Highlights of This Issue

Abstract

Innovative ways to combat KRAS-driven lung cancers are needed. Prior work showed that the deubiquitinase USP18 regulates oncoprotein stability. Mustachio and colleagues now report that loss of USP18 expression destabilizes KRAS and mislocalizes this oncoprotein from the plasma membrane. Notably, Usp18 knockout in KrasLA2/+ mice reduced lung cancer formation when compared to parental KrasLA2/+ mice. Translational relevance was confirmed by showing USP18 expression increased in KRAS mutant versus wild-type human lung adenocarcinomas. Collectively, these findings reveal that inhibiting USP18 destabilizes KRAS protein and represses lung tumors. This is a novel mechanism to target lung cancers that express the KRAS oncoprotein.Maternally expressed gene 3 (MEG3) has tumor suppressor properties; however, the effects and methylation status, and role as a competing endogenous RNA (ceRNA) in esophageal squamous cell carcinoma (ESCC) tumorigenesis have not been clarified. Dong and colleagues found significant down-regulation of MEG3 in ESCC cells and tissues, and aberrant promoter hypermethylation of MEG3 was identified as an epigenetic mechanism leading to its reduced expression. Proliferation and invasiveness were inhibited by MEG3 up-regulation. Mechanistically, MEG3 acts as a ceRNA to regulate the expression of E-cadherin and FOXO1 by binding hsa-miR-9. Furthermore, down-regulation and hypermethylation of MEG3 was associated with poor ESCC patients' survival.Cell phenotypic changes, such as epithelial-mesenchymal transition (EMT), are common in cancer progression. In the progress of phenotypic changes, intracellular proteins are pathophysiologically translocated to the cancer cell plasma membrane. These translocated proteins are potentially excellent biomarkers and candidates for therapeutic intervention. Yoon and colleagues describe the blind-SELEX with RNA aptamers to identify cancer biomarkers and aptamer-binding targets using mass-spectrometry. The aptamer binding target in this study is the intermediate filament vimentin, which is a biomarker of EMT. Anti-vimentin RNA aptamers inhibit cancer cell metastases, via down-regulation of MMP3. This study opens up possibilities for reversal of cell phenotypes by targeting cancer plasma membranes with RNA aptamers.The current study linking dietary influence on metformin-regulated signaling pathways and anti-tumoral response provides new and critical insight on environment-host interactions in cancer and therapy. Specifically, this study reveals that a high-fat diet (HFD) is associated with enhanced prostate cancer growth in vivo and that metformin reduces cancer growth under a low-fat diet but more prominently under HFD conditions, acting through the modulation of several key tumor-associated processes such as cell cycle and/or apoptosis and by modulation of local expression of GH/IGF1 axis components. Additionally, this report demonstrates that metformin had dissimilar effects on proliferation, migration and PSA secretion from different PCa cell lines.