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PURPOSE: Breast cancer type 1 susceptibility (BRCA) mutations not only increase breast cancer (BC) risk but also result in poor survival and prognosis for BC patients. This study will analyze the effect and safety of therapeutic regimens for the treatment of BC patients with germline BRCA (gBRCA) mutations by network meta-analysis. METHODS: Public databases were searched from inception to 29 April 2021. Frequentist network meta-analysis was conducted to analyze the benefit of chemotherapy and targeted drug-related strategies. RESULTS: Seventeen articles were included in the analysis. For progression-free survival (PFS), olaparib (hazard ratio (HR): 0.58; 95% confidence interval (CI): 0.43 - 0.79), platinum (HR: 0.45; 95% CI: 0.22 - 0.89), and talazoparib (HR: 0.54; 95% CI: 0.41 - 0.71) were significantly better than platinum-free chemotherapy (Chemo). The results based on indirect comparisons showed that veliparib (Vel) + platinum + Chemo was also significantly better than Chemo (HR: 0.37; 95% CI: 0.20 - 0.69). For overall survival (OS), olaparib was significantly better than Chemo only in the population who did not receive prior chemotherapy. For pathologic complete response (pCR), bevacizumab+Chemo had a significant advantage over platinum agents (OR: 3.64; 95% CI: 1.07 - 12.39). Olaparib and talazoparib both showed significantly higher objective response rates (ORRs) than Chemo. CONCLUSION: The PFS results suggested that olaparib, talazoparib, and Vel+platinum agent+Chemo were ideal regimens for overall, TNBC, and advanced BC patients with gBRCA mutations. Whether PARPis are suitable for patients with gBRCA mutations who have received prior platinum therapy still needs to be clarified.
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BACKGROUND: As an oncogene, long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor metastasis. Hyperexpression of MALAT1 has been observed in many malignant tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of MALAT1 in HCC remain unclear. METHODS: Thirty human HCC and paracancerous tissue specimens were collected, and the human hepatoma cell lines Huh7 and HepG2 were cultured according to standard methods. MALAT1 and Snail family zinc finger (Slug) expression were measured by real-time PCR, immunohistochemistry, and western blotting. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR-124-3p and Slug(SNAI2) or MALAT1. Wound healing and transwell assays were performed to examine invasion and migration, and a subcutaneous tumor model was established to measure tumor progression in vivo. RESULTS: MALAT1 expression was upregulated in HCC tissues and positively correlated with Slug expression. MALAT1 and miR-124-3p bind directly and reversibly to each other. MALAT1 silencing inhibited cell migration and invasion. miR-124-3p inhibited HCC metastasis by targeting Slug. CONCLUSIONS: MALAT1 regulates Slug through miR-124-3p, affecting HCC cell metastasis. Thus, the MALAT1/miR-124-3p/Slug axis plays an important role in HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Factores de Transcripción de la Familia Snail/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Interferencia de ARN , Curva ROC , Factores de Transcripción de la Familia Snail/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
EMT (epithelial-mesenchymal transition) occurs in a wide range of tumor types, and has been shown to be crucial for metastasis. Epigenetic modifications of histones contribute to chromatin structure and result in the alterations in gene expression. Tri-methylation of histone H3 lysine 4 (H3K4me3) is associated with the promoters of actively transcribed genes and can serve as a transcriptional on/off switch. RbBP5 is a component of the COMPASS/ -like complex, which catalyzes H3K4me3 formation. In this study, we found that in the process of TGF-Beta1 induced EMT in the prostate cancer cell line DU145, H3K4me3 enrichment and RbBP5 binding increased in the vicinity of Snail (SNAI1) transcription start site. Knocking-down of RbBP5 notably decreased Snail expression and EMT. Recruitment of RbBP5 and formation of H3K4me3 at Snail TSS during EMT depend on binding of SMAD2/3 and CBP at Snail TSS. This study links the SMAD2/3 signal with Snail transcription via a histone modification - H3K4me3. Furthermore, our research also demonstrates that RbBP5 and even WRAD may be a promising therapeutic candidates in treating prostate cancer metastasis, and that DU145 cells maintain their incomplete mesenchymal state in an auto/ paracrine manner.
