BackgroundInsulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC.MethodsCaki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array.ResultsIMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients.ConclusionIMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.

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Edited by Gianni CesareniKeywords: FRMD5 Adherens junction p120-Catenin E-cadherin Tumor suppressive protein a b s t r a c t FERM family proteins have been known to play an important role in tumor progression. FERMdomain containing protein 5 (FRMD5), a novel putative cytoskeletal protein, is an unknown function protein. Here, we reported that FRMD5 localized at the cell adherens junction and formed a molecular complex with p120-catenin through its C-terminal region. Functionally, we found that knockdown of endogenous FRMD5 promotes lung cancer cell migration and invasion in vitro as well as tumor growth in vivo, suggesting a tumor suppressive effect. These findings indicated that FRMD5 may play a role in p120-catenin-based cell-cell contact and is involved in the regulation of tumor progression. Structured summary of protein interactionsFRMD5 and p120 catenin colocalize by fluorescence microscopy (View interaction) FRMD5 physically interacts with p120 catenin by anti tag coimmunoprecipitation (View interaction) FRMD5 and Beta-catenin colocalize by fluorescence microscopy (View interaction) FRMD5 and gamma-catenin colocalize by fluorescence microscopy (View interaction) FRMD5 physically interacts with p120 catenin and E cadherin by anti bait coimmunoprecipitation (View interaction)