RESUMO
Brain tumors are responsible for high mortality and morbidity worldwide. The brain tumor treatment depends on identification of molecular pathways involved in progression and malignancy. Enhancer of zeste homolog 2 (EZH2) has obtained much attention in recent years in field of cancer therapy due to its aberrant expression and capacity in modulating expression of genes by binding to their promoter and affecting methylation status. The present review focuses on EZH2 signaling in brain tumors including glioma, glioblastoma, astrocytoma, ependymomas, medulloblastoma and brain rhabdoid tumors. EZH2 signaling mainly participates in increasing proliferation and invasion of cancer cells. However, in medulloblastoma, EZH2 demonstrates tumor-suppressor activity. Furthermore, EZH2 can regulate response of brain tumors to chemotherapy and radiotherapy. Various molecular pathways can function as upstream mediators of EZH2 in brain tumors including lncRNAs and miRNAs. Owing to its enzymatic activity, EZH2 can bind to promoter of target genes to induce methylation and affects their expression. EZH2 can be considered as an independent prognostic factor in brain tumors that its upregulation provides undesirable prognosis. Both anti-tumor agents and gene therapies such as siRNA have been developed for targeting EZH2 in cancer therapy.
Assuntos
Neoplasias Encefálicas , Proteína Potenciadora do Homólogo 2 de Zeste , MicroRNAs , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética , Glioblastoma/genética , Glioblastoma/terapia , Glioma/genética , Glioma/terapia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
The nuclear factor-kappaB (NF-κB) signaling pathway is considered as a potential therapeutic target in cancer therapy. It has been well established that transcription factor NF-κB is involved in regulating physiological and pathological events including inflammation, immune response and differentiation. Increasing evidences suggest that deregulated NF-κB signaling can enhance cancer cell proliferation, metastasis and also mediate radio-as well as chemo-resistance. On the contrary, non-coding RNAs (ncRNAs) have been found to modulate NF-κB signaling pathway under different settings. MicroRNAs (miRNAs) can dually inhibit/induce NF-κB signaling thereby affecting the growth and migration of cancer cells. Furthermore, the response of cancer cells to radiotherapy and chemotherapy may also be regulated by miRNAs. Regulation of NF-κB by miRNAs may be mediated via binding to 3/-UTR region. Interestingly, anti-tumor compounds can increase the expression of tumor-suppressor miRNAs in inhibiting NF-κB activation and the progression of cancers. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can also effectively modulate NF-κB signaling thus affecting tumorigenesis. It is noteworthy that several studies have demonstrated that lncRNAs and circRNAs can affect miRNAs in targeting NF-κB activation. They can act as competing endogenous RNA (ceRNA) thereby reducing miRNA expression to induce NF-κB activation that can in turn promote cancer progression and malignancy.
Assuntos
Transformação Celular Neoplásica/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neoplasias/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Animais , Antineoplásicos/uso terapêutico , Sítios de Ligação , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , NF-kappa B/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , RNA Circular/genética , RNA Longo não Codificante/genética , Transdução de SinaisRESUMO
The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.