B-cell CLL/lymphoma 3 promotes glioma cell proliferation and inhibits apoptosis through the oncogenic STAT3 pathway

Abstract

Aberrant expression of oncogenes and/or tumor suppressors play fundamental roles in the pathogenesis of glioma. B-cell CLL/lymphoma 3 (BCL3) was previously found to be a putative proto-oncogene in human cancers and the decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide in glioblastoma cells. However, its expression status, clinical significance and biological functions in glioma remain largely unknown. In the present study, the levels of BCL3 were overexpressed in glioma compared to normal brain tissues. Furthermore, high expression of BCL3 protein was confirmed by immunoblotting in glioma cells as compared with normal human astrocyte cell line. The positive expression of BCL3 was correlated with adverse prognostic features and reduced overall survival rate of glioma patients. BCL3 silencing resulted in prominent decreased proliferation, cell cycle arrest in G1 phase and increased apoptosis in U251 cells. In contrast, BCL3 overexpression in U87 cells remarkably facilitated proliferative ability and cell cycle progression and induced apoptosis. In vivo studies showed that BCL3 knockdown inhibited the tumor growth of U251 cells in a mouse xenograft model. Mechanistically, BCL3 positively regulated the abundance of STAT3, p-STAT3 and the downstream targets of STAT3 pathway including BCL2, MCL-1 and cyclin D1 in glioma cells. Furthermore, a positive correlation between BCL3 and STAT3 expression was observed in glioma specimens. Notably, we confirmed that STAT3 knockdown abolished the oncogenic roles of BCL3 in glioma. In conclusion, we suggest that BCL3 serves as an oncogene in glioma by modulating proliferation, cell cycle progression and apoptosis, and its oncogenic effects are mediated by the STAT3 signaling pathway.

Early Optic Nerve Head Glial Proliferation and Jak-Stat Pathway Activation in Chronic Experimental Glaucoma

“…In addition to these proliferation findings, we found that minimally injured ONHs showed an upregulation of several interleukin-6 type cytokines ( Il6, Lif, Clcfl ) and Socs3 , the feedback inhibitor of Stat3 phosphorylation (pStat3), suggesting an early activation of the Janus kinase and signal transducer and activator of transcription (Jak-Stat) pathway 18,19. Jak-Stat pathway activation has been shown to regulate glial cell proliferation, as well as astrocytic differentiation, and this pathway may play an important role in the glial responses we have observed in pressure-induced injury 17,18,21–25…”

Current Challenges and Opportunities in Treating Glioblastoma

“…Although many other proteins have been found to contribute to GBM tumor growth, for this review, we will focus on targets that have been discovered through proteomic approaches and TCGA data mining. Some examples of proteins overexpressed in GBM that may represent novel drug targets that were not discovered via proteomic approaches include heat-shock protein 47 ( Jiang et al, 2017b ), cathepsin L ( Xiong et al, 2017 ), glycoprotein nonmetastatic melanoma protein B ( Ono et al, 2016 ), transcription factor 12 ( Godoy et al, 2016 ), targeting protein for Xenopus kinesin-like protein 2 ( Gu et al, 2016 ), and B-cell CLL/lymphoma 3 (BCL3) ( Wu et al, 2016 ). Due to the characteristic intratumoral heterogeneity of GBM, it is likely that a single target approach will not be effective, and appropriate drug combinations will be necessary.…”

Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer

“…15 In glioblastoma cells, Bcl-3 significantly facilitated proliferation by stabilizing the expression of STAT3, p-STAT3, and STAT3 signaling target genes, including Bcl-2, MCL-1, and cyclin D1. 16 Recently, the function of Bcl-3 in CRC has been reported by various research groups. First, Bcl-3 was found to promote CRC cell growth by stabilizing the c-Myc protein level and regulating ERK signaling.…”