Gene Profiling in Patients with Systemic Sclerosis Reveals the Presence of Oncogenic Gene Signatures

Abstract

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by three pathogenetic hallmarks: vasculopathy, dysregulation of the immune system, and fibrosis. A particular feature of SSc is the increased frequency of some types of malignancies, namely breast, lung, and hematological malignancies. Moreover, SSc may also be a paraneoplastic disease, again indicating a strong link between cancer and scleroderma. The reason of this association is still unknown; therefore, we aimed at investigating whether particular genetic or epigenetic factors may play a role in promoting cancer development in patients with SSc and whether some features are shared by the two conditions. We therefore performed a gene expression profiling of peripheral blood mononuclear cells (PBMCs) derived from patients with limited and diffuse SSc, showing that the various classes of genes potentially linked to the pathogenesis of SSc (such as apoptosis, endothelial cell activation, extracellular matrix remodeling, immune response, and inflammation) include genes that directly participate in the development of malignancies or that are involved in pathways known to be associated with carcinogenesis. The transcriptional analysis was then complemented by a complex network analysis of modulated genes which further confirmed the presence of signaling pathways associated with carcinogenesis. Since epigenetic mechanisms, such as microRNAs (miRNAs), are believed to play a central role in the pathogenesis of SSc, we also evaluated whether specific cancer-related miRNAs could be deregulated in the serum of SSc patients. We focused our attention on miRNAs already found upregulated in SSc such as miR-21-5p, miR-92a-3p, and on miR-155-5p, miR 126-3p and miR-16-5p known to be deregulated in malignancies associated to SSc, i.e., breast, lung, and hematological malignancies. miR-21-5p, miR-92a-3p, miR-155-5p, and miR-16-5p expression was significantly higher in SSc sera compared to healthy controls. Our findings indicate the presence of modulated genes and miRNAs that can play a predisposing role in the development of malignancies in SSc and are important for a better risk stratification of patients and for the identification of a better individualized precision medicine strategy.

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

“…Common features may be observed in cancer and scleroderma, with common actors promoting disease development. Strikingly, a recent gene profiling study revealed oncogenic gene patterns in SSc (77). As abovementioned, the implication of EMT in both diseases is particularly interesting and may originate from common genetic and epigenetic alterations, involving telomere shortening, chromosomal instability, senescence, increased proliferation rates, immune deregulation, and impaired cell metabolism.…”

“…Third, numerous microRNAs, including miR-21, miR-29 family and let-7d, have been reported to play key roles in the pathogenesis of cancer and fibrosis, and could even represent potential therapeutic targets in both diseases (77). In SSc, their effects concern collagen gene expression in fibroblasts, collagen degradation, thus extracellular matrix remodeling, apoptosis, and epithelial-mesenchymal transition.…”

“…Thus, an imbalance between these two mediators might contribute to fibrosis. Other miRNAs strongly involved both in cancer and fibrosis are miR-16 (77) and let-7d. The latter is considered as a key regulator of cell proliferation and can act as a tumor suppressor (103).…”

“…Signal transduction pathways may also be shared by cancer and fibrosis, as highlighted by the recent gene profiling study by Dolcino et al revealing oncogenic signature in SSc patients, involving numerous well-known oncogenic proteins such as Ras, janus kinase (jak), Avian Myelocytomatosis Viral Oncogene Homolog (c-myc), B-cell lymphoma (bcl-2), Myeloid differentiation primary response 88 (myd88), poly(ADP-ribose) polymérase (PARP), and the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway (77). Interestingly, the transcription factor Fra (Fos-related antigen) is also involved both in breast cancer (108) and in scleroderma (109).…”

The contribution of epigenetics to the pathogenesis and gender dimorphism of systemic sclerosis: a comprehensive overview

“…Another miRNA which has been found to be overexpressed in the serum, affected skin and explanted fibroblasts from SSc patients is miR-155. [85][86][87] Moreover, it has recently been demonstrated that in SSc fibroblasts the activation of the NOD, LRR and pyrin domain-containing 3 (NLRP3) inflammasome drives miR-155 expression via IL-1 autocrine signaling, that further enhances IL-1 transcription leading to increased collagen production and consequent fibrosis. 87 Besides collagen, miRNAs are also thought to contribute to the regulation of other SSc-related molecules or cytokines.…”