Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510060, Guangzhou, China.
Cell Death Dis. 2018 Oct 22;9(11):1085. doi: 10.1038/s41419-018-0979-x.
Ras-like without CAAX1 (RIT1) protein is a member of Ras family, which plays critical roles in signaling pathways and cellular process regulation. However, the role of RIT1 in esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we found that the expression of RIT1 is downregulated in ESCC compared to corresponding non-tumor tissues. The low-level expression of RIT1 was correlated with poorer prognosis. Then we showed that RIT1 inhibited proliferation, invasion, and migration of ESCC cells, and silencing RIT1 by shRNA promoted tumorigenicity and metastasis in nude mice. We further demonstrated that RIT1 inhibited the malignant behaviors of ESCC through inhibiting the PI3K/AKT and MAPK pathway and epithelial-mesenchymal transition in ESCC cells. Our study also revealed that RIT1 increased drug sensitivity to cisplatin (CDDP), and this function could be carried out through downregulating stemness of ESCC. In conclusion, our study indicates for the first time that RIT1 displays tumor-suppressing functions in ESCC, and these functions were carried out by inhibiting MAPK and PI3K/AKT signaling pathway, inhibiting EMT, and downregulating cancer stemness of ESCC cells.
Ras-like without CAAX1 (RIT1) 蛋白是 Ras 家族的成员，在信号通路和细胞过程调节中发挥着关键作用。然而，RIT1 在食管鳞状细胞癌 (ESCC) 中的作用尚不清楚。在本研究中，我们发现与相应的非肿瘤组织相比，RIT1 在 ESCC 中的表达下调。RIT1 的低表达与预后不良相关。然后，我们表明 RIT1 抑制 ESCC 细胞的增殖、侵袭和迁移，并且通过 shRNA 沉默 RIT1 促进裸鼠的致瘤性和转移。我们进一步证明，RIT1 通过抑制 ESCC 细胞中的 PI3K/AKT 和 MAPK 通路以及上皮-间充质转化来抑制 ESCC 的恶性行为。我们的研究还表明，RIT1 通过下调 ESCC 的干性来增加顺铂 (CDDP) 的药物敏感性。总之，我们的研究首次表明，RIT1 在 ESCC 中显示出肿瘤抑制功能，这些功能是通过抑制 MAPK 和 PI3K/AKT 信号通路、抑制 EMT 和下调 ESCC 细胞的癌症干性来实现的。
