Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ann Surg Oncol. 2011 Dec;18(13):3868-77. doi: 10.1245/s10434-011-1683-6. Epub 2011 Mar 31.
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.
我们之前报道了干扰素-γ（IFN-γ）诱导的 31 种食管鳞状细胞癌（ESCC）细胞系中的 10 种（32%）细胞凋亡。然而，IFN-γ 抗增殖作用的分子基础仍不清楚。在这里，我们证明 IFN-γ 诱导转录因子 Prox1，并探讨了 ESCC 细胞中 Prox1 与 IFN-γ 系统之间的联系。
我们使用 ESCC 细胞系，研究了 p53 突变与 IFN-γ 反应之间的关系，并通过敲低和过表达方法研究了 Prox1 在 IFN-γ 抗增殖作用中的作用。
在对 IFN-γ 有反应的 9 种 ESCC 细胞系中发现了 7 种存在 p53 突变。该频率与总 ESCC 细胞系中的 p53 突变频率（28 种细胞系中有 21 种）没有差异。IFN-β而非 IFN-γ 处理 ESCC 细胞导致 p53 信使 RNA（mRNA）表达增加，而 IFN-γ而非 IFN-β 诱导携带 p53 突变的 ESCC 细胞生长抑制。IFN-γ 在 ESCC 细胞中诱导 Prox1 表达，但在转染显性失活 STAT1 的细胞中则不然。IFN-γ 诱导的 ESCC 细胞生长抑制在转染 Prox1 短发夹 RNA（siRNA）的细胞中显著受到抑制。此外，Prox1 的过表达诱导 ESCC 细胞的抗增殖作用。我们还证明，Prox1 在接受新辅助化疗的原发性食管癌组织中表达（9 个样本中有 5 个在手术前接受了新辅助化疗）。
Prox1 介导 IFN-γ 在 ESCC 细胞中的抗增殖作用。Prox1 可能是 ESCC 新型治疗策略的候选靶标。
