in the wild type. Thus, abnormal transcription and/or RNA processing occur for the psbEFLJ polycistron. Circular reverse transcription polymerase chain reaction and sequence analysis showed that the psbJ transcript terminates 95 nucleotides downstream of the translation stop codon in the wild type, whereas its termination is aberrant in mterf8. Both electrophoresis mobility shift assays and chloroplast chromatin immunoprecipitation analysis showed that mTERF8 specifically binds to the 3' terminal region of psbJ. Transcription analysis using the in vitro T7 RNA polymerase system showed that mTERF8 terminates psbJ transcription. Together, these results suggest that mTERF8 is specifically involved in the transcription termination of the chloroplast gene psbJ.

2.
Nat Commun ; 10(1): 4695, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619685

RESUMO

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

3.
Phytother Res ; 33(9): 2298-2309, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31268205

RESUMO

Cisplatin represents one of the first-line drugs used for non-small-cell lung cancer treatment. However, considerable side effects and the emergence of drug resistance are becoming critical limitations to its application. Combinatorial strategies may be able to extend the use of cisplatin. Both Tanshinone IIA and cisplatin inhibit non-small-cell lung cancer cell growth in a time- and dose-dependent manner. When Tanshinone IIA was combined with cisplatin at a ratio of 20:1, they were observed to exert a synergistic inhibitory effect on non-small-cell lung cancer cells. The combination treatment was shown to impair cell migration and invasion, arrest the cell cycle in the S phases, and induce apoptosis in A549 and PC9 cells in a synergistic manner. KEGG pathway analysis and molecular docking indicated that Tanshinone IIA might mainly influence the phosphatidylinositol 3-kinase-Akt signalling pathway. In all treated groups, the expression levels of Bax and cleaved Caspase-3 were up-regulated, whereas the expression levels of Bcl-2, Caspase-3, p-Akt, and p-PI3K proteins were down-regulated. Among these, the combination of Tan IIA and cisplatin exhibited the most significant difference. Tanshinone IIA may function as a novel option for combination therapy for non-small-cell lung cancer treatment.

5.
J Exp Clin Cancer Res ; 38(1): 164, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987656

RESUMO

BACKGROUND: Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC. METHODS: We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC. RESULTS: C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC. CONCLUSION: Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.


Assuntos
Caderinas/metabolismo , Regulação Neoplásica da Expressão Gênica , NF-kappa B/metabolismo , Proteínas Oncogênicas/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteínas Oncogênicas/metabolismo , Prognóstico , Interferência de RNA , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
6.
J Clin Invest ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30511962

RESUMO

The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC), but remains a challenge for drug development. Long non-coding RNAs (lncRNAs) are invaluable in identifying cancer pathologies, and providing therapeutic options for cancer patients. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening, and examined its expression among a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis of CRC patients. Additionally, APC can enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis and tumor angiogenesis by suppressing exosome production through directly binding Rab5b mRNA and reducing its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through non-canonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest an APC-regulated lncRNA-APC1 program as an exploitable therapeutic maneuver for CRC patients.

7.
Enzyme Microb Technol ; 118: 50-56, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30143199

RESUMO

A rational design method to improve ß-mannanase (ManTJ102) thermostability was developed successfully in this study. The flexible area of residues 330-340 in ManTJ102 was firstly selected from analysis of molecular dynamics simulation and then the critical amino acid residue (Ala336Pro) with the lowest mutation energy was determined by virtual mutation, whose mutant was named as Mutant336. Afterward, the dynamics transition temperature (Tdtt) of ManTJ102 and Mutant336 was evaluated by simulated annealing and heating, and Mutant336 with higher Tdtt was implemented for experimental verification of the enzyme thermostability. As a result, the half-life of Mutant336 activity was 120 min at 60 °C, which was 24-fold of ManTJ102, and the irreversible thermal denaturation constant of Mutant336 was only about 2/5 of ManTJ102, indicating that Mutant336 has better thermostability than ManTJ102. Furthermore, Mutant336 has much higher ß-mannanase activity and specific activity than ManTJ102. Therefore, Mutant336 was more suitable to further research for applications.

