A Positive TGF-β/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer

Abstract

Hepatocellular carcinoma (HCC) is globally the second most common cause of cancer mortality. The majority of HCC patients are diagnosed at advanced stage disease for which no curative treatments exist. TGF-β has been identified as a potential therapeutic target. However, the molecular mechanisms mediating its functional switch from a tumor suppressor to tumor promoter in HCC and its interactions with other signaling pathways are poorly understood. Here, we demonstrate an aberrant molecular network between the TGF-β and c-KIT pathway that mediates the functional switch of TGF-β to a driver of tumor progression in HCC. TGF-β/SMAD2 signaling transcriptionally regulates expression of the c-KIT receptor ligand (stem cell factor [SCF]) with subsequent auto- and paracrine activation of c-KIT/JAK1/STAT3 signaling. SCF induces TGF-β1 ligand expression via STAT3, thereby forming a positive feedback loop between TGF-β/SMAD and SCF/c-KIT signaling. This network neutralizes TGF-β–mediated cell cycle inhibition and induces tumor cell proliferation, epithelial-to-mesenchymal-transition, migration, and invasion. Disruption of this feedback loop inhibits TGF-β tumor-promoting effects and restores its antiproliferative functions. Consistent with our in vitro data, we demonstrate SCF overexpression and its correlation to SMAD2 and STAT3 activation in human HCC tumors, advanced tumor-node-metastasis stages, and shorter survival. CONCLUSIONS: Canonical TGF-β and c-KIT signaling forms a positive, tumor-promoting feedback loop. Disruption of this loop restores TGF-β tumor suppressor function and provides the rationale for targeting the TGF-β/SCF axis as a novel therapeutic strategy for HCC.