HDAC-Linked “Proliferative” miRNA Expression Pattern in Pancreatic Neuroendocrine Tumors

Abstract

Epigenetic factors are essentially involved in carcinogenesis, tumor promotion, and chemoresistance. Two epigenetic key players are miRNAs and histone deacetylases (HDACs). As previously shown by own theoretical databank analysis, the crosstalk between miRNAs and HDACs is relevant in different human chronic diseases and cancerogenic pathways. We aimed to investigate a potential connection between the expression of a well-defined subset of “proliferation-associated” miRNAs and the expression of HDACs as well as clinical parameters in pancreatic neuroendocrine tumors (pNETs). Materials and Methods: Expression levels of miRNA132-3p, miRNA145-5p, miRNA183-5p, miRNA34a-5p, and miRNA449a in 57 pNETs resected between 1997 and 2015 were measured and linked to the immunohistochemical expression pattern of members of the four HDAC classes on human tissue microarrays. All pNET cases were clinically and pathologically characterized according to published guidelines. Correlation analysis revealed a significant association between expression of specific miRNAs and two members of the HDAC family (HDAC3 and HDAC4). Additionally, a linkage between miRNA expression and clinico-pathological parameters like grading, TNM-staging, and hormone activity was found. Moreover, overall and disease-free survival is statistically correlated with the expression of the investigated miRNAs. Overall, we demonstrated that specific miRNAs could be linked to HDAC expression in pNETs. Especially miRNA449a (associated with HDAC3/4) seems to play an important role in pNET proliferation and could be a potential prognostic factor for poor survival. These first data could help, to improve our knowledge of the complex interactions of the epigenetic drivers in pNETs for further therapeutic approaches.

Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

“…Each of the approximately 1800 human miRNAs may have regulatory roles in multiple cell signaling pathways, and some mediate and/or their expression correlates with oncogenesis. Oncogenic miRNAs are linked to several pro-tumorigenic processes, such as apoptosis resistance, cell proliferation, chemoresistance, and EMT, depending on the function of their respective target mRNAs [42]. miRNAs can function as both oncogenes and tumor suppressor genes [43][44][45][46][47][48].…”

Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns

“…Expression levels of proliferation associated miRNAs and immunohistochemical expression patterns of members of the four HDAC classes were published recently for a large subset of the pNEN cases [ 13 ]. No significant correlations of TPM with TC and the expression of epigenetic factors were assessed ( Table 3 ).…”

“…This retrospective study examined the TPM status and TL of FFPE tissue from 58 patients diagnosed with sporadic pNEN and compared the results with clinicopathological parameters and available miRNA and HDAC expression profiles [ 13 ].…”

“…Here we analyzed the TPM status at hot spots C250T and C228T of a patient cohort diagnosed with sporadic pNEN, which was recently studied for expression of epigenetic factors, such as proliferation-associated miRNAs and expression of histone deacetylases (HDACs) [ 13 ]. TPMs were detected in pNENs with varying T allele frequencies and were found associated with parameters for tumor progression, with higher telomere content and changes in miRNA/HDAC expression.…”

Multiple Endocrine Neoplasia Type 1: The Potential Role of microRNAs in the Management of the Syndrome

“…The crosstalk between miRNAs and chromatin remodeling is suspected to be relevant in cancerogenic pathway. In this light, Klieser et al [ 54 ] investigated a potential linkage between the expression levels of a specific subset of “proliferation-associated” miRNAs (miR-132-3p, miR-145-5p, miR-183-5p, miR-34a-5p, and miR-449a) and the expression of histone deacetylases (HDACs), as well as the clinical and biological features in 57 pNET samples. miRNAs ranked in descending order of expression levels were miR-145-5p, miR-34a-5p, miR-132-3p, miR-183-5p, and miR-449a.…”