Role of noncoding RNAs in pancreatic ductal adenocarcinoma associated cachexia

Abstract

Cachexia is an acute syndrome that is very commonly observed in patients with cancer. Cachexia is the number one cause of death in patients with metastatic disease and is also the major factor for physical toxicity and financial burden. More importantly, the majority of patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) cancer undergo cachexia. Pancreatic cancer causes deaths of ∼50,000 Americans and about 400,000 people worldwide every year. The high mortality rates in metastatic PDAC are due to systemic pathologies and cachexia, which quickens death in these patients. About 90% of all patients with PDAC undergo wasting of muscle causing mobility loss and leading to a number of additional pathological conditions. PDAC-associated cancer cachexia emanates from complex signaling cues involving both mechanical and biological signals. Tumor invasion is associated with the loss of pancreatic function-induced digestive disorders and malabsorption, which causes subsequent weight loss and eventually promotes cachexia. Besides, systemic inflammation of patients with PDAC could release chemical cues (e.g., cytokine-mediated Atrogin-1/MAFbx expression) that participate in muscle wasting. Our understanding of genes, proteins, and cytokines involved in promoting cancer cachexia has evolved considerably. However, the role of epigenetic factors, particularly the role of noncoding RNAs (ncRNAs) in regulating PDAC-associated cachexia is less studied. In this review article, the most updated knowledge on the various ncRNAs including microRNAs (miRs), long noncoding RNA (lncRNAs), piwi interacting RNAs (PiwiRNAs), small nucleolar RNA (snoRNAs), and circular RNAs (circRNA) and their roles in cancer cachexia are described.

Keywords: cachexia; muscle wasting; noncoding RNA; pancreatic cancer; tissue biopsy.

Graphical abstract

Figure 1.

Overview of noncoding RNAs (ncRNAs). Among ncRNAs, ribosomal RNA (rRNA), and transfer RNA (tRNA) are most abundant. Other ncRNAs can be categorized based on their size. Small ncRNA consists of <200 nucleotides (nt), whereas long ncRNA consists of more than 200 nt. The ncRNA further can be divided into linear (long ncRNA or lncRNA) and circular (circRNA) types. Small ncRNA such as microRNA (miRNA), guide RNA (gRNA), small interfering RNA (siRNA), small nucleolar RNA (snoRNA) plays a regulatory function. Small nuclear RNA (snRNA) shown to perform a functional role in a cell. The figure created with BioRender.com.

Figure 2.

Noncoding RNAs involved in pancreatic cancer associated cachexia. Secretory microvesicles from pancreatic cancer cells are enriched in miR-21 causing death to myoblast via a currently unknown mechanism that leads to muscle wasting. Micro RNA miR-155 is highly overexpressed in patients with cachexia, which regulate TNF-α leading to muscle wasting via modulation of several downstream molecules. Pancreatic tumor cells release IL-6, which in turn inhibit miR-497. MiR-497 is associated with skeletal muscle hypertrophy via induction of its target genes Igf1r, Insr, and Pik3r1. MiR-373 causes AKT and STAT5 phosphorylation by inhibiting PHLPP2. This results in upregulation of TGF-β and promotes muscle wasting. Circular RNA circANAPC7 acts as a sponge for miR-373, however, in pancreatic cancer this circular RNA is downregulated. Dashed line indicates multiple currently unknown steps; arrows indicate promotion; and blunt ended lines indicate inhibition. TNF, tumor necrosis factor.