8.
Cancer Res ; 78(20): 5848-5862, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30143523

RESUMO

Shortening of the 3' untranslated regions (3'UTR) of mRNA is an important mechanism for oncogene activation. However, 3'UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel RAC1 shorter 3'UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3'UTR isoform of RAC1 substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3'UTR shortening of RAC1 in UCB by mediating slow transcriptional elongation at RAC1 Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3'UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3'UTR shortening program as an exploitable therapeutic strategy for patients with UCB.Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848-62. ©2018 AACR.

9.
Oncogene ; 37(48): 6243-6258, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30013189

RESUMO

It has been suggested that formin-like protein 1 (FMNL1) plays an important role in the pathogenic process of several hematopoietic malignancies. In this study, we performed a series of in vivo and in vitro assays to elucidate the biological functions of FMNL1 and underlying mechanisms in human nasopharyngeal carcinoma (NPC) pathogenesis. Herein, we report that high expression of FMNL1 in NPC is positively associated with an aggressive disease and/or poor patient survival. Ectopic overexpression of FMNL1 in NPC cells substantially promoted cell invadopodia formation, epithelial-mesenchymal transition (EMT) and invasiveness, whereas depletion of FMNL1 potently suppressed NPC cells invadopodia formation, EMT, and invasive/metastatic capacities. We further show that FMNL1 could enhance NPC cell aggressiveness by increasing a key downstream target, the metastasis-associated protein 1 (MTA1) gene. Importantly, ectopic overexpression of FMNL1 in NPC cells markedly improved the binding of HDAC1 with Profilin2 in the cytoplasm and suppressed the enrichment of HDAC1 on the promoter of MTA1 and thereby, leading to an increased MTA1 transcription and expression. Furthermore, in addition to the amplification of FMNL1 gene, decreased level of miR-16 in NPCs is another critical mechanism to upregulate FMNL1 expression. These results, collectively, provide first-line of evidences that high expression of FMNL1, resulted from decreased miR-16 and/or MTA1 amplification, has a potent oncogenic role to drive the development and aggressive process of NPC by upregulating MTA1, and FMNL1 might be employed as a new prognostic biomarker and therapeutic target for human NPC.

10.
Nan Fang Yi Ke Da Xue Xue Bao ; 38(3): 312-317, 2018 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-29643037

RESUMO

OBJECTIVE: To screen the effective components of Shenkangwan that regulate endothelial-mesenchymal transition in endothelial cells for optimizing prescription of Shenkangwan. METHODS: ALK5 was identified as one of the target receptors that regulate endothelial-mesenchymal transition of endothelial cells using molecular docking technique. Nine molecules were screened as the candidate effective components in Shenkangwan, among which calycosin, ononin and stigmasterol were selected for testing. Glomerular epithelial cells were exposed to high glucose and treated with calycosin, ononin, or stigmasterol, and the cellular expressions of α-smooth muscle actin (α-SMA) and vimentin mRNA were detected with real-time fluorescence quantitative PCR. The phosphorylation of SMAD2/3 in the cells was detected using Western blotting. RESULTS: Calycosin, ononin and stigmasterol did not produce significant cytotoxicity in glomerular epithelial cells (P>0.05). The cells exposed to high glucose and calycosin treatment showed significantly decreased mRNA levels of α-SMA and vimentin (P<0.05) and inhibited phosphorylation of SMAD2/3. Ononin and stigmasterol did not produce such effects in the cells. CONCLUSION: In endothelial cells with high glucose-induced injury, calycosin can inhibit the up-regulation of α-SMA and vimentin and inhibit phosphorylation of SMAD2/3 to regulate endothelial-mesenchymal transition and improve diabetic nephropathy.

11.
Oncogene ; 37(20): 2660-2675, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29483646

RESUMO

Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.

