Loss of the Transcription Factor GLI1 Identifies a Signaling Network in the Tumor Microenvironment Mediating KRAS Oncogene-induced Transformation

Abstract

Background: KRAS is a known oncogene driving transformation in multiple tissues. Results: We demonstrate a role for the transcription factor GLI1 in KRAS-induced transformation through regulation of the IL-6/STAT3 axis in the tumor microenvironment. Conclusion: This study defines a novel oncogenic network downstream of KRAS modulating transformation. Significance: This knowledge will contribute to the understanding of the pathogenesis of tumors driven by KRAS.

Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

“…This transcription factor is expressed at low levels in normal adult tissue, but it is often re-expressed and de-regulated in many human cancers carrying signature mutations in the Kras gene (10 -13). Recently, we demonstrated that the loss of GLI1 in a genetically engineered mouse model (GEMM) blocks the progression of pancreatic intraepithelial neoplasms (PanIN) induced by oncogenic KRAS (10). In agreement with these findings, using a transgenic model overexpressing a repressor form of the transcription factor GLI3 to antagonize GLI1 activity, Rajurkar et al (11) showed a requirement for this transcription factor in pancreatic cancer initiation.…”

“…Immunohistochemistry-Paraffin-embedded tissue sections were processed using methods described previously (10). Primary antibodies used are as follows: CK19 (TROMA III, Developmental Studies Hybridoma Bank, Iowa City, IA); PCNA (Abcam, Cambridge, MA); F4/80 (Abcam), and CD31 (Santa Cruz Biotechnology).…”

“…The following primers were used to clone these promoters: fas forward 5Ј-agctcaggtaccgtctgcagcaagggaaaacagcgggc-3Ј and reverse 5Ј-agctcactcgagcctaggtccctgggctatctagtctcagg-3Ј; and fasl forward 5Ј-agctcagctagcctgagctgctaaacgagcatcctggaggtacc-3Ј and reverse 5Ј-agctcactcgagctcctgttctcttctctttgcttctctgtgagac-3Ј. The human GLI1 and shRNA vectors were previously reported (8,10).…”

“…Blots were probed with total ERK (Cell Signaling, Danvers, MA), phosphorylated ERK (pERK) (Cell Signaling), and ␥-tubulin (Sigma) as described previously (10).…”

WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway

“…Constitutive activation of the STAT3 pathway has been noted in a wide range of cancers and typically occurs in response to stimulation by tumor-promoting factors, including epidermal growth factor, IL-6, Tyr kinase, and many others (21,22). Inhibition of aberrantly activated STAT3 signaling pathway may present a novel antitumor strategy (Fig.…”