Oncotarget: The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor

Volume 11, Issue 26 of Oncotarget reported that in this study the authors studied the differences in mi RNA expression between sporadic and FAP-associated Desmoid tumors using microarray confirmed by quantitative PCR.

Among them, mi R-133b levels were significantly lower in FAP-associated Desmoid tumors than in sporadic Desmoid tumors. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated Desmoid tumor than in sporadic Desmoid tumor, whereas no differences in ELAVL1 expression was observed between these two Desmoid tumor types.

In addition, a negative correlation was observed between mi R-133b and SIRT1 in FAP-associated Desmoid tumors, but not in sporadic Desmoid tumors The mi R-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated Desmoid tumor.

Figure 1: Comparison of the miRNA expression between microarray and RT-qPCR assay. Comparison of microarray (Log2 Fold-change) and RT-qPCR data (Log2 (2-ΔΔCq)) was determined for each miRNA (n =19). In RT-qPCR assays, ΔΔCq = ΔCq (sporadic DTs) – ΔCq (FAP-associated DTs). The correlation (rho) and p data were determined by non-parametric Spearman’s test where a single point represents the main value of each miRNA.
Credit: Oncotarget

Dr. Maria Teresa Rotelli from The Department of Emergency and Organ Transplantation at The University of Bari “Aldo Moro” in Bari Italy said, “Desmoid tumor (DT) is a rare, mesenchymal benign tumor, characterized by monoclonal, fibroblastic proliferation with local invasiveness, high risk of recurrence and even mortality, despite metastatization never occurs.

Figure 2: miR-133b levels in FAP-associated DT (FAP-DT), Sporadic DT (Spor DT) and GIST. The distribution is represented by a dot blot graph (mean ± SEM). The miRNA values were obtained by RT-qPCR analysis and ΔCt method with U6 for normalization was used. The differences were evaluated by non-parametric Mann–Whitney test and p < 0.05 was considered statistically significant.
Credit: Oncotarget

The CNNTB1 mutations have been found in approximately 85% of DTs by routine Sanger sequencing, however, using a highly sensitive technique like next-generation sequencing, they may account for 90–95% of sporadic DT cases.

In these DTs, the germline mutations in the APC gene are responsible for the nuclear accumulation of β-catenin.

While the risk of death in sporadic DT is low, FAP-associated DTs are the most frequent cause of death in patients with FAP after the colon has prophylactically been removed.

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It must be emphasized that the disruption of the Wnt signaling represents a common pathway in both DT forms, but sporadic and FAP-associated DTs are associated with mutually exclusive molecular alterations.

Figure 3: mRNA levels in two DT subtypes ELAVL1 (ELAV like RNA binding protein 1) and SIRT1 (Silent Mating Type Information Regulation 2 Homolog 1) mRNA levels in FAP-associated DT (FAP-DT) and sporadic DT (Spor DT). The distribution is represented by a dot blot graph (mean ± SEM). The levels were obtained by RT-qPCR analysis and ΔCt method with β-actin for normalization was used. The differences in mRNA expression were evaluated by non-parametric Mann–Whitney test and p < 0.05 was considered statistically significant.
Credit: Oncotarget

In a previous study, the authors have investigated a possible correlation between mi RNA expression and CTNNB1 mutations in sporadic DTs.

The Rotelli Research Team concluded in their Oncotarget Research Paper that the dialog between MSCs and tumor cells in FAP-associated DT tissue microenvironment could lead to β-catenin deacetylation driven by SIRT1, promoting Wnt/β-catenin signaling cascade in this tumor.

Although the number of specimens of FAP-associated DTs used in the present study was limited, it could be speculated that the β-catenin deacetylation process in FAP-associated DTs mimics the stabilization of that protein induced by CTNNB1 gene mutations occurring in sporadic DTs.

“It could be speculated that the β-catenin deacetylation process in FAP-associated DTs mimics the stabilization of that protein induced by CTNNB1 gene mutations occurring in sporadic DTs”

Therefore, in addition to APC gene mutations, the mi R-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying the progression of FAP-associated DT. However, further studies are needed to fully understand the influence of mi R-133b-SIRT1 in the genesis or progression of FAP-associated DT.

Source:

Impact Journals LLC

Journal Reference:

The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor

Abstract:

Signaling pathways have a key role in driving the uncontrolled development of familial adenomatous polyposis (FAP)- associated and sporadic desmoid tumors (DTs).

The relationship between the Wnt/b-catenin signaling pathway and DTs has been extensively studied, but no reliable biomarkers able to detect their histological subtype have been identified for the accurate diagnosis.

In this study we studied the differences in miRNA expression between sporadic (20 patients) and FAP-associated DTs (7 patients) using microarray confirmed by quantitative PCR (qPCR). The analysis showed 19 dysregulated miRNAs. Among them miR-133b levels were significantly lower in FAP-associated DT than in sporadic DT. Therefore, two mRNAs, associated to miR-133b and β-catenin expression, the SIRT1 and ELAVL1were analyzed.

The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated DT than in sporadic DT, whereas no differences in ELAVL1 expression was observed between these two DT types. In addition, a negative correlation was observed between miR-133b and SIRT1 in FAP-associated DTs, but not in sporadic DTs.

The miR-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated DT.

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