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1.
Genet Res (Camb) ; 2022: 5338956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072013

RESUMO

Objectives: Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/ß-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods: The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results: The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that ß-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. ß-Catenin overexpression (HR: 0.137 (95% CI: 0.131-0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146-0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126-0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772-0.198)) also presented risk for shorter DFS. Conclusions: The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/ß-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.


Assuntos
Neoplasias Colorretais , beta Catenina , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Genes bcl-1 , Humanos , Prognóstico , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Supressora de Tumor p53/genética , beta Catenina/genética , beta Catenina/metabolismo
2.
J Immunol Res ; 2022: 7372202, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36106050

RESUMO

Background: F-box proteins are essential components of the E3 ubiquitin ligases which are involved in the regulation of almost all life activities such as cell cycle, proliferation, and apoptosis, which have become an important research and drug target. However, there are few studies on F-box and leucine-rich repeat protein 16 (FBXL16) in endometrial carcinoma. Methods: Clinical samples were collected for determining the correlation between FBXL16 and endometrial carcinoma. Cells were screened and established with Ishikawa cells which proved the fundamental role of FBXL16 in regulating cell proliferation and cell cycle. The MPA-resistant endometrial carcinoma cell line Ishikawa/MPA was established. FBXL16, PP2AB55α , and cyclin D1 were analyzed separately in MPA sensitive and resistant Ishikawa cells in vitro and in vivo. Results: The high expression of FBXL16 was positively correlated with MPA resistance and poor prognosis of endometrial cancer. MPA tolerance of endometrial cancer cells was inhibited by knockdown of FBXL16 in DNA content assessment, CCK-8, and colony formation. It was confirmed that FBXL16 inhibited the activity of substrate PP2AB55α by binding to PP2A, reduced the phosphorylation level at Thr308 site of AKT1, inhibited the expression of GSK-3ß, and thus led to a significant decrease in the phosphorylation level of cyclin D1, which prevented the ubiquitination recognition and degradation of cyclin D1. Conclusion: In our experiments, FBXL16 binds PP2A to promote the dephosphorylation of Thr286 site of cyclin D1 via AKT1/GSK3ß/cyclin D1 pathway, which is required for resisting the ubiquitination degradation and enhances the MPA resistance of Ishikawa.


Assuntos
Neoplasias do Endométrio , Doenças Uterinas , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/anormalidades , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos
3.
Respir Res ; 23(1): 246, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114572

RESUMO

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common complication of chronic lung disease, which severely affects the survival and prognosis of patients. Several recent reports have shown that DNA damage and repair plays a crucial role in pathogenesis of pulmonary arterial hypertension. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a part of DNA-PK is a molecular sensor for DNA damage that enhances DSB repair. This study aimed to demonstrate the expression and potential mechanism of DNA-PKcs on the pathogenesis of HPH. METHODS: Levels of DNA-PKcs and other proteins in explants of human and rats pulmonary artery from lung tissues and pulmonary artery smooth muscle cells (PASMC) were measured by immunohistochemistry and western blot analysis. The mRNA expression levels of DNA-PKcs and NOR1 in PASMCs were quantified with qRT-PCR. Meanwhile, the interaction among proteins were detected by Co-immunoprecipitation (Co-IP) assays. Cell proliferation and apoptosis was assessed by cell counting kit-8 assay(CCK-8), EdU incorporation and flow cytometry. Rat models of HPH were constructed to verify the role of DNA-PKcs in pulmonary vascular remodeling in vivo. RESULTS: DNA-PKcs protein levels were both significantly up-regulated in explants of pulmonary artery from HPH models and lung tissues of patients with hypoxemia. In human PASMCs, hypoxia up-regulated DNA-PKcs in a time-dependent manner. Downregulation of DNA-PKcs by targeted siRNA or small-molecule inhibitor NU7026 both induced cell proliferation inhibition and cell cycle arrest. DNA-PKcs affected proliferation by regulating NOR1 protein synthesis followed by the expression of cyclin D1. Co-immunoprecipitation of NOR1 with DNA-PKcs was severely increased in hypoxia. Meanwhile, hypoxia promoted G2 + S phase, whereas the down-regulation of DNA-PKcs and NOR1 attenuated the effects of hypoxia. In vivo, inhibition of DNA-PKcs reverses hypoxic pulmonary vascular remodeling and prevented HPH. CONCLUSIONS: Our study indicated the potential mechanism of DNA-PKcs in the development of HPH. It might provide insights into new therapeutic targets for pulmonary vascular remodeling and pulmonary hypertension.


