Hsa‐miR‐139‐5p is a prognostic thyroid cancer marker involved in HNRNPF‐mediated alternative splicing

Abstract

It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow‐up of 96 months. MiRNome profiles correlated with tumor‐specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa‐miR‐139‐5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease‐free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa‐miR‐139‐5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa‐miR‐139‐5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa‐miR‐139‐5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa‐miR‐139‐5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.

Progression Risk Assessment of Post-Surgical Papillary Thyroid Carcinoma Based on Circular RNA-Associated Competing Endogenous RNA Mechanisms

“…RIMS2 was also identi ed to be upregulated in PTC and was potentially regulated by hsa-miR-139-5p. hsa-miR-139-5p was identi ed to be downregulated in the primary tumor and further in PTC metastasis [44]. hsa-miR-139-5p was also able to be sponged by circBACH2 and relieved the suppression of the target gene LMO4 in PTC [45].…”

The Prognostic Value of MicroRNAs in Thyroid Cancers—A Systematic Review and Meta-Analysis

“…Concerning histological subtypes, the most common evaluated was PTC, which was found in 19 studies, followed by medullary thyroid cancer (MTC), assessed in 6 studies [42,53,60,67,68,78] and minimally invasive follicular thyroid cancer (MI-FTC) found in one study [63], respectively. One study included all subtypes of well-differentiated TC (DTC), and one study evaluated patients with poorly differentiated TC (PDTC) [55,56]. From all MTC patients, the average percentage of sporadic MTC ranged from 57% to 89% among individual studies.…”

“…For initial biomarker screening, six studies performed miRNA microarray [42,54,56,64,76,78], one study performed quantitative PCR-based array [63], and one study performed MiRNome sequencing [55], respectively, followed by qualitative reverse transcriptase PCR (qRT-PCR) to validate the results. Conversely, 20 studies identified candidate miRNAs from the literature and performed qRT-PCR after that.…”

“…Conversely, 20 studies identified candidate miRNAs from the literature and performed qRT-PCR after that. The other two studies performed either MiRNome profiling or microarray without subsequent PCR validation [55,56]. The expression of miRNAs was mainly measured in tumor tissues, while five studies examined miRNAs in serum or plasma [62,[73][74][75]78].…”

“…The other two studies used either mir-16 or b-actin as endogenous control [69,73]. Notably, of the studies that set the cut-off values of miRNAs expression, seven studies reported median values [55,58,61,62,72,77,78], and three studies used means [70,71,75]. Two studies set the miRNA threshold by using the receiver operating characteristic (ROC) curve [66,74], and miRNA fold-change was used in one study [56], respectively.…”