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1.
Pathol Res Pract ; 256: 155233, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452583

RESUMO

Gallbladder cancer (GBC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we aimed to investigate the role of SIRT7, a member of the sirtuin family, in GBC and its potential as a prognostic marker and therapeutic target. Through immunohistochemistry analysis of GBC tissue samples, we observed elevated levels of SIRT7, which were correlated with worse clinicopathological parameters and shorter overall survival in GBC patients. Additionally, through cellular and animal experiments, we have discovered that interfering with SIRT7 can effectively suppress the proliferation, migration, and invasive capabilities of GBC cells. Conversely, overexpressing SIRT7 yields the opposite outcome. Furthermore, interference with SIRT7 triggers cell cycle arrest and enhances apoptosis in GBC cells. Mechanistically, we found that SIRT7 inhibition led to reduced activation of the NF-κB signaling pathway, suggesting its involvement in modulating GBC cell behavior. Our findings shed light on the oncogenic role of SIRT7 in GBC and highlight its potential as a promising prognostic marker and therapeutic target. Further research is warranted to explore the therapeutic implications of targeting SIRT7 in GBC treatment.


Assuntos
Neoplasias da Vesícula Biliar , Sirtuínas , Animais , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias da Vesícula Biliar/genética , Prognóstico , Transdução de Sinais , Sirtuínas/metabolismo
2.
Cell Div ; 18(1): 9, 2023 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-37301821

RESUMO

BACKGROUND: Nucleosome-localized sirtuin 4 (SIRT4) was found to function as an oncogene and tumor suppressor gene in different tumors. However, the clinical significance of SIRT4 in bladder urothelial carcinoma (BLCA) has not been assessed, nor has the function of SIRT4 in BLCA been analyzed. METHODS: In this study, we assessed the levels of SIRT4 protein in BLCA tissues and its association with clinicopathological parameters and overall survival time of BLCA patients by immunohistochemical staining of tissue microarrays containing 59 BLCA patients. Then, we constructed BLCA cell lines (T24) with overexpression or interference of SIRT4 by lentiviral infection. The effects of SIRT4 on the proliferation, migration and invasive ability of T24 cells were investigated using cell counting kit-8 (CCK-8) assays, wound healing assays, and migration and invasion assays. Moreover, we also investigated the effect of SIRT4 on the cell cycle and apoptosis of T24 cells. Mechanistically, we explored the relationship between SIRT4 and autophagy and its role in the inhibition of BLCA. RESULTS: We found by immunohistochemistry that SIRT4 protein levels were reduced in BLCA and that lower SIRT4 levels were associated with larger tumor volumes, later T-staging and later AJCC staging in BLCA patients and were an independent prognostic factor in BLCA patients. Overexpression of SIRT4 significantly inhibited the proliferative viability, scratch healing capacity, migratory capacity, and invasive capacity of T24 cells, while interference with SIRT4 had the opposite effect. Moreover, overexpression of SIRT4 significantly inhibited the cell cycle and increased the apoptosis rate of T24 cells. Mechanistically, SIRT4 inhibits BLCA growth by suppressing autophagic flow. CONCLUSIONS: Our study suggests that SIRT4 is an independent prognostic factor for BLCA and that SIRT4 plays a tumor suppressor role in BLCA. This suggests a potential target for SIRT4 in the diagnosis and treatment of BLCA.

3.
Cell Oncol (Dordr) ; 45(6): 1329-1346, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36214997

RESUMO

OBJECTIVE: Specificity protein 1 (SP1), a transcription factor mediated by SUMOylation modifiers, is upregulated in gastric cancer (GC) and shares negative correlation with patient prognosis. Here, we paid main attention to the role of SP1 SUMOylation in the drug resistance of GC cells and the possible long non-coding RNA (lncRNA) SNHG17/microRNA-23b-3p (miR-23b-3p)/Notch2 network engaged in this process. METHODS: Tumor tissues and non-tumor tissues were isolated from GC patients who received treatment with capecitabine and cisplatin (DDP). Co-immunoprecipitation was utilized to detect the SUMOylation level of SP1. Using gain- and loss-of-function approaches, we assessed the impacts of SNHG17/miR-23b-3p/Notch2 on sensitivity of DDP-resistant GC cells in vitro and in vivo. A series of assays such as luciferase activity detection and RNA pull-down were conducted for mechanistic exploration. RESULTS: SP1 expression was increased due to low SP1 SUMOylation level in the recurrent GC tissues. This increase led to upregulated SNHG17 expression and SP1 binding sites existed in the SNHG17 promoter. In addition, SNHG17 could bind to miR-23b-3p while miR-23b-3p targeted Notch2. Loss of SNHG17 reduced the resistance of DDP-resistant GC cells to DDP, which was achieved through miR-23b-3p-dependent Notch2 inhibition. Finally, SP1 silencing attenuated the resistance of GC to DDP in mice. CONCLUSION: Low SP1 SUMOylation induces SNHG17 upregulation and blocks miR-23b-3p-induced Notch2 inhibition, contributing to the resistance of GC to DDP. This study may aid in the development of therapeutic targets overcoming the chemoresistance of GC.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Sumoilação , Regulação para Cima/genética , Humanos
4.
Sci Rep ; 12(1): 12208, 2022 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-35842463

