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1.
J Cell Physiol ; 236(2): 1116-1130, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32730644

RESUMO

Breast cancer is one of the most threatening diseases for women. Long noncoding RNAs were reported to be involved in breast cancer development. In this study, we analyzed The Cancer Genome Atlas breast cancer tissue high-throughput sequencing data and screened and validated the low-expressing long noncoding RNA named MAGI2-AS3. Through gene coexpression analysis, we found that MAGI2-AS3 has a good expression correlation with MAGI2. Overexpression of MAGI2-AS3 or MAGI2 in breast cancer cells MCF-7 would inhibit the Wnt/ß-catenin pathway and inhibit cell proliferation and migration. Gene structure and DNA methylation analysis results indicated that MAGI2-AS3 may act as a cis-acting regulatory element downregulating the DNA methylation level of the MAGI2 promoter region, and the DNA demethylase TET1 inhibitor can reverse MAGI2-AS3 overexpression caused upregulation of MAGI2 and cellular effects. Our findings reveal the role of MAGI2-AS3 in breast cancer and provide potential novel therapeutic targets for metastatic breast cancer intervention.

2.
Eur J Pharmacol ; 889: 173493, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860808

RESUMO

Gastric cancer (GC) is one of the most common malignant neoplasms of the digestive system, with China leading in terms of morbidity and mortality rates. Betulinic acid (BA) is a widely-occurring pentacyclic triterpenoid that has been reported to exhibit potent anti-inflammatory, antioxidant, and antitumor activities. BA can combat tumors by inducing apoptosis, regulating cell cycle, and inhibiting autophagy, but its mechanism of action in the context of GC is unclear. A preliminary study found that higher expression of vasodilator-stimulated phosphoprotein (VASP) was correlated with migration in the GC cell line. In this study, BGC-823 cells and MNK45 cells were treated with BA for investigating its effect on the proliferation and migration of cells. Moreover, the expression of VASP and upstream signal molecules were also investigated in this background. The results showed BA could inhibit the proliferation and migration the GC cells. Furthermore, NF-κB acted as a transcription factor to upregulate VASP expression. Moreover, BA could downregulate the expression of VASP at the protein and mRNA level by inhibiting NF-κB activity. In conclusion, these results suggest that BA could inhibit the expression of VASP by negatively regulating NF-κB, thereby inhibiting the proliferation and migration of the GC cells. Our study provides a theoretical basis for exploring the molecular mechanism underlying BA-induced inhibition of proliferation and migration in GC cells.

3.
Mol Cancer ; 19(1): 128, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32838810

RESUMO

BACKGROUND: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. METHOD: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. RESULTS: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. CONCLUSION: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

4.
Int Urol Nephrol ; 52(7): 1389-1401, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32418008

RESUMO

Acute kidney injury is a complex clinical disease that is associated with a high incidence of morbidity and mortality. Drug-induced acute kidney injury occurs in approximately 19-33% of hospitalized patients. Cisplatin, one of the most commonly used and effective chemotherapeutic drugs not only exerts anti-tumor effects but also causes renal toxicity damage, affecting its clinical application. Vinpocetine is an anti-inflammatory and antioxidant drug that predominately acts in the nervous system. In this study, we investigated the effects and mechanisms of vinpocetine in an animal model of cisplatin-induced acute renal injury. Rats were randomly divided into three experimental groups. During a 10-day trial, rats in the control group were administered a physiological saline solution; rats in the model group received a 5 mg/kg intraperitoneal injection of cisplatin; and rats in the cisplatin + vinpocetine group received a 5 mg/kg intraperitoneal injection of cisplatin as well as a 5 mg/kg dose of vinpocetine via gavage. We observed that following cisplatin administration, the rats exhibited an increase in blood urea and creatinine levels as well as an increase in their inflammation and oxidative stress levels. In renal tissue, cisplatin caused the morphological changes typical of acute tubular injury. Vinpocetine reduced the cisplatin-induced acute renal function damage and tubular injury. In both in vivo and in vitro experiments, we found that vinpocetine can confer protection of rat renal cells by inhibiting the NF-κB signaling pathway and activating the Nrf2/ARE signaling pathway. Therefore, vinpocetine is a promising therapeutic drug for the treatment of cisplatin-induced acute kidney injury.

5.
Biomed Res Int ; 2019: 3235021, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011573

RESUMO

Background: Breast cancer (BC) is one of the most common malignant tumors in women around the world. Atorvastatin (ATO) was found to be associated with a decreased risk of recurrence and mortality in cancer. But the exact mechanism of its carcinostatic effects is unclear. The expression level of Ras homolog family member B (RhoB) in breast cancer cells was found to be upregulated after being treated with ATO. Thus, we conjecture that altered expression of RhoB induced by ATO may be decisive for the migration and progression of breast cancer. Methods: The effects of ATO on breast tumor cells in vivo and in vitro were detected by clone formation assay, CCK-8 assay, flow cytometry, wound healing, transwell assays, tumor xenograft model, and immunohistochemistry. Distribution of RhoB in different breast cancer tissues and its influence on prognosis were analyzed using the data from TCGA or GEO databases. The relationship between RhoB and PTEN/AKT pathway was detected by Western blotting and RT-qPCR. Results: ATO inhibits proliferation, invasion, EMT, and PTEN/AKT pathway and promotes apoptosis in breast tumor cells. In addition, ATO inhibits the volume and weight of breast tumor in tumor-bearing mice and upregulated RhoB in tumor tissues. The expression of RhoB in mRNA and protein level was upregulated in statin-treated breast cancer cells and downregulated in cancer tissues. Low expression of RhoB links with poor prognosis in patients with breast cancer (HR = 0.74[0.66-0.83], p =7e-8, log-rank test). Further research found that RhoB inhibits the proliferation, invasion, EMT, and PTEN/AKT signal pathway in breast tumor cells. Conclusions: The exact mechanism of ATO's carcinostatic effects in breast cancer is related to downregulating PTEN/AKT pathway via promoting RhoB. Our study also demonstrates the potential applicability of RhoB as a therapeutic target for breast cancer.


Assuntos
Atorvastatina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína rhoB de Ligação ao GTP/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/genética , Prognóstico , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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