Interplay Between ncRNAs and Cellular Communication: A Proposal for Understanding Cell-Specific Signaling Pathways

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 (linear or circular), and their functions are described as transcriptional regulation, induction of epigenetic changes and even direct regulation of protein activity. They have also been reported to act as miRNA sponges, interacting with miRNA and modulating its availability to endogenous mRNA targets. Importantly, lncRNAs may have a cell-type-specific expression pattern. In this paper, we propose that lncRNA–miRNA interactions, analogous to receptor–ligand interactions, are responsible for cell-type-specific outcomes. Specific binding of miRNAs to lncRNAs may drive cell-type-specific signaling cascades and modulate biochemical feedback loops that ultimately determine cell identity and response to stress factors.

Cancer is a complex disease and a major cause of death worldwide. Development of neoplastic disease is a multistep process involving the accumulation of numerous molecular changes. These changes impact cellular function within the tumor and its microenvironment, ultimately resulting in the hallmarks of cancer

To date, most researchers have aimed to define the molecular mechanisms of tumorigenesis and cancer progression based on the classical gene expression theory – transcription of coding genes followed by protein synthesis.

However, studies have mainly been based on around 20,000 protein-coding genes, corresponding to approximately 2% of the whole transcribed genome (Bertone et al., 2004; Carninci et al., 2005); the other transcripts include a large variety of non-coding RNAs (ncRNAs). Continuous generation of RNA sequencing (RNAseq) data shows that ncRNAs are strongly deregulated in pathological processes – particularly in multifactorial diseases like cancer (Cipolla et al., 2018). Hence, current limitations to deciphering the molecular mechanisms of cancer might be due to the fact that the putative implications of a large part of the genome remain undefined.

While ncRNA genes were for years considered as an irrelevant part the genome there is growing evidence that mammalian cells produce them in their thousands

in the absence of experimental verification of their function, most (>95%) of these transcripts are still considered transcriptional noise

the variety in their mode of action, ranging from protein activity regulation to epigenetic control and regulation of other ncRNAs, implies that we are just beginning to understand their importance for a multitude of biochemical and cellular functions.

It is therefore conceivable that elucidating the function of lncRNAs in normal cells and their deregulation in cancer cells will be one of the next milestones toward a more detailed understanding of the molecular mechanisms of cancer.

In summary, current limitations in our understanding on the molecular mechanisms of cancer might be due to the fact that, until now, only 2% of the genome has been taken into account. Therefore, future studies should aim at expanding our current view of cancer by including the role of ncRNAs in the interpretation of cancer as a multifactorial disease.

Here’s a clear example of the shamefully negative consequences of the dogmatic reductionist approach to research influenced by the close-mindedness associated with some Darwinian ideas.