PERSPECTIVE published: 02 April 2019 doi: 10.3389/fgene.2019.00281 Interplay Between ncRNAs and Cellular Communication: A Proposal for Understanding Cell-Specific Signaling Pathways Santiago Ramón y Cajal 1,2,3* , Miguel F. Segura 4 and Stefan Hümmer 2,3 1 Department of Pathology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Translational Molecular Pathology, Vall d’Hebron Research Institute, Barcelona, Spain, 3 Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain, 4 Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Barcelona, Spain Intercellular communication is essential for the development of specialized cells, tissues, and organs and is critical in a variety of diseases including cancer. Current knowledge states that different cell types communicate by ligand–receptor interactions: hormones, growth factors, and cytokines are released into the extracellular space and act on receptors, which are often expressed in a cell-type-specific manner. Non-coding RNAs (ncRNAs) are emerging as newly identified communicating factors in both physiological and pathological states. This class of RNA encompasses microRNAs (miRNAs, well- studied post-transcriptional regulators of gene expression), long non-coding RNAs (lncRNAs) and other ncRNAs. lncRNAs are diverse in length, sequence, and structure Edited by: (linear or circular), and their functions are described as transcriptional regulation, Philipp Kapranov, induction of epigenetic changes and even direct regulation of protein activity. They Huaqiao University, China have also been reported to act as miRNA sponges, interacting with miRNA and Reviewed by: Simona Greco, modulating its availability to endogenous mRNA targets. Importantly, lncRNAs may have Policlinico San Donato (IRCCS), Italy a cell-type-specific expression pattern. In this paper, we propose that lncRNA–miRNA Chandrasekhar Kanduri, University of Gothenburg, Sweden interactions, analogous to receptor–ligand interactions, are responsible for cell-type- *Correspondence: specific outcomes. Specific binding of miRNAs to lncRNAs may drive cell-type-specific Santiago Ramón y Cajal signaling cascades and modulate biochemical feedback loops that ultimately determine sramon@vhebron.net cell identity and response to stress factors. Specialty section: Keywords: cancer, cellular communication, cell signaling, long non-coding RNA, microRNA, epigenetics This article was submitted to RNA, a section of the journal INTRODUCTION Frontiers in Genetics Received: 04 January 2019 Cancer is a complex disease and a major cause of death worldwide. Development of neoplastic Accepted: 14 March 2019 disease is a multistep process involving the accumulation of numerous molecular changes. These Published: 02 April 2019 changes impact cellular function within the tumor and its microenvironment, ultimately resulting Citation: in the hallmarks of cancer (Hanahan and Weinberg, 2011). Ramón y Cajal S, Segura MF and To date, most researchers have aimed to define the molecular mechanisms of tumorigenesis Hümmer S (2019) Interplay Between and cancer progression based on the classical gene expression theory – transcription of coding ncRNAs and Cellular Communication: A Proposal for Understanding genes followed by protein synthesis. Following this approach, numerous genetic (e.g., mutations Cell-Specific Signaling Pathways. and genomic aberrations) and epigenetic alterations have been identified to have an association Front. Genet. 10:281. with carcinogenesis (Lengauer et al., 1998; Kagohara et al., 2018). In addition, alterations in doi: 10.3389/fgene.2019.00281 post-transcriptional regulation of gene expression (e.g., splicing), mRNA translation (e.g., miRNAs) Frontiers in Genetics | www.frontiersin.org 1 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication and post-translational protein modification (e.g., phosphory- SMALL NON-CODING RNAS lation) have been reported in almost every type of cancer. When different combinations are taken into consideration, the The group of short ncRNAs consists of microRNAs (miRNAs), potential alterations are almost infinite. However, studies have small interference RNAs (siRNAs), small nucleolar (snoRNAs), mainly