Abstract 5075: Hedgehog Pathway Transcription Factor Gli1 Promotes Glioma Invasiveness through Up-regulating Aquaporin 1

Abstract

Abstract Gliomas, especially Glioblastoma multiformes (GBMs) express increased aquaporin1(AQP1) compared to normal brain. AQPs may contribute to brain edema, cell motility, and tumor angiogenesis. Although the physiology of AQP1 has been the subject of several publications, much less is known about the trans-acting factors involved in the control of AQP1 gene expression and the relationship between the regulation of the AQP1 expression and the major intracellular signaling pathways is also poorly concerned. Hedgehog signaling pathway activation is required for sustained glioma growth and survival. playing an important role in the genesis of glioma and In the present study, we report that Gli1, the transcriptional activator of the Hedgehog pathway, is co-expressed with AQP1 in human glioma tissues and can enhance AQP1 gene transcription by binding to conserved core Gli-binding site in the 5’-flanking promoter region of the AQP1. Transfection of 293T and U251 (human glioblastoma cell line) with Gli1 can markedly increase the AQP1 promoter reporter activity and the AQP1 expression level. Moreover, suppressing the Gli1 expression with the specific RNAi can abort this effect. The ChIP and reporter mutation analysis showed that the -406∼-398 region of the AQP1 promoter is essential for regulation activity of Gli1. To elucidate the possible pathophysiological importance of this molecular interaction, we investigated the migration and invasion ability of cell lines expressing different levels of Gli1 and AQP1. The results demonstrated that restoring the AQP1 expression in the Gli1-knockdown cell line can abort the decrease in the migration ability, which suggested that Gli1 may contribute to the invasion ability of glioma cells through AQP1. The up-regulation of Gli1 and its consequences of increased AQP1 in gliomas may provide a new therapeutic target, either as a cell surface marker or as a functional intervention. Citation Format: Zhenzhen Yao, Chaoxu Yang, Lie Ma, Yexiong Tan. Hedgehog Pathway Transcription Factor Gli1 Promotes Glioma Invasiveness through Up-regulating Aquaporin 1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5075.