Analysis of gene expression array in TSC2-deficient AML cells reveals IRF7 as a pivotal factor in the Rheb/mTOR pathway

Abstract

Mutations in tuberous sclerosis (TSC) genes cause the genetic disorder TSC, as well as other neoplasms, including lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs). AMLs are benign renal tumors occur both in sporadic LAM and in TSC. As they carry the same mutations, AML cell lines serve as a model for TSC and LAM. Rheb/mammalian target of rapamycin complex 1 (mTORC1) pathway is chronically activated in TSC-deficient cells, and this activation can be diminished using the appropriate inhibitors. Rapamycin (sirolimus) is a known specific inhibitor of mTORC1, whereas S-trans,trans-farnesylthiosalicylic acid (FTS; salirasib) has been shown to inhibit Rheb. To examine the effect of the Rheb/mTOR inhibition pathway, we used human TSC2-deficient AML cells, derived from a LAM patient. FTS indeed inhibited Rheb in these cells and attenuated their proliferation. After comparative treatments with FTS or rapamycin or by re-expression of TSC2, we carried out a gene array analysis. This yielded a substantial number of commonly altered genes, many of which we identified as downstream targets of the interferon (IFN) regulatory factor 7 (IRF7) transcription factor, a central activator of the IFN type 1 immune response. Furthermore, nuclear localization of IRF7 was impaired by each of the three treatments. Interestingly, the phenomena seen on FTS or rapamycin treatment were selective for TSC2-deficient cells. Moreover, knockdown of IRF7 by siRNA mimicked the decrease in number of the abovementioned genes and also inhibited AML cell proliferation. Altogether, these findings support FTS as a potential treatment for TSC and its related pathologies and IRF7 as a novel target for treatment.

IRF7 suppresses hematopoietic regeneration under stress via CXCR4

“…It was reported that IRF7 was downstream target of mTOR signaling in angiomyolipoma. 36 Downregulation of mTORC1 was known to be essential for HSC selfrenewal and maintenance. [37][38][39] Inhibition of mTOR with rapamycin (an mTOR inhibitor) promoted in vitro expansion and long-term engraftment of HSCs.…”

IRF7 as an Immune-Related Prognostic Biomarker and Associated with Tumor Microenvironment in Low-Grade Glioma

“… 29 Low expression of IRF7 can inhibit the proliferation of AML cells in human angiomyolipoma through the Rheb/mTOR pathway. 30 In breast cancer, IRF7-mediated IFN-α reduces the production of bone marrow derived suppressor cells (MDSCs) and plays an important role in bone metastasis of breast cancer by activating CD4+ cells. 31 …”

Overexpression of Interferon Regulatory Factor 7 (IRF7) Reduces Bone Metastasis of Prostate Cancer Cells in Mice

“…The IRF7 gene was originally cloned in 1997, in the context of latent Epstein–Barr virus (EBV) infection where the encoded protein binds to and regulates the EBNA1 Q promoter 18 . In human angiomyolipoma (AML) cells 621.102 and 621.103, knockdown of IRF7 in the Rheb/mTOR pathway by si-RNA inhibited the proliferation of AML cells 19 . In addition, it has been reported that ectopic expression of IRF7 in human glioma cells U87MG and LN229 directly induced the production of IL-6, which maintained glioma stem cell properties via the Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signaling 9 .…”