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1.
Cancer Med ; 12(15): 16295-16309, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37329188

RESUMO

BACKGROUND: Breast cancer (BC) is the leading cause of cancer-related death among women. One of the hallmarks of cancer is sustained angiogenesis. YAP/STAT3 may promote angiogenesis and driving BC progression. This study aimed to investigate how YAP/STAT3 affects the immune microenvironment in BC and understand the underlying mechanism. METHODS: To establish a tumor-associated macrophages (TAMs) model, macrophages were cultured in the 4T1 cell culture medium. A BC mouse model was created by injecting 4T1 cells. The expression of YAP, STAT3, p-STAT3, VEGF, VEGFR-2, and PD-L1 was analyzed using immunofluorescence, western blotting, and quantitative real-time PCR. Flow cytometry was used to identify M1 and M2 macrophages, CD4+ T, CD8+ T, and Treg cells. Levels of iNOS, IL-12, IL-10, TGF-ß, Arg-1, and CCL-22 were measured using enzyme-linked immunosorbent assay. Co-IP was used to verify whether YAP binds to STAT3. Hematoxylin-eosin staining was used to observe tumor morphology. Cell counting kit-8 was selected to detect T-cell proliferation. RESULTS: YAP, STAT3, P-STAT3, VEGF, VEGFR-2, and PD-L1 were highly expressed in BC tissues. The M2/M1 macrophages ratio increased in the TAMs group compared with the control group. Inhibiting of YAP and STAT3 decreased the M2/M1 macrophages ratio. YAP was found to bind with STAT3. T-cell proliferation was enhanced after YAP inhibition, and overexpression of STAT3 reversed the regulation of YAP on T-cell proliferation. In animal studies, inhibiting YAP inhibited tumor weight and volume development. After YAP inhibition, inflammatory infiltration, M2/M1 macrophage ratio, and Treg cell ratio declined, while CD8+ and CD4+ T-cell ratio increased. CONCLUSION: In conclusion, this study suggested inhibition of YAP/STAT3 reversed M2 polarization of TAMs and suppressed CD8+ T-cell activity in the BC immune microenvironment. These findings open up new avenues for the development of innovative therapies in the treatment of BC.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Feminino , Animais , Camundongos , Macrófagos Associados a Tumor/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fator A de Crescimento do Endotélio Vascular , Microambiente Tumoral , Linhagem Celular Tumoral
2.
Mol Ther ; 27(10): 1784-1795, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31337603

RESUMO

Hepatocellular carcinoma (HCC) tumors invariably develop resistance to cytotoxic and targeted agents, resulting in failed treatment and tumor recurrence. Previous in vivo short hairpin RNA (shRNA) screening evidence revealed mitochondrial-processing peptidase (PMPC) as a leading gene contributing to tumor cell resistance against sorafenib, a multikinase inhibitor used to treat advanced HCC. Here, we investigated the contributory role of the ß subunit of PMPC (PMPCB) in sorafenib resistance. Silencing PMPCB increased HCC tumor cell susceptibility to sorafenib therapy, decreased liver tumor burden, and improved survival of tumor-bearing mice receiving sorafenib. Moreover, sorafenib + PMPCB shRNA combination therapy led to attenuated liver tumor burden and improved survival outcome for tumor-bearing mice, and it reduced colony formation in murine and human HCC cell lines in vitro. Additionally, PMPCB silencing enhanced PINK1-Parkin signaling and downregulated the anti-apoptotic protein MCL-1 in sorafenib-treated HCC cells, which is indicative of a healthier pro-apoptotic phenotype. Higher pre-treatment MCL-1 expression was associated with inferior survival outcomes in sorafenib-treated HCC patients. Elevated MCL-1 expression was present in sorafenib-resistant murine HCC cells, while MCL-1 knockdown sensitized these cells to sorafenib. In conclusion, our findings advocate combination regimens employing sorafenib with PMPCB knockdown or MCL-1 knockdown to circumvent sorafenib resistance in HCC patients.


Assuntos
Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/patologia , Metaloendopeptidases/genética , Proteínas Mitocondriais/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , RNA Interferente Pequeno/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/metabolismo , Camundongos , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto , Peptidase de Processamento Mitocondrial
3.
Bioorg Med Chem Lett ; 29(17): 2459-2463, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31345633

RESUMO

Human lactate dehydrogenase 5 (hLDH5) is an important metabolic enzyme playing critical roles in the anaerobic glycolysis. Herein, we employed an in silico method and biological validation to identify a novel hLDH5 inhibitor with a promising cellular activity under hypoxia condition. The identified compound 9 bound to hLDH5 with a Kd value of 1.02 µM, and inhibited the enzyme with an EC50 value of 0.7 µM. Compound 9 exhibited a weak potency against NCI-H1975 cell proliferation under normal condition (IC50 = 36.5 µM), while dramatically increased to 5.7 µM under hypoxia condition. In line with the observation, hLDH5 expression in NCI-H1975 cell under hypoxia condition is much higher as compared to the normal oxygenated condition, indicating the hLDH5 inhibition may contribute to the cancer cell death.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Lactato Desidrogenase 5/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Lactato Desidrogenase 5/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Conformação Molecular , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
4.
Onco Targets Ther ; 10: 5667-5675, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29238200