Assuntos
Hipertensão Pulmonar , Animais , Células Cultivadas , Ciclina D1/metabolismo , DNA , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Humanos , Hipertensão Pulmonar/patologia , Hipóxia/metabolismo , RNA Mensageiro , RNA Interferente Pequeno , Ratos , Sincalida/metabolismo , Remodelação Vascular/fisiologia
4.
J Clin Lab Anal ; 36(9): e24628, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35929347

RESUMO

OBJECTIVE: Lung cancer ranking high in the cancer-related list has long perplexed patients, in which glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be highly expressed. Besides, DNA methylation is perceived as a biomarker to assess the prognosis of patients with various cancers. However, the correlation between GNPNAT1 and DNA methylation and the role of GNPNAT1 in lung cancer remain vague. METHODS: Principal component analysis (PCA), heatmap, volcano map, Venn diagram, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to screen out the candidate genes. The viability, migration, and invasion of lung cancer cells were detected by CCK-8 and Transwell assays. An xenograft tumor mouse model was established. The relative expressions of GNPNAT1, E-cadherin, vimentin, Matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), E2F1, and cyclin D1 in cells or xenograft tumor tissues were quantified by Western blot, RT-qPCR, or immunohistochemistry assay. RESULTS: GNPNAT1 was screened as the research object. GNPNAT1 methylation was downregulated, while GNPNAT1 expression was upregulated in lung cancer tissues. The methylation and mRNA levels of GNPNAT1 were correlated with the patient prognosis. GNPNAT1 increased cell viability, migration and invasion, and promoted the xenograft tumor volume and weight, whereas shGNPNAT1 acted oppositely. Moreover, expressions of Vimentin, MMP-2, E2F1, and cyclin D1 were increased, but E-cadherin and TIMP-2 expressions were decreased by overexpressed GNPNAT1, whilst GNPNAT1 knockdown ran conversely. CONCLUSION: GNPNAT1 and methylated GNPNAT1 coverage are biomarkers for the diagnosis and prognosis of lung cancer.


Assuntos
Neoplasias Pulmonares , Metaloproteinase 2 da Matriz , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Glucosamina 6-Fosfato N-Acetiltransferase/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Prognóstico , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Vimentina/metabolismo
5.
Arch Iran Med ; 25(4): 250-256, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35942997

RESUMO

BACKGROUND: Breast cancer represents the most frequent cancer and cause of death in women worldwide and in Tunisia. Cyclin D1 is a gene of cell cycle regulation. It represents a potential oncogene in invasive breast cancer; however; the results are conflicting. We performed a retrospective study aiming to analyze the prognostic impact of cyclin D1 expression in patients with invasive breast carcinoma of no special type and its relation with clinical-pathological features. METHODS: One hundred cases of invasive breast carcinoma of no special type diagnosed between 2009 and 2011 were included in this study. Immunohistochemical (IHC) staining was performed for cyclin D1 in all cases. Results were analyzed statistically. RESULTS: Cyclin D1 positivity was seen in 74 cases (74%), of which 32 cases (32%) showed strong immunoreactivity. Cyclin D1 staining was statistically significantly associated with estrogen receptor (ER) and progesterone receptor (PR) positivity (P<0.0001) and with low grade SBR (P=0.007). None of the clinical data and other pathological features had any association with cyclin D1 expression (P>0.05). Univariate analysis revealed that expression of cyclin D1 was not statistically associated with overall survival (OS) and disease-free survival (DFS) (P=0.459 and P=0.564, respectively). CONCLUSION: These results confirm that cyclin D1 overexpression can be employed as a beneficial prognostic marker and suggest that anti-cyclin D1 therapy may be efficient, especially for ER positive tumors.


