Subcellular localization of RNAs has gained attention in recent years as a prevalent phenomenon that influences numerous cellular processes. This is also evident for the large and relatively novel class of long noncoding RNAs (lncRNAs). Because lncRNAs are defined as RNA transcripts >200 nucleotides that do not encode protein, they are themselves the functional units, making their subcellular localization critical to their function. The discovery of tens of thousands of lncRNAs and the cumulative evidence involving them in almost every cellular activity render assessment of their subcellular localization essential to fully understanding their biology. In this review, we summarize current knowledge of lncRNA subcellular localization, factors controlling their localization, emerging themes, including the role of lncRNA isoforms and the involvement of lncRNAs in phase separation bodies, and the implications of lncRNA localization on their function and on cellular behavior. We also discuss gaps in the current knowledge as well as opportunities that these provide for novel avenues of investigation.
E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue barrier formation, a critical function of epithelial tissues. The colon or large intestine is lined by an epithelial monolayer that encompasses an E-cadherin-dependent barrier, critical for the homeostasis of the organ. Compromised barriers of the colonic epithelium lead to inflammation, fibrosis, and are commonly observed in colorectal cancer. In addition to its architectural role, E-cadherin is also considered a tumor suppressor in the colon, primarily a result of its opposing function to Wnt signaling, the predominant driver of colon tumorigenesis. Beyond these well-established traditional roles, several studies have portrayed an evolving role of E-cadherin as a signaling epicenter that regulates cell behavior in response to intra- and extra-cellular cues. Intriguingly, these recent findings also reveal tumor-promoting functions of E-cadherin in colon tumorigenesis and new interacting partners, opening future avenues of investigation. In this Review, we focus on these emerging aspects of E-cadherin signaling, and we discuss their implications in colon biology and disease.
The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells. Here, we demonstrate that the localization of the core RNAi components is specific and predominant at apical areas of cell-cell contact of human normal colon epithelial tissues and normal primary colon epithelial cells. Importantly, the apical junctional localization of RNAi proteins is disrupted or lost in human colon tumors and in poorly differentiated colon cancer cell lines, correlating with the dysregulation of the adherens junction component PLEKHA7. We show that the restoration of PLEKHA7 expression at adherens junctions of aggressively tumorigenic colon cancer cells restores the junctional localization of RNAi components and suppresses cancer cell growth in vitro and in vivo. In summary, this work identifies the apical junctional localization of the RNAi machinery as a key feature of the differentiated colonic epithelium, with a putative tumor suppressing function.
The extracellular matrix (ECM) plays crucial roles in tissue homeostasis. Abnormalities in ECM composition are associated with pathological conditions, such as fibrosis and cancer. These ECM alterations are sensed by the epithelium and can influence its behavior through crosstalk with other mechanosensitive complexes, including the adherens junctions (AJs). We have previously shown that the AJs, through their component PLEKHA7, recruit the RNAi machinery to regulate miRNA levels and function. We have particularly shown that the junctional localization of RNAi components is critical for their function. Here, we investigated whether different ECM substrates can influence the junctional localization of RNAi complexes. To do this, we plated colon epithelial Caco2 cells on four key ECM substrates found in the colon under normal or pathogenic conditions, namely laminin, fibronectin, collagen I, and collagen IV, and we examined the subcellular distribution of PLEKHA7, and of the key RNAi components AGO2 and DROSHA. Fibronectin and collagen I negatively impacted the junctional localization of PLEKHA7, AGO2, and DROSHA when compared to laminin. Furthermore, fibronectin, collagen I, and collagen IV disrupted interactions of AGO2 and DROSHA with their essential partners GW182 and DGCR8, respectively, both at AJs and throughout the cell. Combinations of all substrates with fibronectin also negatively impacted junctional localization of PLEKHA7 and AGO2. Additionally, collagen I triggered accumulation of DROSHA at tri-cellular junctions, while both collagen I and collagen IV resulted in DROSHA accumulation at basal areas of cell–cell contact. Altogether, fibronectin and collagens I and IV, which are elevated in the stroma of fibrotic and cancerous tissues, altered localization patterns and disrupted complex formation of PLEKHA7 and RNAi components. Combined with our prior studies showing that apical junctional localization of the PLEKHA7-RNAi complex is critical for regulating tumor-suppressing miRNAs, this work points to a yet unstudied mechanism that could contribute to epithelial cell transformation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.