been based on around 20,000 protein-coding genes, and Piwi-interacting RNAs (piRNAs) (Zamore and Haley, 2005). corresponding to approximately 2% of the whole transcribed Of these, miRNAs have been best characterized in terms of genome (Bertone et al., 2004; Carninci et al., 2005); the other their function, regulation and role in multiple human diseases transcripts include a large variety of non-coding RNAs (ncRNAs). such as cancer. Initiated by the discovery of the first miRNA, Continuous generation of RNA sequencing (RNAseq) data shows lin-4 in Caenorhabditis elegans (Lee et al., 1993; Wightman that ncRNAs are strongly deregulated in pathological processes – et al., 1993), large research efforts have led to a detailed particularly in multifactorial diseases like cancer (Cipolla et al., characterization of miRNA biogenesis and regulatory functions 2018). Hence, current limitations to deciphering the molecular in recent years (Ambros, 2004; Bartel, 2004; He and Hannon, mechanisms of cancer might be due to the fact that the putative 2004; Ebert and Sharp, 2012). Binding of miRNAs to specific sites implications of a large part of the genome remain undefined. in their target transcripts, called miRNA recognition elements While ncRNA genes were for years considered as an irrelevant (MRE), results in either transcript degradation or translational part the genome there is growing evidence that mammalian cells inhibition (Lee et al., 1993; Shivdasani, 2006). Currently there produce them in their thousands (Bertone et al., 2004; Carninci are just under 2,000 human high-confidence annotated miRNAs et al., 2005). Yet, in the absence of experimental verification (Kozomara et al., 2018), and it is believed that they collectively of their function, most (>95%) of these transcripts are still regulate at least one third of the genome (Hammond, 2015). considered transcriptional noise (Ponjavic et al., 2007). Studies Importantly, gene expression profiling studies have demonstrated dating back to the early 1990s indicated that certain lncRNAs altered miRNA expression in a wide range of human diseases, may have similar functions to common mRNAs (Brannan et al., including cancer. 1990; Brown et al., 1991), and since then, detailed studies on certain well-characterized non-coding transcripts have provided mechanistic insights. However, the variety in their mode of miRNAs AND CANCER action, ranging from protein activity regulation to epigenetic control and regulation of other ncRNAs, implies that we are miRNAs have been shown to participate in cancer throughout the just beginning to understand their importance for a multitude various stages: from tumor origin, to immortalization, metastatic of biochemical and cellular functions. Importantly, the role of steps and interactions with the host tissue (Saliminejad et al., these transcripts in certain tumor types is beginning to become 2018), and they are able to regulate oncogenes and tumor apparent, and lncRNA expression profile has been proposed as suppressor genes. In the clinical setting, miRNA expression a strong prognostic factor (Jiang et al., 2016; Bolha et al., 2017; signatures are emerging as important diagnostic and prognostic Ali et al., 2018). It is therefore conceivable that elucidating the predictors (Cho, 2007; Kong et al., 2012; Hayes et al., 2014; function of lncRNAs in normal cells and their deregulation in Drusco and Croce, 2017). Functional studies clearly support a cancer cells will be one of the next milestones toward a more relevant role of certain miRNAs in cancer. However, a remaining detailed understanding of the molecular mechanisms of cancer. challenge is to understand the exact signaling pathways altered In this review, we propose a new role of ncRNAs in cancer. by miRNA deregulation. Several factors contribute to this This model, analogous to the well-established ligand–receptor complexity: (1) the 30 UTR of a particular target gene contains interactions, proposes intercellular communication via ncRNA multiple MREs; (2) multiple MREs can act either alone or interactions as a fundamental concept in cancer. This model cooperatively and (3) the same miRNA can regulate different