Assuntos
Neoplasias da Mama , Ciclina D1/metabolismo , Receptores de Estrogênio , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Prognóstico , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos
6.
Zhonghua Xue Ye Xue Za Zhi ; 43(6): 499-505, 2022 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-35968594

RESUMO

Objective: To investigate the effect of blocking P21 activated kinase 1 (PAK1) activity on the proliferation, differentiation, and apoptosis of acute megakaryocytic leukemia (AMKL) cell lines (CHRF and CMK) . Methods: Cell counts were used to detect the effects of PAK1 inhibitors (IPA-3 and G5555) on AMKL cell proliferation inhibition and colony formation, and flow cytometry was used to detect its effects on AMKL cell cycle. The effect of PAK1 inhibitor on the expression of cyclin D1 and apoptosis-related protein Cleaved caspase 3 was detected using Western blot, while interference with the protein expression level of PAK1 in AMKL cells was assessed using lentivirus-mediated shRNA transfection technology. Flow cytometry was used to detect the effects of knockdown of PAK1 kinase activity on the ability of polyploid DNA formation and cell apoptosis in AMKL cells. Results: PAK1 inhibitors inhibited the proliferation of AMKL cells in a dose-dependent manner and reduced the ability of cell colony formation, and the difference was statistically significant when compared with the control group (P<0.05) . Moreover, they also reduced the percentage of AMKL cells in S phase, and Western blot detection showed that the expression levels of phosphorylated PAK1 and cyclin D1 decreased significantly. Finally, PAK1 inhibitors induced AMKL cell apoptosis by up-regulating Cleaved caspase 3 and showed different abilities to increase the content of polyploid DNA in megakaryocytes. Only high concentrations of IPA-3 and low doses of G5555 increased the number of polyploid megakaryocytes, while knockdown of PAK1 kinase activity promoted AMKL cell differentiation and increased the apoptosis rate. Conclusion: PAK1 inhibitor significantly arrests AMKL cell growth and promotes cell apoptosis. Knocking down the expression of PAK1 promotes the formation of polyploid DNA and induces AMKL cell apoptosis. The above findings indicate that inhibiting the activity of PAK1 may control AMKL effectively.


Assuntos
Leucemia Megacarioblástica Aguda , Quinases Ativadas por p21 , Apoptose , Caspase 3/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Megacarioblástica Aguda/tratamento farmacológico , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/metabolismo , Poliploidia , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
7.
BMC Gastroenterol ; 22(1): 378, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941537

RESUMO

BACKGROUND: The stromal antigen 3 (STAG3) gene encodes an adhesion complex subunit that can regulate sister chromatid cohesion during cell division. Chromosome instability caused by STAG3 gene mutation may potentially promote tumor progression, but the effect of STAG3 on hepatocellular carcinoma (HCC) and the related molecular mechanism are not reported in the literature. The mechanism of the occurrence and development of HCC is not adequately understood. Therefore, the biological role of STAG3 in HCC remains to be studied, and whether STAG3 might be a sensitive therapeutic target in HCC remains to be determined. METHODS: The expression and clinical significance of STAG3 in HCC tissues and cell lines were determined by RT-qPCR and immunohistochemistry analyses. The biological functions of STAG3 in HCC were determined through in vitro and in vivo cell function tests. The molecular mechanism of STAG3 in HCC cells was then investigated by western blot assay. RESULTS: The mRNA expression of STAG3 was lower in most HCC cells than in normal cells. Subsequently, an immunohistochemical analysis of STAG3 was performed with 126 samples, and lower STAG3 expression was associated with worse overall survival in HCC patients. Moreover, cytofunctional tests revealed that the lentivirus-mediated overexpression of STAG3 in HCC cells inhibited cell proliferation, migration, and invasion; promoted apoptosis; induced G1/S phase arrest in vitro; and inhibited tumor growth in vivo. Furthermore, studies of the molecular mechanism suggested that the overexpression of STAG3 increased Smad3 expression and decreased CDK4, CDK6, cyclin D1, CXCR4 and RhoA expression. CONCLUSION: STAG3 exhibits anticancer effects against HCC, and these effects involve the Smad3-CDK4/CDK6-cyclin D1 and CXCR4/RhoA pathways. STAG3 is a tumor-suppressor gene that may serve as a potential target for molecular therapy, which provides a new idea for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Receptores CXCR4 , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad3/farmacologia , Regulação para Cima , Proteína rhoA de Ligação ao GTP/genética
8.
Genes (Basel) ; 13(8)2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-36011369

