Clin Exp Otorhinolaryngol.  2023 May;16(2):99-114. 10.21053/ceo.2022.01319.

Research Progress on Non-coding RNAs in Cholesteatoma of the Middle Ear

• Liu D
• zhang H
• Ma X
• Dong Y

• KMID: 2542351
• DOI: http://doi.org/10.21053/ceo.2022.01319

Abstract

Cholesteatoma of the middle ear is a common disease in otolaryngology that is receiving increasing attention. It is estimated that over five million people around the world have suffered from middle ear cholesteatoma. The annual incidence of middle ear cholesteatoma has been reported to be 9.2 per 100,000 in adults and 3 per 100,000 in children. Without timely discovery and intervention, cholesteatomas can become perilously large and damage intratemporal structures, causing various intracranial and extracranial complications. No practical nonsurgical treatments are currently available. Although multiple hypotheses exist, research directions have consistently focused on cell proliferation, apoptosis, and bone destruction. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have recently received increasing attention because of their key roles in gene expression, cell cycle regulation, and the development of many diseases. Although ncRNAs are not involved in protein translation, they are abundant in the genome, with only approximately 2% of genes encoding proteins and the remaining approximately 98% encoding ncRNAs. The purpose of this review is to summarize the current state of knowledge regarding the specific role of ncRNAs in middle ear cholesteatoma.

Keyword

Cholesteatoma of the Middle Ear; CircRNA; MicroRNA; Non-coding RNA

Figure

• 

  Fig. 1 Summary of the main miRNA and molecular mechanisms involved in middle ear cholesteatoma. (A) miR-34a inhibits the proliferation and migration of cholesteatoma cells, promotes the apoptosis of cholesteatoma cells by targeting Bcl-2, Cdk6, cyclin D1, and negatively regulates the PTEN/PI3K/AKT signaling pathway. (B) miR-21, which is a downstream target of CD14, IL-6R, gp130, and STAT3, promotes proliferation and invasion and inhibits apoptosis in cholesteatoma cells by negatively regulating PTEN, PDCD4 and HMGA2. (C) miR-let-7a inhibits cholesteatoma cell proliferation and invasion and promotes their apoptosis, and this biological function might be achieved by negatively regulating miR-21 expression. (D) miR-203a affects p-Akt levels by targeting Bmi1; promoting cholesteatoma proliferation, colony formation, and migration; and inhibiting apoptosis. (E) miR-21-3p and miR-16-1-3p expression are significantly elevated in middle ear cholesteatoma tissues, whereas miR-10a-5p expression is significantly decreased. It is hypothesized that miR-16-1-3p and miRNA-10a-5p might induce cholesteatoma tissue hyperproliferation and regulate cholesteatoma formation through the PI3K-Akt signaling pathway. (F) NF-κB activation by TNF-α, IL-1β, and IL-6 during the development and progression of middle ear cholesteatoma increases miR-802 expression, which in turn promotes cell proliferation, and this is accomplished by downregulating the PTEN/p-AKT pathway. (G) miR-142-5p has a direct negative regulatory effect on CDK5, which is involved in regulating the secretion of inflammatory cytokines, such as TNF-α, TGF-β1, IL-5, IL-6, and IL-17A, in cholesteatomas. (H) Downregulation of exosomal miR-106b-5p derived from cholesteatoma perimatrix fibroblasts promotes angiogenesis via Angpt2 overexpression. miR, microRNA; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PI3K, phosphoinositide 3-kinase; p-Akt, phosphorylated protein kinase B; Bcl-2, B-cell lymphoma-2; Cdk6, cyclin-dependent kinases 6; IL-6R, interleukin 6 receptor; CD14, lipopolysaccharide 14; STAT3, signal transducer and activator of transcription 3; gp130, glycoprotein 130; PDCD4, programmed cell death protein 4; HMGA2, high mobility group AT-hook 2; Bmi1, B cell-specific Moloney murine leukemia virus insertion site 1; TNF, tumor necrosis factor; IL, interleukin; NF-κB, nuclear factor kappa B; CDK5, cyclin-dependent kinase 5; TGF, transforming growth factor; miRNA, microRNA; Angpt2, angiopoietin 2.

• 

  Fig. 2 Summary of the main circRNA/lncRNA and molecular mechanisms involved in middle ear cholesteatoma. (A) hsa_circRNA_104327 and hsa_circRNA_404655 expression is significantly higher and hsa_circRNA_000319 expression is significantly lower in middle ear cholesteatoma than in normal skin tissue. These circRNAs have been found to interact with miRNA-152-5p, miRNA-3664-3p, and miRNA-4436b-5p, respectively, according to the ceRNA hypothesis. (B) hsa_circ_0074491 plays a key role in facilitating cell proliferation, migration, and invasion and repressing cell apoptosis in cholesteatoma through inactivating the PI3K/Akt pathway via competitively binding to miR-22-3p and miR-125a-5p. (C) hsa-circRNA-101458 expression has been confirmed to be significantly lower in cholesteatoma than in epithelial tissues. It could inhibit proliferation by competitively interacting with miR let-7a-3p according to ceRNA network prediction analysis. (D) hsa-circRNA-102747 has been verified to be significantly lower in cholesteatoma by qRT-PCR. According to one hypothesis, circRNA-102747/lncRNA-uc001kfc.1/miR-21-3p/targeted mRNAs might regulate malignant characteristics according to ceRNA network prediction analysis. (E) lncRNA-uc001kfc.1 expression has been confirmed to be significantly lower in cholesteatoma tissues. It is predicted that lncRNA-uc001kfc.1 could regulate the expression of major nodal proteins of the JAK/STAT pathway through miR-21 to alter the proliferative and invasive behavior of cholesteatoma cells. (F) Expression levels of the HOTAIR lncRNA in cholesteatoma tissues are significantly upregulated compared to that in outer ear canal skin tissue. circRNA, circular RNA; miRNA, microRNA; PI3K, phosphoinositide 3-kinase; p-Akt, phosphorylated protein kinase B; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PDCD4, programmed cell death protein 4; HMGA2, high mobility group AT-hook 2; lncRNA, long ncRNA; JAK, Janus kinase; STAT, signal transducer and activator of transcription; ceRNA, competing endogenous RNA; qRT-PCR, quantitative real-time polymerase chain reaction.

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