Gliomas originate from glial cells and are the most frequent primary brain tumors. High-grade gliomas occur ∼4 times more frequently than low-grade gliomas, are highly malignant, and have extremely poor prognosis. Radiotherapy, sometimes combined with chemotherapy, is considered the treatment of choice for gliomas and is used after resective surgery. Despite great technological improvements, the radiotherapeutic effect is generally limited, due to the marked radioresistance exhibited by gliomas cells, especially glioma stem cells (GSCs). The mechanisms underlying this phenomenon are multiple and remain to be fully elucidated. This review attempts to summarize current knowledge on the molecular basis of glioma radioresistance by focusing on signaling pathways, microRNAs, hypoxia, the brain microenvironment, and GSCs. A thorough understanding of the complex interactions between molecular, cellular, and environmental factors should provide new insight into the intrinsic radioresistance of gliomas, potentially enabling improvement, through novel concurrent therapies, of the clinical efficacy of radiotherapy.
N-myc downstream-regulated gene 1 (NDRG1) has been proposed as a tumor suppressor gene in many different types of tumors, but its potential function and corresponding mechanism are not yet fully elucidated. This study aims to detect the possible function of NDRG1 in gastric cancer progression. In this study, 112 paired gastric cancer tissues and corresponding nonmalignant gastric tissues were utilized to identify the differential protein expression of NDRG1 by immunohistochemistry and its clinical significance was analyzed. Furthermore, 49 of 112 paired gastric specimens were used to detect the differential mRNA expression by real-time PCR. The over expression of NDRG1 in human gastric cancer cell line AGS by PcDNA3.1-NDRG1 transfection was utilized to detect the role of NDRG1 in regulating the biological behavior of gastric cancer. NDRG1 expression was significantly decreased in primary gastric cancer tissues, compared with its corresponding nonmalignant gastric tissues (p < 0.05), and its decreased expression was significantly associated with lymph node metastasis (p < 0.01), invasion depth (p < 0.01) and differentiation (p < 0.05). Additionally, the overall survival rate of gastric cancer patients with high expression of NDRG1 was higher than those with low expression during the follow-up period. NDRG1 overexpression suppressed cells proliferation, invasion and induced a G1 cell cycle arrest in gastric cancer. Furthermore, the down-regulation of NDRG1 in gastric cancer metastatic progression was correlated to E-cadherin and MMP-9. Our results verify that NDRG1 acts as a tumor suppressor gene and may play an important role in the metastasis progression and prognosis of gastric cancer.
Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)‐96 and effectively function as a sponge for miR‐96, thus antagonizing the functions of miR‐96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR‐96 and regulate KRAS expression, which highlights the importance of the complicated miRNA‐lncRNA network in modulating the progression of PDAC.
Radiotherapy (RT) is one main method for the treatment of esophageal squamous cell carcinoma (ESCC), and the radioresistance is the predominant cause of patients with local recurrence. The previous results of gene microarray and subsequent verification showed that NRAGE might be involved in radiation resistance of ESCC cells. In this study, we reestablished human esophageal carcinoma radioresistant cell lines TE13R120 and ECA109R60 with gradient dose irradiation as previously reported, respectively. NRAGE expression was high in TE13R120 and ECA109R60 cells and was correlative with ionizing radiation (IR) resistance in clinic. However, the radiosensitivity of TE13R120 cells had a remarkable increase detected by colony formation assays after siRNA against NRAGE (siNRG) transfection into TE13R120 cells. Compared with TE13 cells, an increasing number of TE13R120 cells with NRAGE overexpression in S phase and a lower ratio in G2/M were observed by flow cytometry method (FCM). Intriguingly, the above changes were partially reversed in TE13R120 cells treated with siNRG. More importantly, the ectopic subcellular localization of NRAGE mediated nuclear translocation of β-catenin which may be one reason of IR resistance of esophageal carcinoma cell. These data indicate that NRAGE extremely may be a pivotal factor involved in Wnt/β-catenin signal pathway, mediating nuclear translocation of β-catenin and then facilitating the formation of radioresistance of ESCC.
The purpose of this study is to detect the clinical significance of NDRG1 and its relationship with MMP-9 in gastric cancer metastatic progression. 101 cases of gastric cancer specimens were utilized to identify the protein expression of NDRG1 and MMP-9 by immunohistochemistry, their clinical significance was also analyzed. The suppression by siRNA-NDRG1 was employed to detect the role of NDRG1 in gastric cancer progression and its relationship with MMP-9. NDRG1 expression was correlated inversely with the degree of tumor cell differentiation (p < 0.01), invasion depth (p < 0.05), lymph node metastasis (p < 0.05) and TNM stage (p < 0.05), whereas MMP-9 was positive correlated with the degree of tumor cell differentiation (p < 0.01), lymph node metastasis (p < 0.05) and TNM stage (p < 0.05), but not correlated with invasion depth (p>0.05). Furthermore, cell proliferation and invasion effect were remarkably enhanced when NDRG1 was silencing, but MMP-9 expression was increased. NDRG1 silencing enhances gastric cancer cells progression through upregulating MMP-9. It suggests that NDRG1 may inhibit the metastasis of gastric cancer via regulating MMP-9.
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