RESUMO

(1) Background: Wharton's Jelly stem cells (WJ-MSCs) are multipotent mesenchymal stem cells that can proliferate rapidly and have low immunogenicity. Therefore, WJ-MSCs have gained considerable attention in the fields of immunomodulation and disease treatment and have entered clinical trials for the treatment of various diseases. Therefore, it is crucial to study the underlying mechanisms of WJ-MSCs proliferation, immune regulation, and disease treatment. Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) is a transcription factor that is involved in the regulation of many different genes. However, it remains unknown how NR2F2 regulates stem cell identity in WJ-MSCs. (2) Methods: We used RNAi technology to knock down NR2F2 in WJ-MSCs, and studied the regulatory role of NR2F2 in WJ-MSCs by MTT, flow cytometry, RNA-seq, and other methods. We also utilized a co-culture system in which NR2F2-depleted WJ-MSCs with MH7A and HCT116/HepG2 were used to investigate the role of NR2F2 in immunomodulation and the inhibition of cancer cell growth. (3) Results: NR2F2 knockdown resulted in decreased expressions of Cyclin D1 and CDK4, slower cell proliferation, and increased expressions of IL6 and IL8. Furthermore, Cyclin D1, CDK4, and inflammatory factors were increased in human rheumatoid fibroblast-like synoviocyte line MH7A if co-cultured with NR2F2 depleted WJ-MSCs. In addition, we observed increased p53, decreased BCL-2, and increased cell apoptosis in liver cancer cell line HepG2 if co-cultured with NR2F2-depleted WJ-MSCs. (4) Conclusions: NR2F2 not only plays an important role in the cell cycle and immune regulation of WJ-MSCs but also has potential effects on the WJ-MSCs treatment of related diseases.


Assuntos
Ciclina D1 , Células-Tronco Mesenquimais , Fator II de Transcrição COUP/metabolismo , Proliferação de Células/genética , Ciclina D1/metabolismo , Humanos , Imunomodulação/genética , Cordão Umbilical/metabolismo
9.
J Clin Lab Anal ; 36(8): e24601, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35819123

RESUMO

AIMS: To translate a clinical research finding into daily clinical practice requires well-controlled clinical trials. We have demonstrated the usage of absolute quantitation of Ki67 and cyclinD1 protein levels to improve prognosis of Luminal-like patients based on overall survival (OS) analysis of a cohort of 155 breast cancer specimens (cohort 1). However, this finding is considered the D level of evidence (LOE) to require subsequent validation before it may be used in daily clinical practice. To set the stage for future clinical trials, our findings were validated through OS analysis of an independent cohort (cohort 2) of 173 Luminal-like patients. METHODS: Both Ki67 and cyclinD1 levels were measured absolutely and quantitatively using the Quantitative Dot Blot (QDB) method in cohort 2. The proposed cutoffs for both biomarkers from cohort 1 were re-evaluated in cohort 2 and in the merged cohort of 1 and 2, respectively, through univariate, multivariate and Kaplan-Meier survival analysis. RESULTS: The proposed cutoffs of 2.31 nmol/g for Ki67 and 0.44 µmol/g for cyclinD1 were validated as effective cutoffs in cohort 2 and the merged cohort through OS analysis. The combined use of both biomarkers allowed us to identify patients with both biomarker levels below the cutoffs (59.3%) with10-year survival probability (SP) of 89%, in comparison to those above the cutoffs (8.3%) with 8 year SP of 28% through OS analysis in the merged cohort. CONCLUSIONS: This study validated our findings that absolute quantitation of Ki67 and cyclinD1 allows effective subtyping of luminal-like patients. It sets the stage for prospective or prospective-retrospective clinical studies.


Assuntos
Neoplasias da Mama , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
10.
Phytomedicine ; 104: 154303, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35802997

RESUMO

BACKGROUND: Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. PURPOSE: This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. METHODS: In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. RESULTS: We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, ß-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. CONCLUSIONS: We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and ß-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis.


Assuntos
Berberina , Neoplasias Colorretais , Neoplasias Hepáticas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Berberina/farmacologia , Berberina/uso terapêutico , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Pulmão/patologia , Camundongos , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo
11.
Pathol Res Pract ; 236: 154009, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35803208

