RESUMO
Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Terapia de Alvo Molecular , RNA não Traduzido/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Apoptose , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Células Epiteliais/metabolismo , Feminino , Humanos , RNA não Traduzido/genéticaRESUMO
Di-2-ethylhexyl phthalate (DEHP) has been widely used as a plasticizer in industry. DEHP can cause testicular atrophy, yet the exact mechanism remains unclear. In this study, male mice were intragastrically (i.g.) administered with 0, 100, 200 or 400â¯mg DEHP/kg/day for 21 days. We found that DEHP caused disintegration of the germinal epithelium and decreased sperm density in the epididymis. Furthermore, there was a significant increase in the levels of cleaved Caspase-8, cleaved Caspase-3 and Bax proteins and a decrease in Bcl2 protein. The results indicated that DEHP could induce apoptosis of the testis tissue. Meanwhile, DEHP significantly induced autophagy in the testis tissues with increases in LC3-II, Atg5 and Beclin-1 proteins. The serum testosterone concentration decreased in the DEHP-treated group, implying that DEHP might lead to Leydig cell damage. Furthermore, oxidative stress was induced by DEHP in the testis. To further investigate the potential mechanism, mouse TM3 Leydig cells were treated with 0-80⯵M DEHP for 48â¯h. DEHP significantly inhibited cell viability and induced cell apoptosis. Oxidative stress was involved in DEHP-induced apoptosis as N-Acetyl-L-cysteine (NAC), an inhibitor of oxidative stress, could rescue the inhibition of cell viability and induction of apoptosis by DEHP. Similar to the in vivo findings, DEHP could also induce cell autophagy. However, inhibition of autophagy by 3-Methyladenine (3-MA) significantly increased cell viability and inhibited apoptosis. Taken together, oxidative stress was involved in DEHP-induced apoptosis and autophagy of mouse TM3 Leydig cells, and autophagy might play a cytotoxic role in DEHP-induced cell apoptosis.
Assuntos
Dietilexilftalato/toxicidade , Animais , Apoptose , Autofagia , Caspase 3 , Sobrevivência Celular , Dietilexilftalato/metabolismo , Células Intersticiais do Testículo , Masculino , Camundongos , Estresse Oxidativo , Ácidos Ftálicos , Plastificantes , Testículo/metabolismo , Testosterona/sangue , Testes de ToxicidadeRESUMO
Hepatocellular carcinoma is the sixth most prevalent malignant tumor and the third most common cause of cancer-associated mortality. Statins have been investigated for carcinoma prevention and treatment. In addition, receptor-interacting protein 140 (RIP140) has been observed to inhibit the Wnt/ß-catenin signaling pathway and cell growth. The present study aimed to investigate whether simvastatin (SV) is able to induce SMCC-7721 cell apoptosis through the Wnt/ß-catenin signaling pathway. Initially, a cell model of RIP140 overexpression was established, and then cells were treated with SV. The cell growth, viability and apoptosis were measured by cell counting kit-8 and flow cytometry. Furthermore, the expression levels of RIP140, ß-catenin, c-myc and cyclin D1 were detected by reverse transcription-quantitative polymerase chain, western blot analysis and immunofluorescence. The results demonstrated that SV significantly increased the expression of RIP140 in SMCC-7721 cells; however, ß-catenin, c-myc and cyclin D1 levels were significantly decreased. Furthermore, the immunofluorescence assay of ß-catenin confirmed that SV decreased the content of this protein in SMCC-7721 cells. Notably, RIP140 exerted a synergistic effect on the apoptosis rate induced by SV (RIP140 + SV group), while the alteration in RIP140, ß-catenin, c-myc and cyclin D1 levels was more evident in the combination group as compared with the RIP140 or SV alone groups. In conclusion, these results suggested that SV is able to induce the apoptosis of SMCC-7721 cells through the Wnt/ß-catenin signaling pathway, as well as that RIP140 and SV exert a synergistic effect on the inhibition of cell proliferation and survival.
RESUMO
This study was designed to investigate the effect of digoxin on migration and invasion of human gastric carcinoma MKN45 cells and its possible mechanism. MKN45 cells were treated with different concentrations of digoxin for 24 h. The shRNA-AEG-1 plasmid was transfected into MKN45 cells via lipofectamine to block the expression of astrocyte elevated gene-1 (AEG-1). Western blot was used to analyze the protein levels of matrix metalloproteinase-9 (MMP-9), E-cadherin and AEG-1. The result showed that digoxin reduced the abilities of migration and invasion (P < 0.05), up-regulated the protein level of E-cadherin (P < 0.05), and down-regulated the protein levels of MMP-9 and AEG-1 (P < 0.05) in MKN45 cells in a dose-dependent manner. Compared with shControl group, shAGE-1 group showed inhibited cellular migration and invasion, higher expression level of E-cadherin, and lower expression levels of MMP-9 and AEG-1. These results suggest that digoxin suppresses the migration and invasion of human gastric carcinoma MKN45 cells in a dose-dependent manner through inhibiting the expression of AEG-1, and then resulting in the up-regulation of the protein expression of E-cadherin and the down-regulation of the protein expression of MMP-9.