could provide a hypothetical basis to explain the different types targets (Doench and Sharp, 2004; Grimson et al., 2007). of biochemical feedback in tissues, which in turn could be linked In addition to cell-type-specific gene expression profiles, to the differing response to drugs in tumors harboring similar deregulation of miRNAs can result in tumor suppressive or genetic alterations, the different sites of tumor metastases, and oncogenic effects in a context-dependent manner (Zhang et al., the activation of different microRNA profiles depending on the 2007). Furthermore, the existence of feedback loops involving tumor type and location. certain transcription factors such as c-Myc, which is both a regulator of miRNA expression and a target of miRNAs, adds yet another layer of complexity to the role of miRNAs in cancer THE NON-CODING TRANSCRIPTOME (Jackstadt and Hermeking, 2015). RNAs comprise a diverse range of molecules. In addition to the well-characterized RNAs with established functions such miRNA TRAFFICKING as coding genes (mRNAs), protein synthesis (rRNAs and tRNAs), or mRNA splicing (snRNAs), a multitude of additional While the main mechanism of action is to control mRNA non-protein-coding RNAs has been described in recent years. stability or translation in the cytoplasm, miRNAs can be found According to their size, ncRNAs are categorized as small in unexpected cellular compartments such as the nucleus, (<200 bp) or long non-coding RNAs (lncRNAs, >200 bp). mitochondria, and endoplasmic reticulum (Leung, 2015). Frontiers in Genetics | www.frontiersin.org 2 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication They are also found in the extracellular space – this was first in the mammalian genome, and can be further categorized described in 2008, when it was proposed that circulating miRNAs into long intergenic ncRNAs (lincRNAs), antisense RNAs may serve as biomarkers of certain cancers (Mitchell et al., (asRNAs), pseudogenes, and circular RNAs (circRNAs) (Quinn 2008). Since then, miRNAs have been discovered in various and Chang, 2016; Lagarde et al., 2017). lncRNAs fulfill a variety extracellular environments including blood (Weber et al., 2010), of functions by interacting with DNA, RNA and proteins, urine (Gidlof et al., 2011), saliva (Park et al., 2009; Patel et al., and they may be described according to their mechanism of 2011), and ascitic fluid (Husted et al., 2011). These findings action toward their interacting molecule as enhancers, decoys, opened up two new fields of investigation on miRNA. First, guides or scaffolds (Wang and Chang, 2011; Fok et al., 2017; as they are easy to detect in body fluids, clinical research has Kopp and Mendell, 2018). focused on the use of extracellular miRNAs as biomarkers as The first unsupervised clustering analysis of individual an alternative, non-invasive method for diagnosis and disease transcripts in different tissues revealed that 78% of lncRNAs monitoring (Duttagupta et al., 2011; Ajit, 2012). Second, because (in comparison to 19% of mRNAs) were expressed in a miRNAs are found in the extracellular space, it was proposed that tissue-specific manner (Cabili et al., 2011). As sequencing they may act not only in the cells in which they are transcribed techniques advanced, this specificity of expression has been but also in neighboring cells. This intriguing idea of horizontal observed at the individual cell level, and even differential transfer of genetic material subsequently gained major attention. cell-to-cell expression has been observed by Lv et al. To date, five non-exclusive mechanisms of miRNA release from (2016); we could confirm this in our own (unpublished) donor cells have been proposed: (i) miRNA bound to RNA- studies in the triple negative breast cancer cell line MB- protein complexes (e.g., in complex with Argonaut) (Arroyo MDA231. In the field of cancer biology, lncRNA expression et al., 2011; Turchinovich et al., 2011); (ii) transport via lipid or profile has recently been proposed as a strong prognostic lipoprotein particles (Rayner and Hennessy, 2013); (iii) vesicles factor and even as a therapeutic target (Chen et al., 2014; shed directly from the plasma