5901

RAN

RAN, member RAS oncogene family;RAN;RAN, member RAS oncogene family

GTP-binding nuclear protein Ran|GTPase Ran|OK/SW-cl.81|RanGTPase|androgen receptor-associated protein 24|guanosine triphosphatase Ran|member RAS oncogene family|ras-like protein TC4|ras-related nuclear protein

12q24.3

protein-coding

The Ran small GTPase (Ran) is involved in the regulation of nuclear transport, microtubule nucleation and dynamics, and spindle assembly. To address the question of whether Ran protein is associated with the progression of renal cell carcinoma (RCC), we compared by Western blotting the Ran protein levels in surgical RCC specimens from 180 consecutive Japanese patients with those in the corresponding nontumor tissue from the same patient. We also examined the Ran protein levels in tumors of different grades and stages. Ran proteins were more abundant in RCC tumor tissues than in nontumor tissues (p < 0.0001). High Ran expression was associated with higher grade, local invasion, and metastasis (p < 0.0001). Kaplan-Meier plots linked high Ran protein expression to a shorter overall survival in all cases (p < 0.0001) and a shorter disease-free survival in those without metastasis at radical or partial nephrectomy (M0; 131 cases, p < 0.0001). Ran protein expression was an independent factor influencing overall survival univariate analysis (p < 0.0001) and disease-free survival by multivariate analysis (p < 0.05). Our findings suggest that Ran is associated with the progression of RCC.

BACKGROUND: The Ras-like nuclear protein (Ran) is involved in the regulation of nuclear transport, microtubule nucleation and dynamics, and spindle assembly. Its fundamental function is nucleocytoplasmic transport of RNA and proteins. The expression and potential role of Ran in colorectal cancer (CRC) remain unclear. The aim of this study was to investigate the relationship between Ran expression and CRC characteristics. The potential role of Ran as a prognostic indicator was also evaluated. METHODS: We used immunohistochemistry and western blotting to detect Ran expression in 287 CRC tissues. The relationships between Ran expression and clinicopathological characteristics and overall survival rate were statistically analyzed. RESULTS: CRC tissues had significantly higher Ran expression than normal colorectal epithelial cells. Ran was positively correlated with depth of invasion, lymph node metastases, distant metastases, tumor differentiation, and tumor-node-metastasis stage. However, no correlation was found between Ran expression and patient age or sex. The overall survival rate was consistently and significantly lower in patients with Ran-positive tumors than in those with Ran-negative tumors. CONCLUSION: Our findings emphasize the important role of Ran in differentiation, disease stage, and metastasis in human CRC. Ran may play an important role in the development of CRC and may serve as a novel prognostic indicator of CRC.

AIMS: Our previous work identified thioredoxin-like protein 2 (Txl-2) as the target of the monoclonal antibody MC3 associated with colon cancer, but its underlying mechanisms remain poorly understood. Txl-2, a novel thioredoxin (Trx) and nucleoside diphosphate kinase family member, is alternatively spliced and gives rise to three different Txl-2 isoforms. In this study, Txl-2 expression in colon cancer, differential functions for Txl-2 isoforms in cell invasion and metastasis, and the downstream signaling were investigated. RESULTS: Txl-2 expression was elevated in colon cancer tissues compared to normal colonic tissues, with a high correlation between the histological grade and prognosis. Knockdown of Txl-2 expression significantly inhibited cancer cell motility, and the invasive and metastatic abilities of colon cancer cells. Interestingly, Txl-2 isoforms showed differential effects on cancer cell invasion and metastasis. Cell invasion and metastasis were significantly promoted by Txl-2b but inhibited by Txl-2c, while no obvious effect was observed for Txl-2a. Furthermore, a direct interaction was identified between Txl-2b and Ran, a Ras-related protein, by yeast two-hybrid assay and coimmunoprecipitation. PI3K pathway was found to be a major pathway mediating Txl-2b induced tumor invasion and metastasis. INNOVATION: The current study provides a novel biomarker and target molecule for the diagnosis and treatment of colon cancer and provides a novel paradigm to understand how alternative splicing functions in human cancer. CONCLUSION: Our findings demonstrate an elevated Txl-2 expression in colon cancer and that Txl-2b promotes cell invasion and metastasis through interaction with Ran and PI3K signaling pathway.