RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

Abstract

Loss of function of tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) leads to the activation of mammalian target of rapamycin complex 1 (mTORC1). Hyperactivated mTORC1 plays a critical role in tumor growth, but the underlying mechanism is still not completely elucidated. Here, by analyzing Tsc1- or Tsc2-null mouse embryonic fibroblasts, rat Tsc2-null ELT3 cells, and human cancer cells, we present evidence for the involvement of epidermal growth factor receptor (EGFR) as a downstream target of mTORC1 in tumor growth. We show that mTORC1 leads to increased EGFR expression through upregulation of runt-related transcriptional factor 1 (RUNX1). Knockdown of EGFR impairs proliferation and tumoral growth of Tsc-deficient cells, while overexpression of EGFR promotes the proliferation of the control cells. Moreover, the mTOR signaling pathway has been shown to be positively correlated with EGFR in human cancers. In addition, we demonstrated that EGFR enhances cell growth through activation of signal transducer and activator of transcription 3 (STAT3). We conclude that activation of the RUNX1/EGFR/STAT3 signaling pathway contributes to tumorigenesis caused by hyperactivated mTORC1 and should be targeted for the treatment of mTORC1-related tumors, particularly TSC.

Keywords

• mTOR
• STAT3
• RUNX1
• EGFR
• tuberous sclerosis complex
• tumorigenesis