Implications of Epithelial–Stromal Interaction 1 in Diseases Associated with Inflammatory Signaling

Epithelial–stromal interaction 1 (EPSTI1) was initially identified as an induced gene in breast cancer epithelial cells by cocultured stromal fibroblasts. This discovery led to further investigation and understanding of the role of EPSTI1 in cancer. Aberrant elevation of EPSTI1 occurs primarily in invasive breast cancer epithelial cells. Forced overexpression of EPSTI1 in noninvasive cancer cells can substitute for the stromal fibroblasts. EPSTI1 was further implicated in cancer by our most recent study that identified it as one of the few most upregulated genes in human breast cancer by Krüppel-like factor 8 (KLF8), a pro-cancerous transcription factor in many cancer types. Our study also demonstrated that EPSTI1 interacts with valosin-containing protein to promote the degradation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) inhibitor alpha, leading to the activation and nuclear translocation of NF- κB. Additionally, EPSTI1 was shown to inhibit apoptosis by inactivating caspase 8. Studies on hepatitis C and E viruses have indicated that EPSTI1 plays a role in inhibition of the viral replication by promoting the expression of protein kinase R or protein kinase RNA-activated, a viral response gene, suggesting a role of EPSTI1 in immune response. Interestingly, in addition to transducing stromal signals, EPSTI1 has been implicated in immune privilege and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and histiocytic necrotizing lymphadenitis. This review seeks to comb EPSTI1-related studies as it was cloned a dozen years ago with a particular focus on the mechanisms of its regulation and signaling, as well as its potential roles in the diseases.

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