WISP3 suppresses ESCC progression by inhibiting the IGF-2-IGF1R-AKT signaling cascade

Esophageal squamous cell carcinoma (ESCC) is a major health problem worldwide, especially in the Chinese population. However, the intrinsic molecular mechanisms of ESCC progression are largely unclear, thus there is an unmet need to identify essential genes governing this disease. Here, we discovered WISP3, an important member of the CCN family, is markedly downregulated in ESCC tissues compared to the normal esophageal epithelium. Downregulation of WISP3 in cancer tissue correlates with worse overall survival of ESCC patients. Using ESCC cell lines as models, we found that forced expression of WISP3 not only suppressed proliferation and migration of cancer cells in vitro, but also inhibited ESCC tumor growth and metastasis in vivo. On the contrary, WISP3 depletion strongly promoted the tumorigenicity of ESCC cells. Mechanistically, we found that WISP3 negates the activity of AKT via inhibiting the IGF-2-IGF1R signaling cascade, which mediates the tumor-suppressive function of WISP3 in esophageal cancers. Together, we identified a novel factor driving the development of ESCC, and revealed a potential therapeutic target for ESCC treatment.