p38γ overexpression in gliomas and its role in proliferation and apoptosis

Kui Yang, Yunsheng Liu, Zhixiong Liu, Jinfang Liu, Xin Liu, Xin Chen, Chuntao Li, Yu Zeng
2013 Scientific Reports  
The objective of this study was to confirm the biological role of p38c in human gliomas. The expression profiles of p38c and hTERT in human glioma samples were detected by Western Blot and immunohistochemistry. RNA interference was performed in U251 cells by p38c silencing. Cell proliferation and apoptosis were assayed by CCK-8 and flow cytometric analysis, and then RNA and protein expression levels were measured by real-time RT-PCR and Western Blot, respectively. Telomerase activity assays and
more » ... Caspase-3,-9 activation assays were also conducted. The results showed p38c had a positive correlation with the glioma's malignancy grade and that the treatment of U251 cells with p38c-siRNA inhibited proliferation and induced apoptosis. Correspondingly, hTERT expression and telomerase activity were down regulated and Caspase-3 and -9 activities were elevated. In conclusion, p38c may serve as an oncogenic factor promoting the growth and progression of gliomas and may become a useful therapeutic target. T he p38 mitogen-activated protein kinases (MAPKs) contain four members (p38a, p38b, p38c, and p38d). In addition to a wide variety of biological functions, MAPKs differ in their expression patterns, substrate specificities, and sensitivities to inhibitors 1,2 . It is known that p38 can serve as a tumor suppressor by negatively regulating the proliferation and survival of the cells [3] [4] [5] . Specifically, it is believed that p38a is the most important negative regulation factor because numerous studies have seen its effects by using inhibitors special for p38a/b, which fall to suppress p38c or p38d 6, 7 . Also known as MAPK12, ERK6, and SAPK3, p38c was first observed to be predominately in skeletal muscle, a negative regulator of stimulated glucose uptake in peripheral tissues 8 , and required for the maintenance of slow skeletal muscle size 9 . However, p38c has now been observed in several human cancer cell lines 10, 11 , and its pathway could modulate some processes involved in cellular malignant transformations, such as proliferation, cell cycle progression, or apoptosis [11] [12] [13] . Overexpressions of p38c were also detected in colon and breast cancer tissues, which positively correlated with a poor prognosis of breast cancer 12, 14 . These authors suggested that p38c played a potential oncogenic role in a cancer's development and progression. Gliomas are the most common primary brain tumor, yet few studies have focused on p38, even though it is regarded as a strong promoter of tumor invasion, progression, and poor patient survival 15 . Importantly, the antiproliferation of glioblastoma cells induced by b-elemene was dependent upon p38 activation 16 . This shows p38, and possibly p38c, has a positive function in the tumorigenesis of gliomas. Therefore, we aimed to investigate the expression of p38c MAPK in glioma tissues and explore the relationships between p38c and the progression of glioma. These findings may suggest a new-targeted approach of p38c for future cancer therapy. Results Up-regulation of p38c and hTERT expression in gliomas. To determine the relationship between p38c expression and glioma grade, Western Blotting was performed from the samples of 71 astrocytic glioma patients (grade I: 10; grade II: 18; grade III: 24; grade IV: 19) and 5 control samples. As shown in Figure 1 (also Supplementary Figure S1 ), the expression level of p38c in high-grade glioma patients was significantly higher than that of the normal controls and low-grade glioma patients (P 5 0.0014). Consistent with these results, we observed a significant increased in the level of p38c according to the histological grade of astrocytomas from immunohistochemistry (Figure 2 ). Similar data could also be examined when detecting the level of hTERT (Figure 1 and 2, Supplementary Figure S1 ). Furthermore, there was a correlation between the two indexes (r 5 0.818, P 5 0.0006; Figure 1 ). All the results indicated that p38c overexpression might be associated with the malignant degree of gliomas and have a role in its pathogenesis.
doi:10.1038/srep02089 pmid:23807566 pmcid:PMC3695572 fatcat:q2arixkkrba6fbxpugrzymcaq4