Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu, 210008, China.
Department of Pharmacy, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang, Jiangsu, 212000, China.
Pathol Res Pract. 2019 May;215(5):1012-1019. doi: 10.1016/j.prp.2019.02.008. Epub 2019 Feb 27.
Colorectal cancer (CRC) is the third most common malignancy and a leading cause of cancer-related death worldwide. GEF-H1 is considered a RhoA-specific guanine nucleotide exchange factor. GEF-H1 upregulation may contribute to cancer cell migration and invasion and tumor progression. However, the expression and role of GEF-H1 in CRC have not yet been elucidated. This study attempted to elucidate how GEF-H1 drives tumor formation, motility, invasion and metastasis in colon cancer (CC). The expression of GEF-H1 in CC tissue microarrays (TMAs) was analyzed by immunohistochemistry (IHC). GEF-H1 was upregulated in CC tissues compared with adjacent non-tumoral tissues. In addition, we found that high GEF-H1 expression correlated with shorter overall survival and distant metastasis. Migration and invasion assays showed that GEF-H1 upregulation increased CC cell motility, invasion and metastasis. In contrast, functional knockdown of GEF-H1 by RNAi rescued the effects caused by GEF-H1 overexpression in CC cells. Overexpression of GEF-H1 re-organized the actin cytoskeleton, with increased punctate paxillin staining and F-actin stress fibers. Furthermore, western blotting showed that RhoA activation triggered by GEF-H1 overexpression caused phosphorylation of its downstream target, MLC2, in CC cells. In summary, the present study revealed that GEF-H1 is upregulated in CC tissues and plays a key role in CC metastasis through the GEF-H1-RhoA-MLC2 signaling pathway.
结直肠癌（CRC）是全球第三大常见恶性肿瘤，也是癌症相关死亡的主要原因。GEF-H1 被认为是一种 RhoA 特异性鸟嘌呤核苷酸交换因子。GEF-H1 的上调可能有助于癌细胞的迁移和侵袭以及肿瘤的进展。然而，GEF-H1 在 CRC 中的表达和作用尚未阐明。本研究试图阐明 GEF-H1 如何驱动结肠癌（CC）中的肿瘤形成、运动性、侵袭和转移。通过免疫组织化学（IHC）分析 CC 组织微阵列（TMA）中 GEF-H1 的表达。与相邻非肿瘤组织相比，CC 组织中 GEF-H1 的表达上调。此外，我们发现高 GEF-H1 表达与总生存期和远处转移缩短相关。迁移和侵袭实验表明，GEF-H1 的上调增加了 CC 细胞的迁移、侵袭和转移能力。相比之下，通过 RNAi 进行 GEF-H1 的功能敲低可挽救 GEF-H1 过表达在 CC 细胞中引起的效应。GEF-H1 的过表达重新组织了肌动蛋白细胞骨架，点状的桩蛋白染色和 F-肌动蛋白应力纤维增加。此外，Western blot 显示 GEF-H1 过表达引发的 RhoA 激活导致 CC 细胞中其下游靶标 MLC2 的磷酸化。综上所述，本研究揭示了 GEF-H1 在 CC 组织中上调，并通过 GEF-H1-RhoA-MLC2 信号通路在 CC 转移中发挥关键作用。
