RESUMO
In recent years, with the development of transcriptomics, the effect of long non-coding RNAs (LncRNAs) on the regulation of biological processes is being elucidated. LncRNAs play an important role in tumor occurrence and development. LncRNA associated with microvascular invasion in hepatocellular carcinoma (LncRNA MVIH) was first identified in hepatocellular carcinoma and is associated with angiogenesis, tumor growth and metastasis upregulation, and poor recurrence-free survival. MVIH has an important role in non-small cell lung cancer, in which it promotes cell proliferation and metastasis, and high MVIH expression indicates poor overall survival. However, the involvement of MVIH in breast cancer is unclear. Our research revealed that the expression levels of MVIH in breast cancer tissues were higher than in adjacent noncancerous tissues, and high MVIH expression was correlated with Ki67 expression. Moreover, breast cancer patients with high MVIH expression levels showed poor overall survival and disease-free survival. Multivariate analysis results indicated that MVIH was an independent prognostic factor in breast cancer. In addition, upregulated MVIH expression levels promoted cell proliferation and cell cycle, and inhibited cell apoptosis, while reduced MVIH expression showed the converse. In summary, our findings suggest that MVIH may have an important role in breast cancer and may serve as a new biomarker and a potential therapeutic target.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/genética , Ácido Oleanólico/análogos & derivados , Prognóstico , Pirrolidinas/administração & dosagem , RNA Longo não Codificante/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/biossíntese , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neovascularização Patológica , Ácido Oleanólico/administração & dosagem , RNA Longo não Codificante/genéticaRESUMO
Breast cancer (BRCA) is one of the most deadly cancers worldwide, with poor survival rates that could be due to its high proliferation. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is implicated in numerous diseases, including cancers. However, its role in BRCA is unclear. In this study, we used bioinformatic analyses of the ONCOMINE, UALCAN, and GEPIA databases to determine the expression pattern of DCTPP1 in BRCA. We found that elevated DCTPP1 levels correlate with poor BRCA prognosis. DCTPP1 silencing inhibited BRCA cell proliferation and induced apoptosis in vitro, as well as in vivo. Our data show that this tumorigenic effect depends on DNA repair signaling. Moreover, we found that DCTPP1 is directly modulated by miR-378a-3p, whose downregulation is linked to BRCA progression. Our results showed down-regulation of miR-378a-3p in BRCA. Upregulation of miR-378a-3p, on the other hand, can inhibit BRCA cell growth and proliferation. This study shows that reduced miR-378a-3p level enhances DCTPP1 expression in BRCA, which promotes proliferation by activating DNA repair signaling in BRCA.
RESUMO
Low-dose metronomic (LDM) paclitaxel therapy displayed a stronger anti-angiogenic activity on breast tumors with fewer side effects. Upregulation of anti-angiogenic factor Thrombospondin-1 (TSP-1) accords for therapeutic potency of LDM paclitaxel, but its molecular mechanism has not been elucidated yet. microRNAs (miRNAs) have emerged as new important regulators of tumor growth and metastasis. Here, we hypothesize that miRNAs are involved in TSP-1 overexpression in paclitaxel LDM therapy of breast tumors. The miRNA profile of tumor tissues from control, LDM and MTD groups in 4T1 mouse breast cancer model was detected by microarray, and then verified by quantitative real-time PCR (qRT-PCR). Luciferase assay and western blot were employed to explore the mechanisms of miRNAs involved in this process. We found that let-7f, let-7a, miR-19b and miR-340-5p were reduced by >2 fold, and miR-543* and miR-684 were upregulated by at least 50% in paclitaxel LDM therapy. qRT-PCR verification revealed that let-7f level was reduced most significantly in LDM therapy. Computational prediction using TargetScan and miRanda suggested THBS1 which encodes TSP-1 as a potential target for let-7f. Luciferase activity assay further confirmed that let-7f may bind to 3'UTR of THBS1 gene and inhibit its activity. Moreover, forced expression of let-7f led to a decrease of TSP-1 at both mRNA and protein levels in MCF-7 cells. Contrastly, let-7f inhibition induced an increased expression of THBS1 mRNA and TSP-1 protein, but did not affect the proliferation and apoptosis of MCF-7 cells. Paclitaxel LDM therapy led to a decrease of let-7f and the elevation of TSP-1 protein expression in MCF-7 cells, while overexpression of let-7f may abolish LDM-induced the upregulation of TSP-1 in MCF-7 cells. In summary, let-7f inhibition contributed to the upregulation of TSP-1 in paclitaxel LDM therapy, independently of proliferation, cell cycle arrest and apoptosis of breast cancer. This study indicates let-7f as a potential therapeutic target for breast tumor.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Paclitaxel/farmacologia , Trombospondina 1/metabolismo , Análise de Variância , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Western Blotting , Neoplasias da Mama/metabolismo , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Luciferases , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Paclitaxel/administração & dosagem , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Copy number variation (CNV) is crucial for gene regulation in humans. A number of studies have revealed that CNV contributes to the initiation and progression of cancer. In this study, we analysed four breast cancer cell lines and six fresh frozen tissues from patients to evaluate the CNV present in the genome using microarray-based comparative genomic hybridization (aCGH). Six genes located at 16q22.1 were analysed by real-time PCR. The real-time PCR analysis revealed that the loss of CDH1/E2F4 may be associated with worse clinical and pathological findings. Interestingly, covariation of CDH1, CDH3, CTCF and E2F4 was found to be associated with triple negative breast cancer and HER-2 receptor status. In conclusion, our study supports the idea that CNV at 16q22.1 in breast cancer is a frequent event; furthermore, it reveals the covariation of CDH1, CDH3, CTCF and E2F4. The role of the covariation is more complex than a simple additive effect of these four separate genes, which may provide a novel target for breast cancer.