membrane (Hunter et al., 2008; Yarmishyn and Kurochkin, 2015). Callis et al., 2009; Shefler et al., 2010; Jaiswal et al., 2012); (iv) Despite the growing catalog of lncRNAs, the majority of vesicles of endosomal origin (exosomes) (Valadi et al., 2007; detected transcription products remain functionally unanno- Skog et al., 2008; Rechavi et al., 2009) and (v) vesicles from tated. Gene function prediction based on sequence homology for apoptotic bodies (Zernecke et al., 2009; Hergenreider et al., protein-coding genes is challenging (Ulitsky, 2016). Therefore, 2012). Currently, the coexistence of these different forms of lncRNA classification requires either specialized computational miRNA transport is supported in the literature, but improved tools or genome-wide functional studies as currently performed biochemical methods and molecular tools with higher temporal by the use of gene knockout techniques (e.g., CRISPERi) (Gilbert and spatial resolution are required to strengthen the evidence et al., 2013; Goyal et al., 2017). (Tkach and Thery, 2016). Many groups have clearly demonstrated that isolated miRNA containing fractions (e.g., exosomes) from donor lncRNAs IN CANCER cells are capable of inducing phenotypic alterations in the recipient cells. However, studies on the underlying Differential expression of lncRNAs has been described in a mechanisms are rare thus far, and basic questions concerning variety of pathological conditions including cardiovascular, the amount of miRNA (signaling-like or enzymatic function) autoimmune, neurodegenerative diseases and particularly in or the type of miRNA [individual or pool of miRNA(s)] cancer (Walsh et al., 2014; Nguyen and Carninci, 2016; Zhang remain unaddressed. et al., 2016; Aune et al., 2017; Bhan et al., 2017; Viereck and Thum, 2017; Wan et al., 2017). The first reported lncRNA with an aberrant expression in cancer was prostate cancer LONG NON-CODING RNAs associated 3 (PCA3) (Bussemakers et al., 1999), which was identified via differential display analysis of transcripts in normal All RNAs longer than 200 nucleotides that are not translated human prostate cancer. PCA3 was the first FDA-approved into proteins are collectively categorized as lncRNAs (Carninci lncRNA-based biomarker for use in clinical practice. Since then, et al., 2005; Guttman et al., 2009; Ponting et al., 2009; Cabili it has proven a useful, non-invasive test for prostate cancer et al., 2011; Derrien et al., 2012; Housman and Ulitsky, (Wei et al., 2014). In subsequent years, many other lncRNAs 2016; Lagarde et al., 2017). Similarly to mRNAs, lncRNAs have been identified as having a highly predictive value in are transcribed by RNA polymerase II and are often subject the diagnosis of different cancers. Among those, deregulated to post-transcriptional modification like 50 capping, 30 poly- expression of the lncRNA HOTAIR, originally described in adenylation and splicing (Quinn and Chang, 2016). Although breast cancer, is associated with cancer progression in 26 less well-studied than miRNAs, several thousand lncRNAs have human tumor types (Gupta et al., 2010; Bhan and Mandal, already been described, and thanks to technical advances in 2015; Teschendorff et al., 2015). Recently, the application of RNAseq techniques and computational prediction methods, next-generation sequencing in a variety of different cancer the total number of lncRNAs identified continues to increase transcriptomes uncovered thousands of lncRNAs with aberrant (Quinn and Chang, 2016; Hon et al., 2017). Solely defined by expression in different cancer types (Huarte, 2015). These their length, lncRNAs constitute the largest class of ncRNAs numbers increase further when single nucleotide polymorphisms Frontiers in Genetics | www.frontiersin.org 3 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication (SNPs) that are associated with cancer are taken into account (Freedman et al., 2011). Regarding metastasis, some lncRNAs have been associated with more aggressive, metastatic tumors and even with cancer cell colonization to specific organ sites (Li et al., 2018). For example, in colorectal carcinoma, expression of the lncRNA CCAT2 correlated with a