RNA-binding proteins as molecular links between cancer and neurodegeneration

Abstract

For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways

“…From the point of view of the neurodegeneration, cell cycle dysregulation could have some significance for neuronal pathology as it has been reported that neurons undergoing degeneration re-enter the cell cycle, leading to apoptosis rather than cellular division, as recently reviewed by Campos-Melo et al. ( 68 ). In addition, the finding that TDP-43 can affect STAG2 splicing also offers a new connection with recent reports that depict its possible role in tumorigenesis, since recent cancer genomics analyses have reported a rather large number of somatic mutations at the level of the core cohesin factors ( SMC1A, SMC3, RAD21 and STAG1/2 ) in a particular subset of human tumours including Ewing sarcoma, an aggressive bone tumour ( 69 ).…”

Physiological functions and pathobiology of TDP‐43 and FUS/TLS proteins

“…Furthermore, RBPs have been discovered to be a molecular link between human disease processes that seem to be very different from each other, such as cancer and neurodegeneration (Campos‐Melo et al . ).…”

“…On the other hand, genes that are mainly involved in DNA/RNA metabolism are more closely associated with ALS phenotype (Hardy and Rogaeva 2014). Furthermore, RBPs have been discovered to be a molecular link between human disease processes that seem to be very different from each other, such as cancer and neurodegeneration (Campos-Melo et al 2014).…”

Elevated FUS/TLS expression is negatively associated with E‑cadherin expression and prognosis of patients with non‑small cell lung cancer

“…The unique functions also include pre-mRNA splicing and DNA repair and recombination (11). Notably, chromosomal rearrangements result in the 5' regions of FET genes being fused with different transcription factor genes in sarcomas or other types of cancer (12)(13)(14). FUS/TLS was identified as a fusion gene with DNA damage inducible transcript 3 (CHOP) (also known as GADD153, DDIT3) in human myxoid liposarcoma with chromosomal translocation t(12; 16)(q13; p11) (15).…”