Xiang J, Fu X, Ran W, Wang Z
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Department of General Surgery, Chongqing General Hospital, Chongqing, People's Republic of China.
Oncogenesis. 2017 Jan 9;6(1):e284. doi: 10.1038/oncsis.2016.83.
Metastasis is one of the typical features of malignancy that significantly increases cancer-related mortality. Recent studies have shown that epithelial-mesenchymal transition (EMT) is closely related to the invasion and migration of cancer cells. Grainyhead-like 2 (Grhl2), a transcription factor, has been reported to be associated with several tumor processes including EMT. In the previous study, we have reported that Grhl2 functioned as a tumor suppressor in proliferation and apoptosis of gastric cancer. Here we aim to explore the effects of Grhl2 on invasion and migration of gastric cancer and further clarify its possible underlying mechanisms. As a result, in both SGC7901 and MKN45 cells, Grhl2 overexpression significantly inhibited the ability of invasion and migration. In addition, preliminary experiments showed that Grhl2 reduces the protein expression of matrix metalloproteinase-2, -7 and -9 (MMP-2, MMP-7 and MMP-9). Most importantly, Grhl2 antagonizes transforming growth factor-β (TGFβ)-induced EMT, and inhibition of TGFβ signaling pathways can restore Grhl2 expression. Finally, the results of subcutaneous xenograft model indicated that Grhl2 suppresses the growth of gastric cancer and reverses EMT process in vivo. Meanwhile, the metastatic tumor model further confirmed the inhibition of Grhl2 on metastasis of gastric cancer. Taken together, our findings proved that Grhl2, functioned as a tumor suppressor, reduces the invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer.
转移是恶性肿瘤的典型特征之一，它显著增加了癌症相关死亡率。最近的研究表明，上皮-间质转化（EMT）与癌细胞的侵袭和迁移密切相关。颗粒头样蛋白2（Grhl2）作为一种转录因子，已被报道与包括EMT在内的多种肿瘤进程有关。在先前的研究中，我们报道了Grhl2在胃癌增殖和凋亡过程中发挥肿瘤抑制作用。在此，我们旨在探讨Grhl2对胃癌侵袭和迁移的影响，并进一步阐明其可能的潜在机制。结果显示，在SGC7901和MKN45细胞中，Grhl2过表达均显著抑制了侵袭和迁移能力。此外，初步实验表明，Grhl2可降低基质金属蛋白酶-2、-7和-9（MMP-2、MMP-7和MMP-9）的蛋白表达。最重要的是，Grhl2拮抗转化生长因子-β（TGFβ）诱导的EMT，抑制TGFβ信号通路可恢复Grhl2表达。最后，皮下异种移植模型结果表明，Grhl2在体内可抑制胃癌生长并逆转EMT进程。同时，转移瘤模型进一步证实了Grhl2对胃癌转移的抑制作用。综上所述，我们的研究结果证明，Grhl2作为一种肿瘤抑制因子，通过抑制TGFβ诱导的EMT来降低胃癌的侵袭和迁移能力。