RESUMO

Cyclin D1 has been shown to participate in the pathogenesis of breast cancer. This cell cycle-related protein has direct or indirect interactions with long non-coding RNAs (lncRNAs). In the present two-step study, we first identified CCND1-related lncRNAs through an in silico approach. Then, we measured expression of CCND1 mRNA and five lncRNAs in paired breast cancer samples and their matched non-cancerous samples obtained from adjacent tissues. HOTTIP expression was significantly higher in breast cancer tissues compared with adjacent tissues (expression ratio (95% CI)= 4.63 (1.56-13.76), P value= 0.0070). Similarly, CBR3-AS1 was up-regulated in cancerous tissues compared with control tissues (expression ration (95% CI)= 3.26 (1.35-7.86), P value= 0.0122). Expression of HOTTIP was higher in estrogen receptor (ER) negative samples compared with ER positive ones (-4.35 ± 1.33 versus -4.63 ± 0.62, P value=0.002). CBR3-AS1 could differentiate between these two sets of samples with AUC±SD, sensitivity, specificity and P values of 0.7 ± 0.05, 0.9, 0.49 and 0.003, respectively. These values were 0.68 ± 0.04, 0.87, 0.34 and 0.04 for HOTTIP. Although we could not find difference in expression of CCND1 between these two sets of samples, we reported up-regulation of two CCND1-related lncRNAs in breast cancer samples. These lncRNAs are putative markers for breast cancer.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(6): 905-912, 2022 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-35790442

RESUMO

OBJECTIVE: To investigate the effect of Chaihu Guizhi Decoction (CHGZD) combined with capecitabine on growth and apoptosis of subcutaneous triple-negative breast cancer xenografts in nude mice and explore the possible mechanism. METHODS: Nude mouse models bearing subcutaneous triple-negative breast cancer xenografts were randomized into 6 groups (n=10) for treatment with distilled water (model group), low (10.62 g/kg), medium (21.23 g/kg) and high (42.46 g/kg) doses of CHGZD, capecitabine (0.2 mg/kg), or the combination of CHGZD (42.46 g/kg) and capecitabine (0.2 mg/k) once daily for 21 consecutive days. The general condition of mice was observed, and after 21-day treatments, the tumors were dissected for measurement of tumor volume and weight and histopathological examination with HE staining. Serum IL-6 levels of the mice were determined with enzyme-linked immunosorbent assay (ELISA), and the expression levels of IL-6, STAT3, p-STAT3, Bax, Bcl-2 and cyclin D1 in the tumor tissues were detected using real-time PCR and Western blotting. RESULTS: Compared with those in the model group, the tumor-bearing mice receiving treatments with CHGZD showed significantly increased food intake with good general condition, sensitive responses, increased body weight, and lower tumor mass (P < 0.01). Compared with capecitabine treatment alone, treatment with CHGZD alone at the medium and high doses and the combined treatment all resulted in significantly higher tumor inhibition rates (P < 0.01), induced obvious tumor tissue degeneration and reduced the tumor cell density. Treatments with CHGZD, both alone and in combination with capecitabine, significantly decreased serum IL-6 level, lowered the mRNA expression levels of IL-6 and STAT3, the protein expressions of IL-6, STAT3 and P-STAT3 (P < 0.05), and the mRNA and protein expressions of Bcl-2 and cyclin D1 (P < 0.05), and increased the mRNA and protein expressions of Bax in the tumor tissues (P < 0.05). CONCLUSION: CHGZD combined with capecitabine can significantly inhibit tumor growth in nude mice bearing triple-negative breast cancer xenografts, the mechanism of which may involve the inhibition of IL-6/STAT3 signaling pathway and regulation of Bax, Bcl-2 and cyclin D1 expressions to suppress tumor cell proliferation and differentiation and induce cell apoptosis.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Capecitabina/farmacologia , Ciclina D1/metabolismo , Medicamentos de Ervas Chinesas , Xenoenxertos , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína X Associada a bcl-2/metabolismo
13.
FASEB J ; 36(8): e22423, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35775626

RESUMO

Orthodontic tooth movement (OTM) is induced by biomechanical stimuli and facilitated by periodontal tissue remodeling, where multiple immune cells participate in this progression. It has been demonstrated that macrophage is essential for mechanical force-induced tissue remodeling. In this study, we first found that mechanical force significantly induced macrophage proliferation in human periodontal samples and murine OTM models. Yet, how macrophages perceive mechanical stimuli and thereby modulate their biological behaviors remain elusive. To illustrate the mechanisms of mechanical force-induced macrophage proliferation, we subsequently identified Piezo1, a novel mechanosensory ion channel, to modulate macrophage response subjected to mechanical stimuli. Mechanical force upregulates Piezo1 expression in periodontal tissues and cultured bone-marrow-derived macrophages (BMDMs). Remarkably, suppressing Piezo1 with GsMTx4 retarded OTM through reduced macrophage proliferation. Moreover, knockdown of Piezo1 effectively inhibited mechanical force-induced BMDMs proliferation. RNA sequencing was further performed to dissect the underlying mechanisms of Piezo1-mediated mechanotransduction utilizing mechanical stretch system. We revealed that Piezo1-activated AKT/GSK3ß signaling was closely associated with macrophage proliferation upon mechanical stimuli. Importantly, Cyclin D1 (Ccnd1) was authenticated as a critical downstream factor of Piezo1 that facilitated proliferation by enhancing Rb phosphorylation. We generated genetically modified mice in which Ccnd1 could be deleted in macrophages in an inducible manner. Conditional ablation of Ccnd1 inhibited periodontal macrophage proliferation and therefore delayed OTM. Overall, our findings highlight that proliferation driven by mechanical force is a key process by which macrophages infiltrate in periodontal tissue during OTM, where Piezo1-AKT-Ccnd1 axis plays a pivotal role.


