Temozolomide (TMZ)-based chemotherapy is a standard strategy for glioma, while chemoresistance remains a major therapeutic challenge. Recent evidence highlights the crucial regulatory roles of long non-coding RNAs (lncRNA) in tumor biology. However, the roles and regulatory mechanisms of lncRNA cancer susceptibility candidate 2 (CASC2), in glioma tumorigenesis and chemoresistance are poorly understood. In this study, CASC2 expression was down-regulated in glioma tissues and cell lines, and was related to a clinicopathologic features and shorter survival time. Exogenous CACS2 alone was sufficient to inhibit glioma cells' proliferation and amplified TMZ-induced repression of cell proliferation, while CACS2 knockdown could reverse this process. CACS2 overexpression could sensitize TMZ-resistant glioma cells to TMZ, while CACS2 knockdown exerted the opposite function. Moreover, CASC2 could inhibit the miR-181a expression by direct targeting in TMZ-resistant glioma cells. CASC2 up-regulated PTEN protein and down-regulated p-AKT protein through regulating miR-181a, and the effect of CASC2 on PTEN and p-AKT could be partially restored by miR-181a. With TMZ-resistant glioma tissues, miR-181a was up-regulated while PTEN was down-regulated. Taken together, these observations suggest CASC2 up-regulates PTEN through direct inhibiting miR-181a and plays an important role in glioma sensitivity to TMZ and may serve as a potential target for cancer diagnosis and treatment. J. Cell. Biochem. 118: 1889-1899, 2017. © 2017 Wiley Periodicals, Inc.
Temozolomide (TMZ) is the most commonly used alkylating agent in glioma chemotherapy. However, growing resistance to TMZ remains a major challenge for clinicians. Recent evidence emphasizes the key regulatory roles of non-coding RNAs (lncRNAs and miRNAs) in tumor biology, including the chemoresistance of cancers. However, little is known about the role and regulation mechanisms of lncRNA cancer X-inactive specific transcripts (XIST) in glioma tumorigenesis and chemotherapy resistance. In the present study, higher XIST expression was observed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. XIST knockdown alone was sufficient to inhibit glioma cell proliferation and to amplify TMZ-induced cell proliferation inhibition. Moreover, XIST knockdown can sensitize TMZ-resistant glioma cells to TMZ. XIST can inhibit miR-29c expression by directly targetting TMZ-resistant glioma cells. DNA repair protein O6-methylguanine-DNA methytransferase (MGMT) plays a key role in TMZ resistance; transcription factor specificity protein 1 (SP1), a regulator of DNA mismatch repair (MMR) key protein MSH6, has been reported to be up-regulated in TMZ-resistant glioma cell lines. In the present study, we show that XIST/miR-29c coregulates SP1 and MGMT expression in TMZ-resistant glioma cell lines. Our data suggest that XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR-29c via SP1 and MGMT. XIST/miR-29c may be a potential therapeutic target for glioma treatment.
Based on the 2005 and 2008 Chinese Longitudinal Healthy Longevity Survey, this study examined the prevalence of undermet needs for assistance in personal activities of daily living (ADL) and its associated risk factors among the oldest old aged 80+. Multilevel multinomial logistic modeling was used to analyze the risk factors and changes of undermet needs over time. The results show that the prevalence of slightly undermet needs decreased in urban China from 2005 to 2008. However, the prevalence of undermet needs remained high; 50% or more for both rural and urban residents. Compared to 2005, the likelihood of having slightly undermet needs in 2008 significantly decreased by 28% among rural residents and 22% among urban residents. The common risk factors of undermet needs among rural and urban residents included financial dependence, living alone, having unwilling caregivers, more ADL disabilities, and having poor self-rated health.