12.
Stem Cells ; 36(2): 180-191, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29119708

RESUMO

Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are suggested responsible for driving cancer resistance to conventional therapies and for cancer recurrence and/or metastasis. CD133 is served as a key biomarker to identify and characterize this subpopulation of cells in hepatocellular carcinoma (HCC). Our previous study indicated that overexpression of eukaryotic initiation factor 5A2 (EIF5A2) promotes HCC cell metastasis and angiogenesis. In this study, we demonstrated that EIF5A2 might play a crucial role in CSCs regulation and investigated its potential molecular mechanisms. Using quantitative real-time polymerase chain reaction assay, we observed that the expression of EIF5A2 positively correlated with CD133 levels in a cohort of cancerous and noncancerous liver tissues and cells. Next, HCC cells with high expression of EIF5A2 have a strong capacity to form undifferentiated tumor spheres in vitro and show elevated levels of stem cell-related genes, leading to an increased ability to develop tumors when subcutaneously injected into nude mice. Furthermore, differential microRNA expression was profiling between two EIF5A2-depleted HCC cell lines and their control one identified a decreased expression of miR-29b in EIF5A2-depleted cell lines. Further functional studies illustrated that downregulated miR-29b level is responsible for EIF5A2-maintained HCC cell stemness either in vitro or in vivo. Moreover, enforced expression of EIF5A2 in HCC cells largely enhanced the binding of c-Myc on the promoter of miR-29b and downregulation of miR-29b by EIF5A2 was dependent on c-Myc. Our findings, collectively, reveal that EIF5A2 contributes to the maintenance of CD133+ HCC cells via the c-Myc/miR-29b axis. Stem Cells 2018;36:180-191.


Assuntos
Antígeno AC133/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/metabolismo , Antígeno AC133/genética , Animais , Western Blotting , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Theranostics ; 7(19): 4836-4849, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29187907

RESUMO

Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). However, the role of lncRNA in CRC liver metastasis remains unclear. Methods: a microarray was performed to identify the differentially expressed lncRNAs between CRC tissues with and without liver metastasis. Survival analysis was evaluated using the Kaplan-Meier method and assessed using the log-rank test. In vitro and in vivo assays were preformed to explore the biological effects of the differentially expressed lncRNA in CRC cells. Results: the lncRNA UICLM (up-regulated in colorectal cancer liver metastasis) was significantly up-regulated in cases of CRC with liver metastasis. Moreover, UICLM expression was higher in CRC tissues than in normal tissues, and UICLM expression was associated with poor patient survival. Knockdown of UICLM inhibited CRC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and liver metastasis in vivo. Ectopic expression of UICLM promoted CRC cell proliferation and invasion. Mechanistic investigations revealed that UICLM induced its biological effects by regulating ZEB2, as the oncogenesis facilitated by UICLM was inhibited by ZEB2 depletion. Further study indicated that UICLM acted as a competing endogenous RNA (ceRNA) for miR-215 to regulate ZEB2 expression. Conclusions: taken together, our findings demonstrate how UICLM induces CRC liver metastasis and may offer a novel prognostic marker and therapeutic target for this disease.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Animais , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Feminino , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
14.
Mol Cancer ; 16(1): 74, 2017 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-28372542

RESUMO

BACKGROUND: The telomerase/telomere interacting protein PinX1 has been suggested as a tumor suppressor. However, the clinical and biological significance of PinX1 in human non-small cell lung cancer (NSCLC) is unclear. METHODS: PinX1 gene/expression pattern and its association with NSCLC patient survival were analyzed in cBioportal Web resource and two cohorts of NSCLC samples. A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on NSCLC cells proliferation and underlying mechanisms. RESULTS: More frequency of gene PinX1 homozygous deletion and heterozygote deficiency was first retrieved from cBioportal Web resource. Low expression of PinX1 correlated with smoking condition, histological type, T stage, N stage, M stage and TNM stage, and was an independent predictor for overall survival in a learning cohort (n = 93) and a validation cohort (n = 51) of NSCLC patients. Furthermore, knockdown of PinX1 dramatically accelerated NSCLC cell proliferation and G1/S transition, whereas ectopic overexpression of PinX1 substantially inhibited cell viability and cell cycle transition in vitro and in vivo. p15/cyclin D1 pathway and BMP5 might contribute to PinX1-associated cell proliferation and cell cycle transition. CONCLUSION: The cost-effective expression of PinX1 could constitute a novel molecular predictor/marker for NSCLC management.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Animais , Biomarcadores Tumorais , Proteína Morfogenética Óssea 5/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados de Ácidos Nucleicos , Modelos Animais de Doenças , Feminino , Deleção de Genes , Inativação Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cell Death Dis ; 8(2): e2581, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28151475

