RESUMO
Under normal physiological conditions, growth hormones (GH) play an important role in body growth and metabolism. A recent study showed that GH has important biological effects on gastric cancer (GC) both in vitro and in vivo. However, the biological properties of GH/GHR (GHR, growth hormone receptor) in GC cells have not been fully elucidated. To this end, we systemically studied the biological properties of GH in GC cells and found that GH/GHR was transported into the nuclei of GC cells. Furthermore, we investigated the functions of nuclear GHR and its potential mechanisms of action. We found that nuclear-localized GHR was closely related to the proliferation of GC cells. In addition, we systematically studied the effect of a GHR inhibitor (pegvisomant) on GC in vivo and in vitro, and the results showed that pegvisomant can not only inhibit the proliferation of GC cells but also inhibit the nuclear localization of GHR, suggesting that pegvisomant may be a dual-effect antagonist. Current research indicates that GHR may be a potential target for the treatment of GC.
Assuntos
Hormônio do Crescimento Humano , Neoplasias Gástricas , Proliferação de Células , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Receptores da Somatotropina/metabolismo , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Long non-coding RNAs are associated with a spectrum of biological processes such as gene regulation on transcriptional and post-transcriptional levels. Increasing evidence indicates that SPRY4-IT1 plays an important role in carcinogenesis, and the mechanisms whereby SPRY4-IT1 induces colorectal carcinoma progression remain largely unknown. The aim of this study is to evaluate the expression and function of SPRY4-IT1 in colorectal carcinoma. In this study, we analyzed SPRY4-IT1 expression levels in a series of colorectal carcinoma patients by quantitative reverse transcription polymerase chain reaction. Knockdown of SPRY4-IT1 by RNA interference was performed to explore its roles in cell proliferation, migration, and invasion. Our results found that SPRY4-IT1 was upregulated in human primary colorectal carcinoma tissues. Knockdown of SPRY4-IT1 inhibited colorectal carcinoma cell proliferation, migration, and invasion. Moreover, we confirmed that the expression of epithelial-mesenchymal transition-related genes was modulated through alteration of SPRY4-IT1 expression. SPRY4-IT1 could negatively regulate the expression of miR-101-3p in colorectal carcinoma cells. The bioinformatics prediction revealed putative miR-101-3p binding sites within SPRY4-IT1 transcripts. Above all, knockdown of SPRY4-IT1 could represent a rational therapeutic strategy for colorectal carcinoma.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Sítios de Ligação/genética , Biomarcadores Tumorais/biossíntese , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , MicroRNAs/biossíntese , Invasividade Neoplásica/genética , RNA Longo não Codificante/biossínteseRESUMO
SIRT1 plays an important role in human malignant progression, inducing cancer cell proliferation and metastasis by regulating downstream gene expressions. However, little is known about the underlying mechanisms in which SIRT1 promotes pancreatic cancer tumorigenesis. The aim of this study is to investigate the SIRT1 expression levels and biological functions in promoting pancreatic cancer progression. We first investigated the expression of SIRT1 in a series of pancreatic cancer tissues as well as in a panel of pancreatic cancer cell lines. The effect of SIRT1 on cell activity was explored by knockdown experiments. Cell growth was measured using the MTT assay and colony-formation assay. Migration and invasion were tested using transwell assay. Our results showed that the expression of SIRT1 was significantly up-regulated both in pancreatic cancer tissues and cell lines. Knockdown of SIRT1 suppressed cell proliferation and migration of pancreatic cancer cells. This is the first report to disclose the role of SIRT1 in regulation of pancreatic cancer cell proliferation and migration, which may provide a potential therapeutic target for pancreatic cancer patients.
Assuntos
Proliferação de Células/genética , Neoplasias Pancreáticas/genética , Sirtuína 1/genética , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Sirtuína 1/biossínteseRESUMO
PURPOSE: In this study, miR-542-3p appended SRF/ATRA-loaded solid lipid nanoparticle was successfully prepared and demonstrated for its therapeutic efficacy against gastric cancers. METHODS: The particles were nanosized and typically spherical in shape. In vitro release study showed that release of ATRA was significantly slower compared to that of SRF from the NPs. RESULTS: MTT assay showed that miR-542-3p have a strong inhibitory effect on the proliferation of MGC-803 cancer cells in a typical dose dependent manner. Nanocarrier encapsulation of SRF + ATRA induced a significantly higher cytotoxic effect compared to either individual drug or cocktail combinations indicating that the cellular uptake of different formulations was rate limiting factor in the therapeutic efficacy. Importantly, miR-542-3p-based miSRNP exhibited an extremely significant toxic effect compared to any other treated group. Importantly, miSRNP induced a significantly higher early (~55%) and late (~15%) apoptotic effect in gastric cancer cells. In vivo anticancer analysis results clearly suggest that nanoparticle encapsulation of combination of SRF and miRNA (with miRNA) will have greater antitumor efficacy in tumor mice. CONCLUSION: Overall, unique combination of miRNA coupled with SRF + ATRA in a lipid nanocarrier could be a promising therapeutic approach in gastric cancer treatment.
Assuntos
Antineoplásicos/uso terapêutico , MicroRNAs/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Neoplasias Gástricas/terapia , Tretinoína/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos Nus , MicroRNAs/administração & dosagem , Nanopartículas/química , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Sorafenibe , Neoplasias Gástricas/patologia , Tretinoína/administração & dosagemRESUMO
The prognosis of pancreatic cancer remains dismal, with little advance in chemotherapy because of its high frequency of chemoresistance. Metformin is widely used to treat type II diabetes, and was shown recently to inhibit pancreatic cancer stem cell proliferation. In the present study, we investigated the role of metformin in chemoresistance of pancreatic cancer cells to gemcitabine, and its possible cellular and molecular mechanisms. Metformin increases sensitivity of pancreatic cancer cells to gemcitabine. The mechanism involves, at least in part, the inhibition of CD133(+) cells proliferation and suppression of P70S6K signaling activation via inhibition of ERK phosphorylation. Studies of primary tumor samples revealed a relationship between P70S6K signaling activation and the malignancy of pancreatic cancer. Analysis of clinical data revealed a trend of the benefit of metformin for pancreatic cancer patients with diabetes. The results suggested that metformin has a potential clinical use in overcoming chemoresistance of pancreatic cancer.