Regulation of Glioma Cell Invasion by 3q26 Gene Products PIK3CA, SOX2, and OPA1

Aims: Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor gene SOX2 is highly expressed in invasive gliomas and maps to 3q26 together with the genes for the PI3K/AKT signaling activator PIK3CA, and those encoding effectors of mitochondria fusion and cell invasion inhibitors MFN1 and OPA1.

Methods: We aimed at investigating their respective roles in glioma cell invasion in vitro and by exploiting retrospective patient neuroimaging data.

Results: Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion. Conversely, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in a mTORC1-independent manner, showing that PI3K/AKT signaling sustains SOX2 activity. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 transactivates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counter-act OPA1 transactivation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors.

Conclusions: Whereas glioma invasion is activated by an oncogenic PI3K/AKT-SOX2 loop, it is reduced by a cryptic tumor suppressor SOX2-OPA1 pathway. Thus, RTK/PI3K/AKT-SOX2 and mitochondria fission represent potential signaling networks to be targeted to control glioma invasion. In addition, our results indicate that necrosis volume is a potential surrogate marker for the evaluation of invasion.