RESUMO

Localized in the mitochondria, SIRT4 is a nicotinamide adenine dinucleotide (NAD +) -dependent adenosine diphosphate (ADP) -ribosyltransferase and is one of the least characterized members of the sirtuin family. Although it is well known that it shows deacetylase activity for energy metabolism, little is understood about its function in tumorigenesis. Recent research suggests that SIRT4 may work as both a tumor suppressor gene and an oncogene. However, the clinical significance of SIRT4 in prostate cancer remains unknown. In this study, we evaluated SIRT4 protein levels in cancerous prostate tissue and corresponding non-tumor prostate tissue via immunohistochemical staining on a tissue microarray including tissues from 89 prostate cancer patients. The association between SIRT4 expression and Gleason score was also determined. Further, shSIRT4 or stable prostate cancer cell lines (22RV1) overexpressing SIRT4 were constructed via lentiviral infection. Using Cell-Counting Kit-8 (CCK-8) assay, wound healing assay, migration, and invasion and apoptosis assays, the effects of SIRT4 on the migration, invasion ability, and proliferation of prostate cancer cells were investigated. We also determined the effect of SIRT4 on glutamine metabolism in 22RV1 cells. We found the protein levels of SIRT4 in prostate cancer tissues were significantly lower than those in their non-neoplastic tissue counterparts (P < 0.01); a lower SIRT4 level was also significantly associated with a higher Gleason score (P < 0.01). SIRT4 suppressed the migration, invasion capabilities, and proliferation of prostate cancer cells and induced cellular apoptosis. Furthermore, the invasion and migration of 22RV1 cells were mechanistically inhibited by SIRT4 via glutamine metabolism inhibition. In conclusion, the present study's findings showed that SIRT4 protein levels are significantly associated with the Gleason score in patients with prostate cancer, and SIRT4 exerts a tumor-suppressive effect on prostate cancer cells by inhibiting glutamine metabolism. Thus, SIRT4 may serve as a potential novel therapeutic target for prostate cancer.


Assuntos
Neoplasias da Próstata , Sirtuínas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Genes Supressores de Tumor , Glutamina/metabolismo , Humanos , Masculino , Proteínas Mitocondriais/metabolismo , NAD/metabolismo , Neoplasias da Próstata/genética , Sirtuínas/genética , Sirtuínas/metabolismo
5.
Open Life Sci ; 16(1): 266-276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33817318

RESUMO

Gastric cancer (GC) is ranked the fourth leading cause of cancer-related death, with an over 75% mortality rate worldwide. In recent years, miR-299-3p has been identified as a biomarker in multiple cancers, such as acute promyelocytic leukemia, thyroid cancer, and lung cancer. However, the regulatory mechanism of miR-299-3p in GC cell progression is still largely unclear. Cell viability and apoptosis tests were performed by CCK8 and flow cytometry assay, respectively. Transwell assay was recruited to examine cell invasion ability. The interaction between miR-299-3p and PAX3 was determined by the luciferase reporter system. PAX3 protein level was evaluated by western blot assay. The expression of miR-299-3p was downregulated in GC tissues and cell lines (MKN-45, AGS, and MGC-803) compared with the normal tissues and cells. Besides, overexpression of miR-299-3p significantly suppressed proliferation and invasion and promoted apoptosis in GC. Next, we clarified that PAX3 expression was regulated by miR-299-3p using a luciferase reporter system, qRT-PCR, and western blot assay. Additionally, downregulation of PAX3 repressed GC cell progression. The rescue experiments indicated that restoration of PAX3 inversed miR-299-3p-mediated inhibition on cell proliferation and invasion. miR-299-3p suppresses cell proliferation and invasion as well as induces apoptosis by regulating PAX3 expression in GC, representing desirable biomarkers for GC diagnosis and therapy.