higher incidence of liver metastasis (Ling et al., 2013). Another example is the association of elevated levels of HOTAIR with a higher incidence of liver metastasis in gastric cancer (Zhang et al., 2015) and with brain metastasis in non-small cell lung carcinoma (Nakagawa et al., 2013). Despite the enormous number of lncRNAs described as having aberrant expression in different cancer types, to date, only a few have been functionally characterized (reviewed in Huarte, 2015); existing studies have identified tumor-suppressor and oncogenic functions of lncRNAs (Prensner and Chinnaiyan, 2011; Huarte, 2015). In many FIGURE 1 | Modified version of the central dogma of molecular biology. The cases, the functional role of these lncRNAs has been linked classical “DNA-RNA-protein” pathway is extended by functional role of ncRNAs. to well-known oncogenic pathways like p53 and c-myc or participating in different steps of classical cancer processes such as epithelial mesenchymal transition (EMT). Functional analysis will probably expand with the recent application of the CRISPR/Cas9 system, which will provide the tools required to study the function of lncRNAs in genome-wide studies. These unsupervised studies will be crucial to functionally annotate the role of lncRNAs in cancer and shed further light on the regulation of the underlying molecular events (Han et al., 2014; Ho et al., 2015). lncRNA AND miRNA INTERPLAY Different lncRNAs are known to interact with DNA, RNA, FIGURE 2 | Competing lncRNAs (ceRNAs) in cancer. LncRNAs can act either and proteins; therefore, the functions of the class of lncRNAs as oncogenes (A) or as tumor suppressor (B) as exemplified by the role UCA1 and CASC2. A detailed literature survey of the reported roles ceRNAs in appear to be pleiotropic, ranging from chromatin remodeling to cancer is summarized in Supplementary Table S1. the regulation of transcription, splicing, and translation (Wang and Chang, 2011; Fok et al., 2017; Kopp and Mendell, 2018). A subclass of lncRNA has recently been shown to regulate gene expression in trans by acting as miRNA “sponges” (Karreth et al., RNA for miR-21 (Figure 2B; Xie et al., 2017). In recent years, 2011; Salmena et al., 2011; Tay et al., 2011; Karreth and Pandolfi, many more ceRNAs have been described in cancer. We have 2013; Su et al., 2013; Yoon et al., 2014; Ulitsky, 2018). These summarized the known lncRNA/miRNA/mRNA combinations lncRNAs belong to a group of RNAs named ceRNA (competitor in Supplementary Table S1. of endogenous RNA) (Tay et al., 2014; Thomson and Dinger, In addition to sequestering miRNAs, lncRNAs have also been 2016; Zhong et al., 2018). While there is no unifying definition of reported to compete with miRNAs by binding directly to mRNAs ceRNAs, their function as miRNA “sponges” minimally requires (Faghihi et al., 2010). miRNAs have been reported to induce their cytoplasmic localization and the presence of MRE in their destabilization of lncRNAs, yet some lncRNAs contain miRNAs sequence. ceRNAs contain MREs for one or multiple miRNAs, precursors (Cui et al., 2016). This suggests a complex interplay and binding is thought to sequester miRNAs and thereby enable between lncRNAs and miRNAs, which ultimately determines translation of endogenous miRNA targets (Figure 1). stability and translation of protein-coding mRNAs. Notably, In recent years, this concept has been described for the recent studies have revealed that ceRNAs have significant roles in expression of different genes involved in tumor progression (de cancer pathogenesis (Cheng et al., 2015; Wang et al., 2016). For Giorgio et al., 2013; Cheng et al., 2015; Wang et al., 2016; example, alterations in the expression of key factors in oncogenic Song et al., 2017). An example of an oncogenic lncRNA is signaling pathways, like BRAF, have been linked to changes UCA1, which controls the availability of miR-18a and thereby in the level of ceRNAs (Ergun and Oztuzcu, 2015; Karreth determines the expression of the oncogene YAP1 (Zhu et al., et al., 2015). We are just starting to understand these complex 2018; Figure 2A). In contrast, the tumor suppressor gene PTEN molecular interactions, their place in functional