RNAkines are secreted messengers shaping health and disease

Abstract

Extracellular noncoding RNAs (ncRNAs) have crucial roles in intercellular communications. The process of ncRNA secretion is highly regulated, with specific ncRNA profiles produced under different physiological and pathological circumstances. These ncRNAs are transported primarily via extracellular vesicles (EVs) from their origin cells to target cells, utilising both endocrine and paracrine pathways. The intercellular impacts of extracellular ncRNAs are essential for maintaining homeostasis and the pathogenesis of various diseases. Given the unique aspects of extracellular ncRNAs, here we propose the term 'RNAkine' to describe these recently identified secreted factors. We explore their roles as intercellular modulators, particularly in their ability to regulate metabolism and influence tumorigenesis, highlighting their definition and importance as a distinct class of secreted factors.

Keywords: RNAkine; cancer; extracellular noncoding RNA; metabolism.

Figure 1. RNAkine-mediated metabolic regulatory network.

The diagram illustrates the RNAkine-mediated metabolic regulatory network involving various secreted organs, including the pancreas, adipose tissue, skeletal muscle, and liver, which play critical roles in interorgan communication and metabolic regulation. The pancreas utilises RNAkines to regulate glucose homeostasis. Adipose tissue-secreted RNAkines are involved in regulating insulin sensitivity and glucose homeostasis. Skeletal muscle-secreted RNAkines contribute to the mechanisms underlying the metabolic benefits associated with physical activity. Liver-secreted RNAkines play pathological roles in various types of liver disease and pulmonary inflammation. This figure was generated using BioRender (https://biorender.com/).

Figure 2. RNAkine-mediated crosstalk between malignant cancer cells and nonmalignant cells within the TME.

Cancer cell-secreted RNAkines play crucial roles in various processes of tumorigenesis, including angiogenesis, migration, metastasis, immune envision and metabolic reprogramming. 1) RNAkines regulate EC migration, promoting angiogenesis; 2-3) RNAkines facilitate the formation of a metastatic niche in distant tissues. CAFs can also secrete RNAkines, contributing to the migration and progression of tumour cells, 4) RNAkines induce immune evasion by expanding Tregs and M2 polarisation; 5-6) RNAkines initiate metabolic reprogramming in both adjacent cells and distant organs. This figure highlights the complex RNAkine-mediated interplay between cancer cells and cells within the TME.

Figure 3. Classifications of secreted factors.

In addition to conventional secreted factors, cells also secrete ncRNA molecules (RNAkines). The molecular types of secreted factors are presented in bold, and representative examples or subfamilies, such as chemokines, are listed. This figure provides an overview of the diverse types of secreted factors contributing to intercellular signalling. This figure was created using BioRender (https://biorender.com/)