6.
Cancer Manag Res ; 13: 2717-2731, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790646

RESUMO

BACKGROUND: Chemoresistance is one key factor for the failure of cisplatin (CDDP)-based therapy in colorectal cancer (CRC). Although circular RNAs (circRNAs) are associated with chemoresistance development, the role and mechanism of hsa_circ_0071589 (circ_0071589) in the development of CDDP resistance in CRC remain unclear. METHODS: CDDP-resistant and sensitive CRC samples were collected. CDDP-resistant HCT116/CDDP and LOVO/CDDP cells were established. The levels of circ_0071589, microRNA (miR)-526b-3p and Krüppel-like factor 12 (KLF12) were detected via quantitative reverse transcription polymerase chain reaction, Western blot or immunohistochemistry. Cell viability, proliferation, cycle process, apoptosis, migration and invasion were examined via Cell Counting Kit-8, flow cytometry, transwell assay and Western blot. The association between miR-526b-3p and circ_0071589 or KLF12 was predicted by starBase, and explored via dual-luciferase reporter assay and RNA immunoprecipitation. The effect of circ_0071589 on CDDP resistance in CRC in vivo was investigated using a xenograft model. RESULTS: Circ_0071589 level was upregulated in CDDP-resistant CRC tissue samples and cell lines. Circ_0071589 knockdown inhibited CDDP resistance, proliferation, migration and invasion, and promoted apoptosis in CDDP-resistant CRC cells. Circ_0071589 was a sponge for miR-526b-3p. MiR-526b-3p knockdown reversed the role of circ_0071589 inhibition in CDDP resistance. MiR-526b-3p suppressed CDDP resistance by directly targeting KLF12. Circ_0071589 regulated KLF12 expression through modulating miR-526b-3p. Circ_0071589 knockdown aggravated CDDP-induced reduction of xenograft tumor growth by upregulating miR-526b-3p and decreasing KLF12. CONCLUSION: Knockdown of circ_0071589 repressed CDDP resistance in CDDP-resistant CRC cells by regulating the miR-526b-3p/KLF12 axis.

7.
World J Surg Oncol ; 19(1): 67, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33685455

RESUMO

BACKGROUND: Circular RNAs (circRNAs) take part in colorectal cancer malignancies. CircRNA dedicator of cytokinesis 1 (circ_DOCK1) is involved in colorectal cancer progression, but the mechanism underlying this circRNA that takes part in colorectal cancer development remains largely undetermined. METHODS: Tumor and normal para-cancerous tissues were collected from 42 colorectal cancer patients. Human colorectal cancer cell lines (HCT116 and SW480) were used for the experiments in vitro. Circ_DOCK1, microRNA (miR)-132-3p, and ubiquitin-specific protease 11 (USP11) levels were measured through quantitative real-time polymerase chain reaction and Western blotting. Cell growth, metastasis, and apoptosis were investigated via colony formation, 5-ethynyl-2'-deoxyuridine (EdU) staining, MTT, flow cytometry, Western blotting, and transwell analyses. The target association was evaluated via dual-luciferase reporter analysis, RNA pull-down, and immunoprecipitation (RIP). Xenograft assay was performed using HCT116 cells. USP11 and Ki67 levels in tumor tissues were detected via immunohistochemistry. RESULTS: Circ_DOCK1 expression was enhanced in colorectal cancer tissues and cells. Silencing circ_DOCK1 repressed cell growth, migration, and invasion, and facilitated apoptosis. Circ_DOCK1 sponged miR-132-3p, and miR-132-3p silence mitigated the effect of circ_DOCK1 interference on cell growth, metastasis, and apoptosis. MiR-132-3p targeted USP11, and circ_DOCK1 could regulate USP11 level by miR-132-3p. MiR-132-3p suppressed cell growth, metastasis, and apoptosis, and USP11 attenuated these effects. Knockdown of circ_DOCK1 decreased colorectal cancer cell xenograft tumor growth. CONCLUSION: Circ_DOCK1 interference suppressed cell growth and metastasis, and increased apoptosis of colorectal cancer via decreasing USP11 by increasing miR-132-3p.


Assuntos
Neoplasias Colorretais , MicroRNAs , Movimento Celular , Neoplasias Colorretais/genética , Humanos , MicroRNAs/genética , Prognóstico , RNA Circular , Tioléster Hidrolases , Proteínas rac de Ligação ao GTP
8.
J Surg Res ; 202(2): 398-402, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27229115

RESUMO

BACKGROUND: The aim of the study was to evaluate the clinical utility of the colon leakage score (CLS) in predicting the risk of anastomotic leakage (AL) after left-sided colorectal surgery. MATERIALS AND METHODS: This investigation was designed as a retrospective study of 304 patients who underwent left-sided colorectal surgery. The patients were classified into two groups as those who developed AL and those who did not develop AL, and the CLSs of the two groups were compared. The predictive value and the cutoff value of the CLS were assessed by receiver operating characteristic and logistic regression analysis. RESULTS: A significant difference was noted in the mean CLSs of the groups with and without AL (P < 0.001). The values of the area under the receiver operating characteristic curve (0.965; confidence interval, 0.913-1.00) and the odds ratio (2.9; confidence interval, 1.59-4.83; P < 0.001) indicated that CLS was a good predictor of AL. A CLS of 11 was found to be the best cutoff value, with a sensitivity and specificity of 84.6% and 87.2%, respectively. CONCLUSIONS: Our findings indicate that CLS can effectively predict the risk of AL after left-sided colorectal surgery and that a CLS of 11 can be used as a cutoff value for the risk level.


Assuntos
Fístula Anastomótica/diagnóstico , Colectomia , Colo/cirurgia , Técnicas de Apoio para a Decisão , Reto/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fístula Anastomótica/etiologia , Fístula Anastomótica/prevenção & controle , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade
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