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)

Kindlin-2 functions in the maintenance of homeostasis and in human diseases. This study investigated the interrelationship between Kindlin-2 expression in tissues and the corresponding germ layers from which these tissues originated. Kindlin-2 expression was examined in normal adult human organs and human cancer tissues by immunohistochemical analyses. Analysis of Kindlin-2 mRNA levels in adult human organs in the Oncomine dataset revealed Kindlin-2 is highly expressed in mesoderm-derived organs. However, Kindlin-2 was negative or weakly expressed in endoderm/ectoderm-derived organs. Interestingly, the abnormal expression of Kindlin-2 was observed in a variety of human cancers. In agreement with its expression profile in humans, Kindlin-2 was also highly expressed in mesoderm-derived organs in mouse embryos with the exception of strong Kindlin-2 expression in ectoderm-derived spinal cord and ganglia, tissues that are highly mobile during embryonic development. Importantly, we demonstrated the expression level of Kindlin-2 in adult organs correlated with their embryonic dermal origins and deregulation of Kindlin-2 in tissues is associated with tumor progression. This finding will help us understand the dual role of Kindlin-2 in the regulation of tumor progression and embryonic development.

Kindlin-2 is an integrin-interacting, FERMdomain containing protein, which plays a critical role in tumor progression. However, the specific role of Kindlin-2 in renal cell carcinoma (RCC) progression has not been described. In this study we investigated the role of Kindlin-2 in progression of clear cell RCC (CCRCC), which is the most common RCC subtype, and its underlying mechanisms. Immunohistochemistry studies show that expression of Kindlin-2 in CCRCC is positively correlated with tumor grade, and Kindlin-2 expression in advanced CCRCC with lymph node metastasis was greater than in localized CCRCC. Kindlin-2 expression in CCRCC tumor specimens is also correlated with short patient survival, but is not an independent prognostic factor. Kindlin-2 promotes CCRCC cell migration and invasion in vitro, whereas knockdown of Kindlin-2 inhibited cell migration and invasion. Knockdown of Kindlin-2 also inhibits ACHN cell proliferation in vitro and tumorigenesis in vivo. Kindlin-2 may be required for Wnt pathway activation which underlies the mechanisms of Kindlin-2 promoting CCRCC progression. These findings demonstrate that expression of Kindlin-2 is associated with tumor grade, lymph node metastasis and poor prognosis in CCRCC patients. Kindlin-2 may regulate CCRCC progression through the Wnt signaling pathway, promoting CCRCC cell proliferation, migration and invasion.