Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Cancer Sci. 2020 Apr;111(4):1203-1217. doi: 10.1111/cas.14341. Epub 2020 Mar 17.
GINS complex subunit 4 (GINS4) is essential for DNA replication initiation and elongation in the G /S phase cell cycle in eukaryotes, however, its functional roles and molecular mechanisms remain unclear in many aspects. Our study was designed to investigate the clinical significance, biological function, and molecular mechanism of GINS4 in colorectal cancer (CRC). First, we confirmed that GINS4 expression was significantly overexpressed in CRC cells and tissues. The immunohistochemical results in tissue microarray from 106 CRC patients showed that a high level of GINS4 expression was positively correlated with advanced T stage, higher tumor TNM stage, and poor differentiation. The results from univariate and multivariate survival analysis models based on 106 CRC patients revealed that GINS4 might serve as an independent prognostic indicator for overall survival and disease-free survival of CRC patients. Moreover, downregulated GINS4 can inhibit growth and the cell cycle and accelerate cell apoptosis progression in vitro as well as inhibit tumorigenesis in vivo. Besides, our results also indicated that Krüppel-like factor 4 (KLF4) can negatively regulate GINS4 expression at the transcriptional level and the KLF/GINS4 pathway might play a vital role in the growth and prognosis of CRC.
GINS 复合物亚基 4（GINS4）在真核生物的 G1/S 期细胞周期中对于 DNA 复制的起始和延伸是必不可少的，然而，其在许多方面的功能作用和分子机制仍不清楚。我们的研究旨在探讨 GINS4 在结直肠癌（CRC）中的临床意义、生物学功能和分子机制。首先，我们证实 GINS4 在 CRC 细胞和组织中表达明显过表达。对 106 例 CRC 患者组织微阵列的免疫组织化学结果表明，高水平的 GINS4 表达与晚期 T 分期、更高的肿瘤 TNM 分期和分化不良呈正相关。基于 106 例 CRC 患者的单变量和多变量生存分析模型的结果表明，GINS4 可能是 CRC 患者总生存和无病生存的独立预后指标。此外，下调 GINS4 可以抑制体外生长和细胞周期，并加速细胞凋亡进展，以及抑制体内肿瘤发生。此外，我们的结果还表明，Krüppel 样因子 4（KLF4）可以在转录水平上负调控 GINS4 的表达，KLF/GINS4 通路可能在 CRC 的生长和预后中发挥重要作用。
