Transcriptional Factor Prox1 Plays an Essential Role in the Antiproliferative Action of Interferon-γ in Esophageal Cancer Cells

Abstract

We previously reported interferon-γ (IFN-γ)-induced apoptosis in 10 (32%) of 31 esophageal squamous cell carcinoma (ESCC) cell lines. However, the molecular basis of antiproliferative action by IFN-γ remains elusive. Here we demonstrate that IFN-γ induces transcriptional factor Prox1, and we explore the link between Prox1 and the IFN-γ system in ESCC cells. By using ESCC cell lines, we investigated the relationship between p53 mutations and the responsibility to IFN-γ, and studied the role of Prox1 in the antiproliferative effect of IFN-γ by knockdown and overexpression methods. p53 mutations were found in seven of nine ESCC cell lines responsible for IFN-γ. The frequency was not different from that of p53 mutations in total ESCC cell lines (21 of 28 cell lines). Treatment of ESCC cells with IFN-β but not IFN-γ resulted in increase of p53 messenger RNA (mRNA) expression, whereas IFN-γ but not IFN-β induced cell growth inhibition of ESCCs harboring p53 mutations. IFN-γ induced Prox1 expression in ESCC cells but not in those transfected with dominant-negative STAT1. Cell growth inhibition by IFN-γ was significantly suppressed in ESCC cells transfected with Prox1 short interfering RNA (siRNA). In addition, overexpression of Prox1 induced antiproliferative effect in ESCC cells. We also demonstrate that Prox1 is expressed in primary esophageal cancer tissues (five of nine samples treated with neoadjuvant chemotherapy before surgery). Prox1 mediates the antiproliferative effect by IFN-γ in ESCC cells. Prox1 may be a candidate target for novel therapeutic strategies of ESCCs.