The Role of Rho/Rho-Kinase Pathway in the Pathogenesis of Cholesteatoma

Abstract

Given Rho-kinase could take essential roles in cell differentiation, the results of this study implicate that down-regulated Rho-kinase could be responsible for the keratinocyte undifferentiation seen in cholesteatoma pathogenesis.

RhoA, ROCK-1, and ROCK-2 Gene Expression and Polymorphisms in Cholesteatoma Patients

“…In our previous study, we demonstrated for the first time that Rho kinase (ROCK-2) protein could be downregulated in the cholesteatoma as demonstrated by Western blotting. 13 In this study, however, we demonstrated that the expression levels of Rho-A, ROCK-1, and ROCK-2 genes were lower in patients with cholesteatoma than in the control group. There was no difference in Rho-A (A/T) and ROCK-1 (G/T) variations in cholesteatoma patients compared to the control indicating that having these variations of both Rho-A and ROCK-1 was not associated with the expression level of Rho-A and ROCK-1.…”

“…The diminished protein level, which was found in our previous study, may be due to the downregulated ROCK-2 gene expression as has been demonstrated in this study. 13 ROCK-1 variant is localized in upstream region of gene; however, ROCK-2 and Rho-A variant are localized in intron of the gene. Variation in the upstream and intron regions can affect the amount of synthesis without changing the structure of the corresponding protein.…”

“…The exact signaling pathway of this communication, as has been reported in our previous study, that diminished activity and expression of Rho-kinase may be responsible for the hyperproliferation and undifferentiation of keratinocytes which are hallmarks of cholesteatoma. 13 Rho kinase belongs to a family of serine/threonine kinases, which is one of numerous targets and an important downstream effector of Rho proteins. 14 There are 2 known isoforms of Rho kinase, that is, ROCK-1 and ROCK-2, which are encoded by separate genes on human chromosomes 18q11 (ROCK-1) and 2p24 (ROCK-2).…”

“…Signaling events downstream of ROCK are responsible for smooth muscle contraction, proliferation, differentiation, migration, apoptosis, changing cell membrane shape, secretory function, extension and retraction of neuron, intercellular divergence, and carcinogenesis. 13 ,17- 20 Chapman et al 21 reported that the presence of a ROCK inhibitor stimulated the proliferation and immortalized human keratinocytes. Existence of a ROCK inhibitor in the medium maintains an indefinite extension of life span, and when the ROCK inhibitor was removed from the medium, cells senescence develops after a few passages.…”

“…In our previous study, we demonstrated for the first time that Rho kinase protein could be downregulated in the cholesteatoma, and keratinocyte undifferentiation could be controlled by this pathway. 13 For this reason, in this study, we aimed to investigate any possible genetic association of Rho and ROCK (ROCK-1 and ROCK-2) genes polymorphism, expression, and cholesteatoma. We studied ROCK-1(G/T) rs35996865, ROCK-2(A/C) rs10178332, and Rho-A(A/T) rs2177268 single-­nucleotide polymorphisms (SNPs) in the blood samples of cholesteatoma and control group patients due to the relatively high minor allele frequencies of these SNPs in the Caucasian population and due to the location of these SNPs within the promoter region, exonic and intronic sites that could potentially impact on ROCK expression and function.…”