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Histonas/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/metabolismo , Factores de Transcripción de la Familia Snail/genética , Línea Celular Tumoral , Proteínas de Unión al ADN , Epigénesis Genética , Transición Epitelial-Mesenquimal/genética , Humanos , Masculino , Metilación , Proteínas Nucleares/genética , Fragmentos de Péptidos/metabolismo , Neoplasias de la Próstata/genética , Unión Proteica , ARN Interferente Pequeño/genética , Sialoglicoproteínas/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Sitio de Iniciación de la Transcripción , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OCT4 is an essential transcription factor for maintaining the self-renewal and the pluripotency of embryonic stem cells (ESCs). The human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B and OCT4B1) by alternative splicing. OCT4A protein is a transcription factor for the stemness of ESCs, while the function of OCT4B isoforms remains unclear. Most types of cancer express a relatively low level of OCT4 protein, particularly the OCT4B isoforms. In the present study, we found that OCT4A and OCT4B mRNA were co-expressed in several types of tumor cell lines and tumor samples, and we demonstrated that OCT4B functioned as a non-coding RNA, modulating OCT4A expression in an miRNA-dependent manner [competing endogenous RNA (ceRNA) regulation] at the post-transcription level in the tumor cell lines. This is the first time that ceRNA regulation was observed among spliced isoforms of one gene, and may pave the way for identification of new targets for cancer treatment.
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Factor 3 de Transcripción de Unión a Octámeros/genética , ARN Mensajero/genética , ARN no Traducido/genética , Empalme Alternativo/genética , Línea Celular Tumoral , Células HCT116 , Humanos , Isoformas de Proteínas/genética , Procesamiento Postranscripcional del ARN/genética , Factores de Transcripción/genéticaRESUMEN
Gastric cancer is the fourth most common cancer type and the second leading cause of cancerassociated mortality worldwide. Metastasis is a crucial feature of its progression. DNA methylation provides a key epigenetic signature in the epigenetic regulation pathway, and is implicated in transcriptional regulation. CpG sites, which are associated with gene transcriptional activity, are underrepresented in the mammalian genome and tend to be clustered within CpG islands (CGIs) located in the vicinity of the transcription start sites of the majority of the proteincoding genes in humans. The DNA methylation inhibitor, decitabine (DAC), has been demonstrated to be active in hematological disorders. The majority of previous studies in cancer cells demonstrated that DAC inhibits cell proliferation and the motility of the cells. However, since demethylation across the entire genome alters the expression of a large number of genes, the effects of DAC in different tumor cell types are difficult to accurately predict. Neural precursor cellexpressed, developmentally downregulated (NEDD)41, a member of the NEDD4 family, which belongs to the E3ubiquitin ligase family, was reported to be highly expressed in a wide range of tumor types, and it activates the phosphoinositide 3kinase/Akt pathway by degrading phosphatase and tensin homolog. NEDD41 promotes the migration and invasion of glioma cells via the ubiquitination and subsequent degradation of cyclic nucleotideRas guanine nucleotide exchange factors (CNrasGEFs). In gastric cardia adenocarcinoma, NEDD41 acts as an exceptional prognostic biomarker. In the present study, DAC was revealed to promote the invasive properties of MGC803 gastric cancer cells. NEDD41 targeted the CNrasGEFmediated DAC invasionpromoting activity in MGC803 cells, and CGI methylation in neither the NEDD4 promoter nor the first intron was demonstrated to be associated with this effect. The results of the present study revealed that DAC exerts variable effects in different gastric cancer cell lines and may provide a reference for DAC administration in the clinic.
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Azacitidina/análogos & derivados , Movimiento Celular/efectos de los fármacos , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba , Azacitidina/farmacología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Metilación de ADN/efectos de los fármacos , Decitabina , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/fisiología , Humanos , Ubiquitina-Proteína Ligasas Nedd4 , Invasividad Neoplásica/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/fisiologíaRESUMEN
Prostate cancer is the most commonly diagnosed type of cancer and the second leading cause of cancerassociated mortality in males. The efficacy of prostate cancer chemotherapy is frequently impaired by drug resistance; however, the underlying mechanisms of this resistance remain elusive. Sex determining region Y-box 2 (Sox2) is of vital importance in the regulation of stem cell proliferation and carcinogenesis. In the present study, using MTT, clone formation, cell cycle and apoptosis assays, over-expression of Sox2 was demonstrated to enhance the paclitaxel (Pac) resistance of the PC-3 prostate cancer cell line, promoting cell proliferation and exhibiting an antiapoptotic effect. Western blot analysis revealed that the phosphoinositide 3-kinase/Akt signaling pathway was activated in cells overexpressing Sox2, and by targeting cyclin E and survivin, Sox2 promoted G1/S phase transition and prevented apoptosis under Pac treatment. The present study provided an understanding of Pac resistance in prostate cancer and may indicate novel therapeutic methods for chemoresistant prostate cancer.