Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion

Abstract

AimsRan GTPase is involved in nucleocytoplasmic shuttling of proteins and is overexpressed in several cancers. The expression of Ran in malignant melanoma (MM) and its functional activity have not been described and were investigated in this study.MethodsThe prognostic value of Ran expression was tested in a series of 185 primary cutaneous MM cases using immunohistochemistry. The functional activity of Ran was investigated in the two melanoma cell lines. Ran expression was knocked down using two siRNAs and the effect on the expression of the c-Met oncogene, a potential downstream target of Ran, was tested. Functional effects of Ran knockdown on cell motility and cell proliferation were also assessed.ResultsPositive Ran expression was seen in 12.4% of MM and was associated with advanced clinical stage and greater Breslow thickness. Positive expression was an independent marker of shorter overall survival (p=0.023). Knockdown of Ran results in decreased expression of c-Met and the downstream c-met signalling targets ERK1/2. There was a significant reduction in cell migration (p<0.001) and cell invasion (p<0.001). c-Met knockdown decreased the expression of Ran through MAPK and PI3K-AKT in A375 cell line, inhibited the cell viability and migration of both A375 and G361 melanoma cell lines while invasion was enhanced.ConclusionRan is a poor prognostic marker in cutaneous MM. It upregulates expression of the oncogene c-Met and, possibly through this, it promotes cell motility which may in turn promote metastasis.

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

“…RAN is a RAS-related GTPase with numerous cellular functions, including the transportation of molecules between the nucleus and cytoplasm, the regulation of cell cycle-related proteins, and the assembly of the mitotic spindle. Ran GTPase is overexpressed in several cancer types, and its high levels correlate with malignant features [ 49 , 50 , 51 ]. Another molecule at the crossroads of the KRAS pathway is the farnesyl pyrophosphate synthase (FPPS).…”

Ran GTPase and Its Importance in Cellular Signaling and Malignant Phenotype

“…These outcomes were also reported in colorectal cancer patients with PI3K and K-Ras mutations; increased Ran expression was associated with a shorter survival time [ 6 , 107 , 108 ]. Moreover, Ran is overexpressed in numerous human cancers, including those of the stomach [ 91 , 109 ], lung [ 6 , 8 ], head and neck [ 110 ], pancreas [ 111 ], ovary [ 112 ], malignant melanoma [ 5 ], colorectal [ 113 ], and kidney [ 96 ], but not in non-tumor tissue [ 5 ].…”

“…The expression of Ran has also been shown to play a vital role in the regulation of mitosis and nucleocytoplasmic transport in tumor cells, further implicating it as a mediator of tumor cell survival [ 5 , 6 , 7 , 8 ]. Ran plays an important role in regulating the directionality of nucleocytoplasmic transport.…”

“…Furthermore, Ran has been identified as a downstream effector in multiple signaling pathways that are frequently disrupted in various types of cancer. The disruption of these pathways plays an important role in increasing tumor cell dependence on Ran, and this has a significant impact on the regulation of tumor cell survival [ 5 , 6 , 8 , 25 ]. Ran has been implicated in multiple human cancer cell lines [ 7 , 26 , 27 ].…”

Association ofRANandRANBP2Gene Polymorphisms With Glioma Susceptibility in Chinese Children

“…Some studies have found RAN overexpression in the cells of several tumors, including neuroblastoma [ 26 ], breast cancer [ 27 , 28 ], pancreatic cancer [ 23 ], gastric cancer [ 29 ], and squamous cell carcinoma of the head and neck [ 30 ], indicating that it may influence cancer susceptibility. Knockdown of the RAN gene reduces expression of c‐Met and its downstream signaling target ERK1/2, significantly reducing the ability of A375 and G361 melanoma cells to migrate and invade [ 31 ]. RAN rs7132224 A>G was found to increase Wilms tumor risk [ 32 ].…”