STAT3 activation and risk of recurrence in meningiomas

Abstract

Abstract. Several studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) is associated with initiation, progression and metastasis of numerous types of malignancy. However, the role of the Janus kinase-interleukin 6-STAT3 signaling pathway in the pathogenesis and recurrence of meningiomas is unknown. The present study evaluated STAT3 activation by western blotting and immunohistochemistry and assessed its association with Ki-67 labeling in 13 cases of meningioma in which frozen tissue and ≥5.5-year follow-up information were available, and in formalin-fixed meningioma tissues from 14 cases with an 8.4-year follow-up. The results of the western blot analysis indicated that STAT3 phosphorylation was markedly higher in grade II meningiomas compared with that in grade I, with mean densitometric values of 8.6 and 1.7 following normalization to actin, respectively. High STAT3 phosphorylation/activation was identified in 2 of 3 recurrent World Health Organization (WHO) grade I meningiomas and 0 of 3 non-recurrent meningiomas. Strong STAT3 phosphorylation/activation signal was also found in 2 of 4 recurrent grade II meningiomas and 1 of 3 non-recurrent cases. According to the immunohistochemistry results, phospho-STAT3 was not increased in WHO grade II tumors compared with that in grade I tumors, and was not significantly different between recurrent and non-recurrent cases. Ki-67 labeling was significantly increased in grade II vs. grade I tumors, and was also significantly increased in recurrent compared with non-recurrent grade I meningiomas. The results of the current study suggest that, while detection of phosphorylated/activated STAT3 may be useful in isolated cases, identifying activation may be of little value in predicting recurrence.

Identification of Meningioma Patients at High Risk of Tumor Recurrence Using MicroRNA Profiling

“…Additionally, a strong STAT3 phosphorylation/activation signal was observed in 2 out of 4 recurrent WHO grade II meningiomas and one out of 3 nonrecurrent tumors. 21 Although the suppression of IL-6 by miR-146a leading to reduced STAT3 expression has not yet been demonstrated in meningiomas, 22 these findings highlight the potential therapeutic value of miR-146a in these tumors. Combining GLA with irradiation might be an effective treatment strategy for overexpression of the miRNA, deactivation of the STAT3 pathway, and, thus, reducing the likelihood of meningioma recurrence.…”

“…The importance of miR-146 in meningioma recurrence is suggested by the existence of a negative feedback loop between signal transducer and activator of transcription 3 ( STAT3 ) and NF-κB involving miR-146b, 20 and the fact that STAT3 expression was significantly higher in recurrent WHO grade I and/or grade II meningiomas than in nonrecurrent ones. 21 STAT3 targets miR-146b, which reduces IL-6 production by downregulating NF-κB. This is the final step in the negative feedback loop because IL-6 activates STAT3 .…”

“… 20 Upon miR-146b downregulation, its uninhibited target gene NF-κB induces increased IL-6 production followed by STAT3 activation. Notably, Johnson et al 21 reported that STAT3 activation was markedly stronger in WHO grade II meningiomas than those of lower grade. High STAT3 activation was also identified in 2 out of 3 recurrent WHO grade I meningiomas and in none out of 3 nonrecurrent lesions.…”

STAT3 Expression and Correlation Between Ki-67 and PHH3 in Meningiomas: Is it Possible to Predict Recurrence?

“…Meningiomas may recur, at a rate of up to 25% even in grade I tumors, and high recurrence rates remain a challenge in clinical management (1). Being able to predict early recurrence in meningiomas will be beneficial in providing sufficient postoperative treatment (16). The benefits of post-operative radiation, extending the resection area, and drug therapies in high-grade meningiomas are…”

Systematic analysis of gene expression alterations and clinical outcomes of STAT3 in cancer

“…Aberrant expression and persistent activation of STAT3 is implicated in cell proliferation, differentiation, apoptosis and immune escape, inducing and maintaining a pro-carcinogenic inflammatory microenvironment [ 7 ]. Continuously activated STAT3 has been found in many human tumors, such as lung cancer [ 8 ], gastric carcinoma [ 9 ], cervical carcinoma [ 10 ], and meningiomas [ 11 ]. Moreover, mounting evidence have demonstrated STAT3-targeted therapy could effectively inhibit tumor development in various human cancers [ 12 ].…”