Assuntos
Ciclina D1 , Canais Iônicos , Macrófagos , Proteínas Proto-Oncogênicas c-akt , Animais , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Mecanotransdução Celular , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
14.
Int J Biol Sci ; 18(10): 3944-3960, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844799

RESUMO

Our understanding of coding gene functions in lung cancer leads to the development of multiple generations of targeted drugs. Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play a vital role in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of circFAT1 in lung adenocarcinoma (LUAD) progression and the potential impact of circFAT1 on LUAD treatment. We found that circFAT1 was one of the top expressed circRNAs in A549 cells by circRNA-seq and was significantly upregulated in human LUAD tissues. Multiple cellular assays with A549 and PC9 LAUD cell lines under both gain-of-function and loss-of-function conditions demonstrated that circFAT1 promoted proliferation of LUAD cells in vitro and in vivo. At molecular level, circFAT1 sequestered miR-7 to upregulate IRS2, which in turn regulated downstream ERK1/2 phosphorylation and CCND1 expression, ultimately promoting tumor progression. In addition, we showed that DDP treatment was much more effective in circFAT1 knockdown tumor cells in vitro and in a xenograft tumor model. Our results indicate that circFAT1 promote tumorigenesis in LUAD through sequestering miR-7, consequently upregulating IRS2-ERK1/2-mediated CCND1 expression, and can be a valuable therapeutic target and an important parameter for precision treatment in LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Adenocarcinoma de Pulmão/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
15.
Med Oncol ; 39(10): 144, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834029

RESUMO

Despite the huge efforts employed to implement novel chemotherapeutic paradigms for lung cancer, the disease still remains a major concern worldwide. Targeting molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) represent a new hope in lung cancer treatment. This work was undertaken to evaluate the antitumor effects of GANT61 (5 µM), BI-847325(30 µM), and GANT61 (5 µM)/BI-847325(30 µM) combination on A549 adenocarcinoma lung cancer cell line. The growth inhibition 50 (GI50) for both drugs was performed using MTT. The protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) gene expression was assessed by quantitative real-time PCR. The GI50 for GANT61 and BI-8473255 were 5 µM and 30 µM, respectively. Caspase-3 and Bax protein levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, and pHH3 levels were significantly reduced by both drugs and their combination relative to the control group. Gli1 gene expression was down-regulated in all groups relative to the control group. GANT61, BI-847325 and their combination inhibited proliferation and angiogenesis but activated the apoptotic pathway. Both drugs conferred a profound negative impact on the crosstalk between each of Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of BI-847325/GANT61 combination have not been tested before. Further in-vitro and in-vivo studies are warranted to support the findings.


Assuntos
Proteínas Hedgehog , Neoplasias Pulmonares , Compostos de Anilina , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas , Pirimidinas , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/farmacologia
16.
Appl Immunohistochem Mol Morphol ; 30(6): 441-445, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35797676

RESUMO

BACKGROUND: Distinction of superficial spreading melanoma (SSM) from compound nevi (CN) sometimes poses difficult diagnostic challenges. Herein, we studied cyclin D1 protein expression by immunohistochemistry in SSM and CN and evaluated the results by digital image analysis. DESIGN: A total of 13 CN and 12 SSM cases were retrospectively reviewed and cyclin D1 immunohistochemistry was performed. Immunohistochemical stained slides were evaluated by digital imaging analysis that included quantification and staining intensity of the cyclin D1 expressing dermal cells. RESULTS: Cyclin D1 expression was observed in all CN and SSM. CN-positive staining was present in 30% to 93% of the dermal nevocytes, more positive in the upper (mean 85%), than lower half (mean 57%). SSM-positive staining was present in 44% to 96% of the dermal lesion, more positive in the upper (mean 88%) than lower half (mean 49%). When analyzed based on 3+ strong staining intensity, similar regional differences in cyclin D1 expression were observed. CONCLUSIONS: Digital image analysis of Cyclin D1 expression showed no differences between CN and SSM. Quantity and regional distribution of cyclin D1 positivity were found to be similar in both lesions. Our findings argue against the routine use of cyclin D1 immunohistochemistry as a diagnostic tool for differentiating CN from SSM.