RESUMO

Recent studies have shown that microRNAs play a pivotal role in the pathogenesis of cancer. In our current study, the expression levels of microRNA-211 (miR-211) were measured in human non-small-cell lung cancer (NSCLC) tissues and cell lines. We found that miR-211 expression levels were increased in NSCLC tissues and cell lines and that the overexpression of miR-211 promotes cell proliferation and invasion. Using bioinformatics, we demonstrated that miR-211 binds to the 3'-untranslated region of MxA and overexpression of miR-211 suppresses the expression of MxA at both the transcriptional and translational levels in NSCLC cell lines. Furthermore, knockdown of MxA increased the proliferation and invasion of NSCLC cell lines in vitro. High levels of miR-211 expression were associated with a shorter survival time in patients with NSCLC. Taken together, these results suggest that miR-211 promotes tumor proliferation and invasion by regulating MxA expression in NSCLC. This study provides insights into molecular mechanisms of miR-211-mediated tumorigenesis and oncogenesis.

5.
Mol Cells ; 40(11): 847-854, 2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-29127951

RESUMO

Recent studies on molecular carcinogenesis suggest that the chemo-resistance of some cancers is largely due to presence of cancer stem cells (CSCs), which affect the chemotherapy outcome for hepatocellular carcinoma (HCC). However, currently no consensus on a CSC phenotype in HCC has been obtained. Here, we examined Sox12 as a novel CSC marker in HCC. Sox12+ versus Sox12- cells were purified from HCC cell lines. The Sox12+ cells were compared with Sox12- HCC cells for tumor sphere formation, chemo-resistance, tumor formation after serial adoptive transplantations in nude mice, and the frequency of developing distal metastasis. We found that compared to Sox12- HCC cells, Sox12+ HCC cells generated significantly more tumor spheres in culture, were more chemo-resistant to cisplatin, were detected in circulation more frequently, and formed distal tumor more frequently. Moreover, Sox12 appeared to functionally contribute to the stemness of HCC cells. Thus, we conclude that Sox12 may be a novel marker for enriching CSCs in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
6.
Int J Clin Exp Med ; 8(11): 20014-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26884913

RESUMO

Signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (pSTAT3) play important roles in the development of gastric cancer. STAT3 is often associated with cell survival, proliferation, and transformation. The prognostic value of STAT3/pSTAT3 in patients with gastric cancer remains controversial in numerous published studies. The aim of this study was to summarize recent findings relevant to the prognostic role of STAT3 and pSTAT3 in patients with gastric cancer. A meta-analysis was performed by searching Web of Knowledge, EMBASE, and PubMed to identify studies on the prognostic impact of STAT3/pSTAT3 in gastric cancers in August 2014. In all, 10 studies were included in the analysis. Data were collected for comparing survival rates in patients with high STAT3 levels compared to those with low levels. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Sensitivity analysis was conducted, and publication bias was evaluated. Eventually, 1667 cases of gastric cancer were subjected to the final analysis. Among patients with gastric cancer, poor survival was predicted by higher expressions of STAT3 (HR=2.30; 95% CI=1.13-4.68; P=0.02) and pSTAT3 (HR=1.75; 95% CI=1.17-2.61; P=0.006). Moreover, overexpression of STAT3 was associated with poor tumor stage. Additionally, our analysis did not show any statistically significant effect of publication bias regarding STAT3 or pSTAT3. The results of this meta-analysis demonstrated that overexpression of STAT3 and pSTAT3 was associated with poor prognosis in gastric cancer.

11.
Cell Physiol Biochem ; 34(6): 2061-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25562154

RESUMO

AIMS: To investigate the association of Sirtuin 3 (SIRT 3) expression between the clinical characteristics and prognosis in breast cancer patients. METHODS: 308 female patients with histologically confirmed breast cancer were enrolled in this study. The SIRT 3 expressions in tumor samples were detected. All the patients were followed up overall survival time (OS) and disease-free survival (DFS) time. RESULTS: SIRT 3 expression was significantly correlated with clinical characteristics including lymph node metastasis, pathological grade and tumor size of breast cancer. SIRT 3 expression status also affected the DFS and OS of breast cancer. Patients with high expression of SIRT 3 had shorter DFS and OS than those with low expression. Univariate and multivariate Cox analyses confirmed that high SIRT 3 expression predicted a poor prognosis in breast cancer patient. In vitro study revealed that the SIRT 3 knockdown by small interfering RNA technique dramatically reduced the proliferation, migration and invasion of breast cancer cell lines. CONCLUSION: Our results suggest that SIRT 3 may serve as a marker for clinical feature and prognosis for breast cancer.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/genética , Prognóstico , Sirtuína 3/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sirtuína 3/genética
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