regulatory is regulated by the lncRNA CCAT2 by acting as a competing networks controlling cellular processes, and their implications in Frontiers in Genetics | www.frontiersin.org 4 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication cancer (Liz and Esteller, 2016; Yang et al., 2016; Cao et al., 2017; Chan and Tay, 2018). PROPOSAL: TISSUE-SPECIFIC INTERPLAY BETWEEN miRNA AND lncRNA SUPPORTS CONTEXT-DEPENDENT CELL SIGNALING Currently, the mechanisms involved in cancer origin and progression have been elaborated according to the alterations found in protein-coding genes, barely 2% of the translated genome. Following this approach, most of the described alterations merge into few biochemical routes such as the PI3K/AKT/mTOR or RAS/MAPK pathways. However, the outcome of these alterations is sometimes tissue-specific and cell-context-dependent. It is, for example, still unclear how certain oncogenic mutations progress to tumor formation only in a particular set of tissues. There are clear examples with germline mutations in genes like adenomatous polyposis coli (APC), cadherin 1 (CDH1), BRCA1, von Hippel-Lindau tumor suppressor (VHL), and ataxia telangiectasia mutated (ATM) which are causative for the development of cancer in specific FIGURE 3 | Proposal on the role of tissue specific ceRNAs in cancer types of tissue (Schneider et al., 2017). Another paradigmatic (A) Tissue specific expression of lncRNAs can induce malignant transformation in cells expressing an equal set of miRNAs and mRNAs. example is the initial good response to specific inhibitors in (B) Tissue specific response to secreted miRNAs dependent on the melanomas harboring the BRAFV600E mutation, compared to the expression profile of lncRNAs. protumor effect of the same inhibitors in colon adenocarcinomas carrying similar BRAF mutations (Prahallad et al., 2012; Sclafani et al., 2013). Finally, the development of metastases in different selectively interact with the target cell receptors and activate types of cancer is often restricted to certain organs (organotropic signaling cascades which ultimately alter the phenotype of the metastasis), and even clonal subpopulations within the primary target cell. miRNAs have been shown to be released into the tumor display preferences for certain organs (Obenauf and extracellular space, and lncRNAs are expressed in an organ-, Massague, 2015). tissue- or cell-type-specific manner. As described above, the Therefore, in addition to the classical oncogenic signaling abundance of lncRNAs may ultimately determine the effect of pathways (PI3K/AKT/mTOR or RAS/MAPK), additional layers miRNAs on the expression of protein-coding genes. Therefore, of regulation must exist, to explain tissue- and organ-specific as occurs in the ligand-receptor model, exposure to the same processes. We hypothesize that these cell-type-specific outcomes miRNA may result in cell-type-specific alterations dependent on may be caused by interplay between lncRNAs and miRNAs. the expression of lncRNAs (Figure 3B). Building on the concept of ceRNAs, the tissue and cell-type- In summary, the interplay between lncRNAs and miRNAs specific expression of lncRNAs might be a key mechanism at an intra- and intercellular level may provide a framework to support tissue-specific regulation of oncogenic signaling for understanding context-specific phenomena in cancer. In the pathways. In this sense, the translational profile (i.e., proteome) following section, we will exemplify these putative mechanisms of miRNA-regulated mRNAs can be controlled by the cell- in two concrete cases. type-specific expression of lncRNAs. Consequently, the interplay between lncRNAs and miRNAs might affect signaling cascades by regulating the abundance of proteins within these pathways in a cell-type-specific manner (Figure 3A). INTRACELLULAR INTERPLAY BETWEEN This core mechanism, acting on the intracellular level, can lncRNAs AND miRNAs – BRAFV600E IN also be extended to communication between different cells. COLON ADENOCARCINOMA VS This is because miRNAs not only act in the cells in which MELANOMA they are transcribed but can also be transferred into different cells (intercellular level). In