Diagnostic and therapeutic application of checkpoint gene CHFR in oral squamous cell cancer.

在口腔鳞状细胞癌（OSCCs）中经常发现细胞周期检查点功能的改变，并且通常与癌细胞对化疗药物的敏感性有关。最近，有丝分裂检查点基因Chfr在各种人类肿瘤中被证明通过启动子甲基化和点突变而失活。在这里，我们证明其产物CHFR的缺乏与有丝分裂检查点功能障碍有关，并且缺乏CHFR的癌细胞对微管抑制剂敏感。在这种情况下，检查点损伤似乎是由前期缺陷引起的，因为缺乏CHFR的OSCC细胞显示Ser10上的组蛋白H3磷酸化和细胞周期蛋白B1易位到细胞核。当用微管抑制剂（多西紫杉醇或紫杉醇）处理chfr缺陷的OSCC细胞时，观察到大量凋亡细胞。此外，使用小干扰RNA （siRNA）破坏CHFR会破坏有丝分裂检查点，从而降低OSCC细胞在G2/M期阻滞的能力，并使其对微管抑制剂更敏感。我们的结果表明CHFR可能是一个有用的化疗分子靶点。

Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G2/M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.