Ras-association (RA) domain family number 6 (RASSF6) is a member of the Ras-association domain protein family. It is epigenetically inactive and negatively regulates the malignant progression of some tumors. However, its precise role in esophageal squamous cell carcinoma (ESCC) has not been reported. In this study, we performed immunohistochemistry (IHC) assay. The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients. Consistent with the clinical observations, the upregulation of RASSF6 greatly promotes ESCC cell proliferation, migration and invasion as well as the cell cycle transition to G1/S phase in vitro. According to models in vivo, the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis. Mechanistically, RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16 (TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelial-mesenchymal transition (EMT). Together, these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.

Ras关联（RA）域家族6（RASSF6）是Ras关联域蛋白家族的成员。它在表观遗传上是无活性的，并且负面地调节某些肿瘤的恶性进展。然而，其在食管鳞状细胞癌（ESCC）中的确切作用尚未见报道。在这项研究中，我们进行了免疫组织化学（IHC）测定。结果显示RASSF6在ESCC中被上调，并且RASSF6的表达水平升高与ESCC患者的淋巴结转移和不良的生存有关。与临床观察结果一致，RASSF6的上调极大地促进了ESCC细胞增殖，迁移和侵袭，以及细胞周期过渡到G1 / S期体外。根据体内模型，下调了RASSF6显着抑制ESCC肿瘤的生长和肺转移。从机理上讲，RASSF6通过促进其泛素化依赖性降解来负调节含抑癌基因三基体的蛋白质16（TRIM16），并最终激活与细胞周期和上皮-间质转化（EMT）相关的途径。在一起，这些结果表明RASSF6-TRIM16轴是ESCC进展中的关键效应器，并且RASSF6可以作为ESCC治疗的潜在靶标。