this regard, the interplay between Transduction of a signal from an activated receptor is dependent miRNAs and lncRNAs suggests many parallelisms to ligand– on the levels of kinases and phosphatases in these pathways and receptor interactions. Ligands like cytokines, hormones and is regulated by positive and negative feedback loops. Alterations growth factors are released as soluble factors by the donor cell, in the stoichiometry of factors involved in signaling cascades Frontiers in Genetics | www.frontiersin.org 5 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication FIGURE 4 | The potential role of lncRNAs in the failure of Vemurafenib in the treatment of colon cancer. Upper panel: BRAFV600E mutation induces malignant transformation in melanoma and colon cancer. Lower panel (left): treatment with Vemurafenib inhibits malignant transformation in melanoma. Bypassing the inhibition of BRAFV600E by Vemurafenib might be prevented by miRNAs (e.g., miR-34a or miR-218a) inhibiting the expression of ARAF (Lal et al., 2011; Agarwal et al., 2015). Lower panel (right): sequestering of the ARAF controlling miRNA(s) by lncRNAs in colon cancer enables the bypass of Vemurafenib inhibition, resulting in malignant transformation. can be crucial for the ultimate cellular effect. A paradigmatic BRAFV600E –bearing tumors with BRAF inhibitors has a good example for such alterations in the same oncogenic pathway response in melanomas, a protumor effect has been described is described for the BRAFV600E mutation. While treatment of in colon adenocarcinomas. It has been proposed that the local Frontiers in Genetics | www.frontiersin.org 6 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication feedback in the different cell-signaling pathways could partly explain this unexpected contradictory effect (Schneider et al., 2017). In this respect, miRNAs have been described as key players in fine-tuning the expression of proteins involved in the Ras/Raf signaling pathway (reviewed in Masliah-Planchon et al., 2016). However, the expression of the majority of these miRNAs is not specific for single tissues; therefore, additional layers of regulation must exist, to explain the different responses. We propose that the tissue-specific interplay between ncRNAs might partly explain the different sensitivity to BRAF inhibitors in colon adenocarcinoma and melanoma harboring the same oncogenic mutation in BRAF (Figure 4). INTERCELLULAR INTERPLAY BETWEEN lncRNAs AND miRNAs – ORGANOTROPIC METASTASIS miRNAs are released into the extracellular space and transferred to target cells. lncRNAs (the “receptors”) show organ-, tissue- and cell-type-specific expression. Binding of miRNAs to lncRNAs (akin to a ligand-receptor complex) occurs via a sequence- specific MRE within the lncRNA. Finally, this interaction results in miRNA sequestration and/or degradation of miRNA or lncRNA. As the ligand-receptor model would predict, these interactions should result in the activation of signaling cascades enabling significant alterations in biochemical and cellular functions. Applying this model to cancer, the mechanisms underlying organotropic metastasis might be explained in part by the interplay between miRNAs and lncRNAs. Even though there is no direct experimental evidence for this hypothesis, there are theoretical possibilities for FIGURE 5 | The potential role of lncRNAs in organotropic metastasis. Cancer cell secreted miRNA (e.g., miR-105 and miR181c prevent the expression of how this interplay could contribute to the development of proteins with barrier function in endothelial cells Zhou et al., 2014; Tominaga site-specific metastasis. et al., 2015). The presence of tissue specific competing lncRNAs can High levels of secreted miRNAs from cancer cells have been sequester those miRNAs (lung and brain), the endothelial barrier is maintained reported for almost all types of tumor cells. Upon arrival of and cancer cells are not able to invade. a disseminated tumor cell to a distant tissue (e.g., lung, bone, or brain), these miRNAs are first taken up by tissue-specific endothelial cells. Transfer of miRNAs to endothelial cells in turn It is tempting to speculate that the