School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China.
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
Cancer Sci. 2019 Feb;110(2):608-616. doi: 10.1111/cas.13905. Epub 2019 Jan 28.
Sine oculis homeobox 1 (Six1) is a homeodomain transcription factor that is aberrantly expressed in a variety of human cancers, including colorectal cancer (CRC). Six1 has been reported to play a key role in the proliferation and migration of CRC cells but the underlying molecular mechanisms are still poorly characterized. In the present study, we found that Six1 overexpression promoted the proliferation and migration of CRC cells. Consistently, Six1 knockdown (KD) significantly inhibited proliferation and migration of CRC cells. In addition, we showed that Six1 promoted proliferation and migration of CRC cells through activation of Wnt/β-catenin signaling, as evidenced by promotion of nuclear localization of β-catenin. Silencing of β-catenin expression with siRNA or inhibiting Wnt signaling with a specific inhibitor, xav939, significantly blocked Six1-induced nuclear localization of β-catenin and mitigated Six1-promoted proliferation and migration of CRC cells. We further confirmed the involvement of β-catenin in Six1-promoted proliferation and migration of CRC cells by activation of Wnt signaling with lithium chloride (LiCl) in Six1 KD CRC cells and results showed that LiCl restores defective β-catenin nuclear localization and proliferation and migration of CRC cells. Taken together, these results suggest that Six1 homeoprotein promotes the proliferation and migration of CRC cells by activating the Wnt/β-catenin signaling pathway, and strategies targeting Six1 may be promising for the treatment of CRC.
Sine oculis homeobox 1（Six1）是一种同源域转录因子，在多种人类癌症中异常表达，包括结直肠癌（CRC）。已经报道 Six1 在 CRC 细胞的增殖和迁移中发挥关键作用，但潜在的分子机制仍知之甚少。在本研究中，我们发现 Six1 过表达促进了 CRC 细胞的增殖和迁移。一致地，Six1 敲低（KD）显著抑制了 CRC 细胞的增殖和迁移。此外，我们表明 Six1 通过激活 Wnt/β-catenin 信号促进 CRC 细胞的增殖和迁移，这表现为β-catenin 的核定位增加。用 siRNA 沉默 β-catenin 表达或用特异性抑制剂 xav939 抑制 Wnt 信号，显著阻断了 Six1 诱导的 β-catenin 核定位，并减轻了 Six1 促进的 CRC 细胞的增殖和迁移。我们进一步通过在 Six1 KD CRC 细胞中用氯化锂（LiCl）激活 Wnt 信号证实了 β-catenin 在 Six1 促进的 CRC 细胞增殖和迁移中的作用，结果表明 LiCl 恢复了缺陷型 β-catenin 的核定位以及 CRC 细胞的增殖和迁移。总之，这些结果表明 Six1 同源蛋白通过激活 Wnt/β-catenin 信号通路促进 CRC 细胞的增殖和迁移，针对 Six1 的策略可能有望用于 CRC 的治疗。
