Cholesteatoma Growth and Proliferation

Abstract

Objectives The goal of this study was to identify novel regulatory mechanisms controlling the growth and proliferation of cholesteatoma. Specifically, the potential role of microRNAs, regulators of protein translation, was studied in cholesteatoma. Study Design This study represents a molecular biological investigation characterizing and comparing microRNA and protein expression in cholesteatoma and normal post-auricular skin. Methods Cholesteatoma and normal skin were taken from patients at the time of surgery. Tissue was processed for RNA and protein extraction. Real-time RT-PCR was used to assess levels of human microRNAs, RT-PCR was used to confirm the presence of upstream regulators, and western blot analyses were used to assess levels of downstream target proteins. Results Among the microRNAs investigated, human microRNA-21 (hsa-mir-21) showed a 4.4-fold higher expression in cholesteatoma as compared to normal skin (p=0.0011). The downstream targets of hsa-mir-21, PTEN and PDCD4, were found to be greatly reduced in 3 of 4 cholesteatoma samples. Proposed upstream regulators of hsa-mir-21 expression (CD14, IL-6R, gp130 and STAT3) were present in all cholesteatoma tissues. Conclusions MicroRNAs represent powerful regulators of protein translation and their dysregulation has been implicated in many neoplastic diseases. This study specifically identified up-regulation of hsa-mir-21 concurrent with down-regulation of potent tumor suppressor proteins, PTEN and PDCD4. These proteins control aspects of apoptosis, proliferation, invasion and migration. The results of this study were used to develop a model for cholesteatoma proliferation through microRNA dysregulation. This model can serve as a template for further study into potential RNA-based therapies for the treatment of cholesteatoma.

Microarray Analysis of Differentially-expressed MicroRNAs in Acquired Middle Ear Cholesteatoma

“…In fact, researches on miRNA functions in the etiopathogenesis of middle ear cholesteatoma are rare so far, and the current researches mainly focus on miRNA-21, miRNA let-7a, and miRNA-802. Friedland et al and Chen et al 12 , 13 detected the potential role of miRNA-21 in regulating growth and proliferation in acquired cholesteatoma. They postulated that the up-regulation of miRNA-21 could lead to suppression of PTEN and PDCD4, resulting in cholesteatoma keratinocytes proliferation and invasion.…”

Long noncoding RNAs show differential expression profiles and display ceRNA potential in cholesteatoma pathogenesis

“…Cytokines are also supposed to play important roles in the aggressive behavior of cholesteatoma ( 6 ). In addition to those inflammatory mediators and growth factors, aberrant expression of regulatory microRNAs (miRNAs), the best-studied non-coding RNAs (ncRNAs), play a role in cholesteatoma formation ( 7 – 10 ). However, due to a complementarity of merely 6 base pairs (bp) nt can be sufficient for target recognition, a miRNA can regulate hundreds of mRNAs, and correspondingly, a mRNA can be regulated by several miRNAs ( 11 ), leading to the difficulties encountered when clarifying the molecular mechanisms underlying cholesteatoma.…”

Association of microRNA 146 with middle ear hyperplasia in pediatric otitis media

“…[6] miRNAs have been shown to be involved nearly every biological process and have recently been implicated in a variety of otologic pathologies including OM. [2–5]…”