Assuntos
Moléculas de Adesão Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Digoxina/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/patologia , Antígenos CD , Caderinas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana , Invasividade Neoplásica , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA , Transfecção , Regulação para CimaRESUMO
Numerous pieces of evidence have revealed that oxaliplatin (OXA) evokes mechanical and cold hypersensitivity. However, the mechanism underlying these bothersome side effects needs to be further investigated. It is well known that cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinases (ERK1/2) signaling play crucial roles in several pain states. Our previous data showed that Akt2 in the dorsal root ganglion (DRG) participated in the regulation of OXA-induced neuropathic pain. But it is still unclear whether spinal ERK1/2 signaling is involved in the regulation of OXA-induced hyperalgesia, and the linkage between COX-2 and ERK1/2 signaling in mediating OXA-induced hyperalgesia also remains unclear. In this research, we investigated the possible mechanism of celecoxib, a COX-2 inhibitor, in OXA-induced neuropathic pain. Our results show that single dose of OXA (12 mg/kg) significantly attenuated both the tail withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) at days 4 after the OXA treatment. Administration of celecoxib (30 mg/kg/day) for 4 and 6 days inhibited the decrease in TWL and MWT, and each was significantly higher than that of the OXA+vehicle group and was equivalent to that of the vehicles group. OXA increased the expression of cyclooxygenase-2 (COX-2) mRNA and phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2) protein in the lumbar 4-5 (L4-5) spinal cord dorsal horn neurons. Administration of celecoxib for 7 days suppressed the increase in expression of COX-2 and pERK1/2 induced by OXA. Our findings suggested that COX-2 and ERK1/2 signaling in spinal cord contributed to the OXA-induced neuropathic pain.
RESUMO
AIM: This study sought to explore the exact mechanism of Matrine inhibited migration and invasion of human pancreatic cancer cells. METHODS: HPAC or Capan-1 cells were cultured in completed RPMI-1640 medium, contained with 50 µg/ml Matrine or 0.05 µg/ml docetaxel, respectively. Cell viability was evaluated by spectrophotometric analysis using MTT assay. Wound healing assay and transwell approach were used to detect the effects of Matrine on HPAC cell migration and invasion. Western Blot and RT-PCR were performed to detect the expressions of MT1-MMP, Wnt and ß-Catenin. CHIP assay was used to detect whether the MT1-MMP transcription activity correlated with Wnt signaling pathway. RESULTS: MTT results indicated that cell proliferration was inhibited by Matrine at a range of concentrations, especially at high dose. We further found that Matrine treatment significantly induced cell migration and invasion decreased. Interestingly, the expression of MT1-MMP decreased evidently upon Matrine treatment, paralleled with the expressions of Wnt and ß-Catenin detected by Western Blot and RT-PCR assay. Further analysis of MT1-MMP transcription activity revealed that Matrine reduced the expression of MT1-MMP mediated by Wnt signaling pathway. CONCLUSION: Matrine play a vital role in inhibiting HPAC cellular migration and invasion through down-regulating the expression of MT1-MMP via Wnt signaling pathway.
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Importin α (Imα) plays an important role during the shuttling of the HIV-1 preintegration complex (PIC) from the cytoplasm to the nucleus. Imα may bind to the glucocorticoid receptor (GR), which is localized to nucleus following hormone binding. However, it remains unclear whether the binding of dexamethasone (Dex) to GR affects the Imα redistribution and, thus, alters PIC import. In our study, 293T cells were transfected with the lentiviral vector (LV) carrying the luciferase (Luci) gene following Dex or RU486 pretreatment. The Luci activity (LucA) in the Dex or RU486 group was significantly higher compared to that in the control group (P≤0.01). The effects of Dex and RU486 were inhibited by the Imα inhibitor Bimax1 (P≤0.01), although the inhibitory effect of Bimax1 was alleviated by increasing the Dex dose. Furthermore, it was observed that the LucA in the 30-min Dex treatment group was lower compared to that in the 30-min Dex pretreatment group (P≤0.01). These results suggested that Dex may improve PIC import via increasing the cytoplasmic Imα levels. Kunming mice were transfected in vivo with the LV, either 30 min or 15 h following an intraperitoneal injection of Dex. The LucA in the liver of the 30-min group mice was significantly lower compared to that of the 15-h group mice (P≤0.01), suggesting that the effect of Dex on LV infection depends mainly on the suppression of immune and inflammatory responses in vivo. Taken together, our data indicated that the effect of Dex on LV infection may be associated with Imα, constituting a novel signaling pathway mediating the effects of Dex on HIV-1 infection.
RESUMO
OBJECTIVE: To locate round window area and its related structure on auris transection and CT for anatomical evidence of image diagnosis and clinical operation. METHODS: Fifteen normal head specimen fixed with 10% dehyde were scanned by high-resolution computed tomography on canthomeatal line. CT image (depth 1.00 mm, thick 1.00 mm) was obtained. Temporal bone-centered tissues were taken, decalcified, desiccated and socked with collodion, then embedded and made into sequential transactions (thick 1.00 mm). Lower surface of section was observed by both naked eyes and microscope, then scanned and photographed. Versus CT image, auditory ossicle, osseous semicircular canals, vestibule, round window, niche, cochlea, pyramidal eminence, internal acoustic meatus and cochlear aqueduct were identified respectively. RESULTS: There were 18-22 layers of temporal transection on CT image. Round window and round window niche always appeared on the 10th layer (R) and the 11th layer (L). The mean of the depth of anterior wall was 0.92 mm (R) and 0.90 mm (L), and depth 1.89 mm (R) and 2.04 mm (L). The average distance from niche to jugular fossa wall was 2.10 mm (R) and 2.39 mm (L). No significant difference among of thickness, depth and distance from niche to jugular fossa wall. CONCLUSIONS: Temporal bone transection specimen had a clear picture of anatomical position between round window area and its related structure. Versus CT, the result contributed to image diagnosis and operation on auris diseases.