Assuntos
Ciclina D1 , Melanoma , Nevo , Neoplasias Cutâneas , Ciclina D1/metabolismo , Humanos , Melanoma/patologia , Nevo/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
17.
Front Endocrinol (Lausanne) ; 13: 895729, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784572

RESUMO

Background: Up to 80% of breast cancers (BCa) are estrogen receptor positive and current treatments target the estrogen receptor (endocrine therapies) and/or CDK4/6 (CDK4/6 inhibitors). CCND1 encodes the protein cyclin D1, responsible for regulation of G1 to S phase transition in the cell cycle. CCND1 amplification is common in BCa and contributes to increased cyclin D1 expression. As there are signalling interactions between cyclin D1 and the estrogen receptor, understanding the impact of CCND1 amplification on estrogen receptor positive patients' disease outcomes, is vital. This review aims to evaluate CCND1 amplification as a prognostic and predictive biomarker in BCa. Materials and Methods: Publications were retrieved from the databases: PubMed, MEDLINE, Embase and Cochrane library. Exclusion criteria were duplication, publication type, non-English language, in vitro and animal studies, not BCa, male BCa, premenopausal BCa, cohort size <35, CCND1 amplification not reported. Publications with cohort duplication, and inadequate recurrence free survival (RFS) and overall survival (OS) data, were also excluded. Included publications were assessed for Risk of Bias (RoB) using the Quality In Prognosis Studies tool. Statistical analyses (Inverse Variance and Mantel-Haenszel) were performed in Review Manager. The PROSPERO registration number is [CRD42020208179]. Results: CCND1 amplification was significantly associated with positive estrogen receptor status (OR:1.70, 95% CI:1.19-2.43, p = 0.004) and cyclin D1 overexpression (OR: 5.64, 95% CI: 2.32-13.74, p=0.0001). CCND1 amplification was significantly associated with shorter RFS (OR: 1.64, 95% CI: 1.13-2.38, p = 0.009), and OS (OR: 1.51, 95% CI: 1.19-1.92, p = 0.0008) after removal of studies with a high RoB. In endocrine therapy treated patients specifically, CCND1 amplification predicted shorter RFS (HR: 2.59, 95% CI: 1.96-3.41, p < 0.00001) and OS (HR: 1.59, 95% CI: 1.00-2.49, p = 0.05) also after removal of studies with a high RoB. Conclusion: While a lack of standardised approach for the detection of CCND1 amplification is to be considered as a limitation, CCND1 amplification was found to be prognostic of shorter RFS and OS in BCa. CCND1 amplification is also predictive of reduced RFS and OS in endocrine therapy treated patients specifically. With standardised methods and cut offs for the detection of CCND1 amplification, CCND1 amplification would have potential as a predictive biomarker in breast cancer patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020208179.


Assuntos
Neoplasias da Mama , Ciclina D1 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Amplificação de Genes , Humanos , Pós-Menopausa/genética , Prognóstico , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo
18.
Anticancer Res ; 42(8): 4071-4077, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35896251

RESUMO

BACKGROUND/AIM: Abnormalities in the cyclin D1-CDK4/6 complex have been implicated in breast cancer proliferation and resistance to treatment. Recently, new drugs have been developed to target CDK4/6. Meanwhile, liquid biopsy has received great interest in oncology. In this study, we analyzed cyclin D1 gene (CCND1) copy number variation (CNV) in circulating tumor DNA (ctDNA) from luminal B breast cancer patients. PATIENTS AND METHODS: This study included 31 patients with luminal B breast cancer who underwent resection. We analyzed CCND1 CNV in ctDNA by digital droplet PCR. RESULTS: Of the 31 luminal B breast cancers, CCND1 CNV was positive in 5 cases. Patients with CCND1 CNV positivity had significantly shorter recurrence-free survival than patients with negative CCND1 CNV. CONCLUSION: CCND1 CNV in ctDNA was associated with poor prognosis in patients with luminal B breast cancer. This biomarker could be a useful prognostic factor.


Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Neoplasias da Mama/patologia , DNA Tumoral Circulante/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Variações do Número de Cópias de DNA , Feminino , Amplificação de Genes , Genes bcl-1 , Humanos , Prognóstico , Receptores de Estrogênio/metabolismo
19.
J Cell Physiol ; 237(9): 3671-3686, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35861939

RESUMO

Myosin-related proteins play an important role in cancer progression. However, the clinical significance, biological functions, and mechanisms of myosin 1B (MYO1B), in esophageal squamous cell carcinoma (ESCC) remain unclear. The clinical relevance of MYO1B, SNAI2, and cyclin D1 in ESCC was determined by immunohistochemistry, Oncomine, and GEPIA databases. The oncogenic roles of MYO1B were determined by CCK8, colony formation assays, wound healing, and Transwell assay. MYO1B, SNAI2, and cyclin D1 at mRNA and protein levels in ESCC cells were detected by qPCR and Western blot analysis. In our study, we found that MYO1B expression was increased in ESCC tissue samples and correlated with tumor stage, TNM stage, and poor outcomes. Functional assays indicated that depletion of MYO1B impaired oncogenesis, and enhanced chemosensitivity in ESCC. Bioinformatic analysis and mechanistic studies illustrated that SNAI2 was a key downstream effector of MYO1B. Suppression of MYO1B downregulated expression of SNAI2, thereby inhibiting the SNAI2/cyclin D1 pathway. Furthermore, a selective inhibitor of cyclin D1 activation reversed siMYO1B cells overexpressing SNAI2-elicited aggressive phenotypes of ESCC cells. MYO1B positively correlated with SNAI2 and cyclin D1 in ESCC samples, and higher SNAI2 expression was also associated with poor prognosis in ESCC patients. Our finding demonstrated that MYO1B activates the SNAI2/cyclin D1 pathway to drive tumorigenesis and cisplatin cytotoxicity in ESCC, indicating that MYO1B is a potential therapeutic target for patients with ESCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinogênese/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Miosina Tipo I/genética , Miosina Tipo I/metabolismo , Miosinas/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(7): 598-604, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-35786453

RESUMO

Objective To investigate the effect of rat serum containing oxymatrine (OM) on the activation of LX2 human hepatic stellate cells induced by sodium arsenite and its mechanism. Methods SD rats were gavaged with 100 mg/kg OM or equal volume of normal saline to prepare OM-containing serum and blank serum. LO2 human embryonic liver cell line was treated with 100 µmol/L sodium arsenite for 24 hours, and then the supernatant was collected. LX2 cells were incubated with the mixture of the supernatant and normal medium at the ratio of 1:4 for 24 hours to establish the cell model of indirect arsenic exposure. Blank serum group (160 mL/L blank serum), indirect arsenic exposure group (160 mL/L blank serum with arsenic exposure), low-dose OM-containing serum group (80 mL/L blank serum and 80 mL/L OM-containing serum with arsenic exposure), high-dose OM-containing serum group (160 mL/L medicated serum with arsenic exposure) were set up. MTT assay and flow cytometry were used to detect cell proliferation and cell cycle, respectively. Western blot analysis was performed to detect the protein expressions of α-SMA, Bcl2, BAX, cyclin D1, PI3K, and phospho-AKT (p-AKT) in LX2 cells. Results After indirect arsenic treatment, the proliferation rate of LX2 cells increased, the proportion of G1 phase decreased, the proportion of apoptosis decreased, the expression of α-SMA, PI3K, p-AKT, cyclin D1, Bcl2 were significantly up-regulated, and the expression of BAX decreased. After OM-containing serum treatment, the proportion of cells in G1 phase increased, the proportion of apoptosis increased, the expression of BAX protein increased significantly, and the expression of other proteins were significantly down-regulated, especially in the high-dose group. Conclusion OM-containing serum can effectively inhibit the proliferation of LX2 hepatic stellate cells induced by arsenite and promote their apoptosis, which may be related to the blocking of PI3K/AKT signaling pathway.


Assuntos
Arsênio , Arsenitos , Alcaloides , Animais , Arsenitos/metabolismo , Arsenitos/toxicidade , Proliferação de Células , Ciclina D1/metabolismo , Células Estreladas do Fígado , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolizinas , Ratos , Ratos Sprague-Dawley , Compostos de Sódio , Proteína X Associada a bcl-2/metabolismo
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