RESUMO

Solute carrier family 34 member 2 (SLC34A2), a pH-sensitive sodium-dependent phosphate transporter, is associated with several human cancers. In this study, we investigate the clinical significance of SLC34A2 and its function in human bladder cancer (BC). The expression dynamics of SLC34A2 were examined in two independent cohorts of BC samples by quantitative PCR, western blotting and immunohistochemical staining. In the training cohort (156 cases), we applied the X-tile program software to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (130 cases), the cutoff score derived from X-title analysis was investigated to determine the association of SLC34A2 expression with survival outcome. A series of in vitro and in vivo assays were then performed to elucidate the function of SLC34A2 in BC and its underlying mechanisms. Results showed that SLC34A2 was significantly upregulated in BC cell lines and clinical samples. In both two cohorts of BC samples, high expression of SLC34A2 was associated with large tumor size, advanced T status and poor patients' survival. The depletion of SLC34A2 in BC suppressed cellular viability, colony formation and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo, whereas overexpression of SLC34A2 had the converse effect. Simultaneously, downregulation of SLC34A2 decreased the transcriptional activity and protein expression level of c-Myc in BC cells, whereas restoration of c-Myc expression could compromise the anti-proliferation effect of SLC34A2 depletion. Furthermore, miR-214 was proved as a negative regulator of SLC34A2. Our present study illustrated that SLC34A2 has an important role in promoting proliferation and tumorigenicity of BC, and may represent a novel therapeutic target for this disease.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Ativação Transcricional/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Regulação para Baixo/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/genética , Regulação para Cima/genética
16.
Mol Cancer ; 16(1): 18, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28114937

RESUMO

BACKGROUND: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated. METHODS: In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC. RESULTS: We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients. CONCLUSION: Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Quinases raf/metabolismo , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Fosforilação , Interferência de RNA , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
17.
Clin Cancer Res ; 23(1): 298-310, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27407092

RESUMO

PURPOSE: We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC. EXPERIMENTAL DESIGN: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy. RESULTS: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain- and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3ß/ß-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC. CONCLUSIONS: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. ©2016 AACR.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Interferência de RNA , Fatores de Transcrição/genética , Animais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Metilação de DNA , Modelos Animais de Doenças , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Perfilação da Expressão Gênica , Quinase 3 da Glicogênio Sintase/genética , Xenoenxertos , Humanos , Imunofenotipagem , Camundongos , Metástase Neoplásica , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carga Tumoral/genética , Via de Sinalização Wnt
18.
Nat Commun ; 7: 12720, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27625043

RESUMO

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.

19.
Org Lett ; 18(19): 4774-4777, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27626465

RESUMO

A highly enantioselective 1,3-dipolar cycloaddition of imino esters with methyleneindolinones has been realized by using readily available thiourea-quaternary ammonium salts as phase-transfer catalysts, enabling efficient construction of a range of chiral spiro[pyrrolidin-3,3'-oxindoles] in good yields with excellent enantioselectivities under mild conditions.

20.
Brain Res ; 1648(Pt A): 243-249, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27421182

RESUMO

The aim of the present study was to determine the effect of high altitude (HA) immigration on cerebral electrical activity. Electro-EncephaloGraphic (EEG) activity were recorded from 25 lowland soldiers during eyes-closed resting conditions under the following conditions: 7 days at lowland before ascending to altitude (Test 1), during the first 7 days (Test 2) and 30 days (Test 3) at 3800m altitude, and 7 days after return to lowland (Test 4). The EEG was Fourier transformed to provide absolute and relative power estimates for the alpha, beta, delta, and theta bands. HA immigrants showed changes of EEG power confined in the posterior parietal cortex, right posterior temporal cortex, and occipital cortex. Compared with baseline Test 1, acute acclimatization (Test 2) only decreased theta power; chronic acclimatization (Test 3) discriminately increased alpha and beta powers but decreased delta power; after descending to lowland (Test 4), alpha power decreased, beta power remained increase, but delta and theta power recovered to the baseline level. Our findings demonstrated different EEG patterns during hypoxia exposure at HA as time goes on and after following reoxygenation at lowland, showing hypoxia decreased lower EEG frequencies while hypoxia/reoxygenation increased higher EEG frequencies. Our findings supports for the hypothesis that certain behavioral and physiological changes induced by sojourn at altitude could be caused by alterations in central nervous system function.


Assuntos
Doença da Altitude/fisiopatologia , Ondas Encefálicas , Córtex Cerebral/fisiopatologia , Adulto , Altitude , China , Eletroencefalografia , Humanos , Masculino , Militares , Processamento de Sinais Assistido por Computador , Adulto Jovem
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