interplay between has been shown to alter the expression of proteins required lncRNAs and miRNAs combined with the tissue- or clone- for maintenance of the endothelial barrier (Zhou et al., 2014; specific expression of lncRNAs might favor the formation Tominaga et al., 2015). Therefore, the expression profile of of metastatic niches in an organ- or tissue-specific manner. competing lncRNAs within endothelial cells might determine if However, future detailed studies will be required to prove the barrier function can be sustained in the presence of exogenous this hypothesis. miRNAs, and metastasis will be favored in organs in which ceRNAs are absent (Figure 5). In addition, aberrant expression of lncRNAs has been FUTURE DIRECTIONS reported in different tumor types, and differential cell-to- cell expression has even been observed in certain tumor In our opinion, the continuous accumulation of large amounts of types (Lv et al., 2016). Therefore, the presence of sponging data by RNAseq of whole cancer transcriptomes or extracellular lncRNAs might alter (a) the miRNA secretome of tumor cells, miRNAs might be only partially helpful to move forward. and (b) the responsiveness to secreted miRNAs from other We propose exploring the mechanistic basics in cell-culture- cells. The latter case in particular might account for clonal based systems or even model organisms with a reduced populations of tumor cells with site-specific patterns of metastasis complexity. Models derived from these studies could later be used (Obenauf and Massague, 2015). to predict how the extracellular miRNA composition combined Frontiers in Genetics | www.frontiersin.org 7 April 2019 | Volume 10 | Article 281 Ramón y Cajal et al. ncRNAs in Cellular Communication with a distinct set of intracellular lncRNAs might impact on FUNDING disease progression. In summary, current limitations in our understanding on SRyC acknowledges support from Fondo de Investigaciones the molecular mechanisms of cancer might be due to the fact Sanitarias (FIS; PI17/02247 and PI14/01320), Centro de that, until now, only 2% of the genome has been taken into Investigación Biomédica en Red de Cáncer (CIBERONC; account. Therefore, future studies should aim at expanding our CB16/12/00363), and Generalitat de Catalunya (AGAUR; 2017 current view of cancer by including the role of ncRNAs in SGR 1799 and 2014 SGR 1131). MFS acknowledges support from the interpretation of cancer as a multifactorial disease. The the Instituto de Salud Carlos III (CPII16/00006 and PI17/00564) proposed model, combining lncRNA-miRNA interactions with and the European Regional Development Fund (ERDF). intercellular communication might be particularly helpful in understanding the tissue-specificity of many cancers, hitherto one of the least understood phenomena of cancer. ACKNOWLEDGMENTS The authors thank Trond Aasen for helpful suggestions and DATA AVAILABILITY discussion on the manuscript. The authors apologize to their colleagues whose work could not be cited in this manuscript due Publicly available datasets were analyzed in this study. This data to space limitations. can be found here: https://www.ncbi.nlm.nih.gov/pubmed/. SUPPLEMENTARY MATERIAL AUTHOR CONTRIBUTIONS The Supplementary Material for this article can be found All authors listed have made a substantial, direct and intellectual online at: https://www.frontiersin.org/articles/10.3389/fgene. contribution to the work, and approved it for publication. 2019.00281/full#supplementary-material REFERENCES Brown, C. J., Ballabio, A., Rupert, J. L., Lafreniere, R. G., Grompe, M., Tonlorenzi, R., et al. (1991). A gene from the region of the human X inactivation Agarwal, V., Bell, G. W., Nam, J. W., and Bartel, D. P. (2015). Predicting effective centre is expressed exclusively from the inactive X chromosome. Nature 349, microRNA target sites in mammalian mRNAs. eLife 4:e05005 doi: 10.7554/ 38–44. doi: 10.1038/349038a0 eLife.05005 Bussemakers, M. J., van Bokhoven, A., Verhaegh, G. W., Smit, F. P., Karthaus, Ajit, S. K. (2012). Circulating microRNAs as biomarkers, therapeutic targets, and H. F., Schalken, J. A., et al. (1999). 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