Cell migration and invasion are key processes involved during tumor metastasis. Recently, microRNAs (miRs) have been demonstrated to play important roles in the regulation of cancer metastasis. However, the underlying mechanisms remain unknown. Here, we aimed to investigate the exact role of miR-663 in the metastasis of glioblastoma as well as the underlying mechanisms. By performing quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, we demonstrated that miR-663 was significantly downregulated in glioblastoma tissues (n=25), when compared to that in normal brain tissues (n=15). In addition, its expression levels were also reduced in human glioblastoma cell lines, A172 and U87. Furthermore, restoration of miR-663 expression led to a significant decrease in the cell proliferation, migration and invasion of human glioblastoma A172 and U87 cells. We further identified TGF-β1 as a direct target of miR-663, and found that the expression of TGF-β1 was negatively mediated by miR-663 at the post-transcriptional level in glioblastoma cells. Moreover, overexpression of TGF-β1 significantly reversed the inhibitory effects of miR-663 upregulation on the proliferation, migration and invasion in A172 and U87 cells. In addition, our data suggest that MMP2 and E-cadherin, a key factor in epithelial-mesenchymal transition (EMT), are involved in the miR-633/TGF-β1-mediated metastasis of glioblastoma. In summary, miR-663 plays an inhibitory role in the regulation of proliferation, migration and invasion of glioblastoma cells, partly at least, via direct mediation of TGF-β1 as well as downstream MMP2 and E-cadherin. Therefore, we suggest that miR-663 is a potential candidate for the prevention of glioblastoma metastasis.
SOX9 gene encodes a transcription factor essential for a central role in the development and differentiation of multiple cell lineages, such as in neurogenesis, neural crest development, etc. Recent study reported that overexpression of SOX9 mRNA is closely associated with poor clinical outcome of patients with malignant gliomas. In the present study, we have explored the regulatory role of SOX9 in glioma metastasis. To investigate the role of SOX9 in glioma metastasis, SOX9 overexpressed in human glioma cell line U251 on cell migration and invasion was evaluated via wound scratch, Transwell assay without or with Matrigel. SOX9-induced changes in EMT process were evaluated by Western blot. Furthermore, the role of β-catenin in the regulatory effect of SOX9 on cell migration and invasion, and EMT process was explored by suppressing β-catenin expression in SOX9-overexpressed U251 cells. SOX9 overexpression in U251 cells resulted in a significant increase in cell migration and invasion. SOX9 overexpression also markedly promoted the EMT process. More importantly, our results revealed that SOX9 stimulated metastasis through activating Wnt/β-catenin signaling. In summary, this study indicated that the promoting effect of SOX9 on glioma metastasis was, at least in part, through Wnt/β-catenin signaling. The findings in this study highlight the effectiveness and therapeutic potential to utilize SOX9 targeted strategies in the treatment of glioma.
Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.
MicroRNAs (miRNAs) have been demonstrated to be important in the development and progression of various types of cancer. However, the exact roles of certain anti‑oncogenic miRNAs in human malignant gliomas remain to be elucidated. The present study aimed to reveal the expression of microRNA‑203 (miR-203) in normal brain tissues and gliomas, and to investigate the role of miR-203 in cell proliferation and migration in human glioblastoma U251 cells. Real-time reverse transcription polymerase chain reaction (RT-PCR) showed that the expression of miR-203 in high WHO grade glioma tissues was significantly decreased compared with low WHO grade glioma tissues and normal brain tissues, and its expression demonstrated a decreasing tendency with ascending WHO grades. The transfection of the miR-203 mimic into U251 cells markedly downregulated the expression of phospholipase D2 (PLD2), which was identified as a direct target of miR-203. Furthermore, miR-203 overexpression significantly suppressed the proliferation and invasion of U251 cells, while the overexpression of PLD2 abrogated these effects induced by the miR-203 mimic. In conclusion, the present study demonstrated the clinical significance of miR-203 in gliomas and suggested that miR-203 was able to inhibit the proliferation and invasion of glioma cells, partially at least via suppressing the protein expression of PLD2. Thus, miR-203 may be a novel candidate for the development of therapeutic strategies for gliomas.
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