High expression of KITLG is a new hallmark activating the MAPK pathway in type A and AB thymoma

Abstract

BackgroundKIT proto‐oncogene ligand (KITLG) is a pleiotropic factor which is found in diverse cancers and is involved in cell proliferation, differentiation, and survival. However, the value of KITLG in thymoma remains unclear.MethodsA total of 121 thymoma samples from The Cancer Genome Atlas Thymoma (TCGA‐THYM) dataset were used to analyze KITLG related genome‐wide expression profiles, and microRNA profiles and methylation alterations and a GEO dataset‐GSE29695, including 37 samples was used as verification. For cell‐based studies, specific small interfering RNA targeting KITLG or a KITLG overexpression vector were used to clarify the changes of the MAPK pathway in an AB thymoma cell line Thy0517.ResultsBoth datasets showed that high expression of KITLG was significantly associated with type A and AB thymoma. Through multiomic analysis of the TCGA‐THYM, it was found that with the high expression of KITLG, there were 220 upregulated and 72 downregulated genes at the mRNA level, 79 positive and 78 negative miRNAs, 28 hypermethylation and 163 hypomethylation regions. In the thymoma cell line Thy0517, it was found that the expression of GRB2 and the phosphorylation levels of BRAF, MEK1/2, and ERK1/2 in the MAPK pathway were positively correlated with the change in KITLG.ConclusionsHigh expression of KITLG is a new hallmark of WHO type A and AB thymomas in which it might play a critical role through the activation of the MAPK signaling pathway. Additionally, it is hoped that KITLG will become a potential target for the diagnosis of type A and AB thymoma through further research in the future.Key pointsSignificant findings of the studyKIT proto‐oncogene ligand (KITLG) is a new hallmark of type A and AB thymomas which induce a series of aberrant alteration of mRNA, miRNA and DNA methylation. The expression of KITLG is significantly higher in type A and AB than other subtypes of thymoma.What this study addsKITLG activated the MAPK signaling pathway to promote type A and AB thymoma which might be a potential diagnostic biomarker or target.

Identification of Molecular Characteristics and New Prognostic Targets for Thymoma by Multiomics Analysis

“…ERK 1/2 is also an effective target for anticancer [ 25 ]. Studies have shown that MAPK signal and ERK 1/2 were significantly activated in thymoma [ 26 ]. TGF- β inhibited apoptosis and had reduced expression of IFN- γ in effector cell, a key mediator of antitumor immunity [ 27 ].…”

Exploring the biological behavior and underlying mechanism of KITLG in triple-negative breast cancer

“…Moreover, Elevated expression of KITLG has been associated with the pathological advancement of various malignancies, such as neurofibromatosis [21], glioma, and papillary thyroid carcinoma [14]. Furthermore, KITLG is now considered characteristic of WHO AB thymoma, potentially signifying a novel marker for differentiating WHO AB thymoma from other thymic tumors [22]. Recent investigations suggest that KITLG inhibits cancer through the induction and Amplification of multiple signaling pathways [23][24][25].…”

Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations

“…Importantly, DNA methylation levels seem to significantly correlate with overall and relapse-free survival in patients with TEN, thus representing a significant prognostic factor. All in all, both non-coding RNAs and DNA methylation levels could be regarded as potential epigenetic biomarkers in terms of accurate patient stratification in low versus high risk TEN, effective recurrence probability prediction and, most importantly, overall patient survival, with a great number of studies incorporating hundreds of samples from datasets, such as the TCGA, and providing reliable and reproducible data that prove the role of epigenetic modifications in TEN pathogenesis and prognosis [ 31 , 36 , 39 , 60 ]. Interestingly, HDACIs seem to represent promising epigenetic therapeutic agents with potent antitumor effects in TEN.…”

“…Interestingly, the positive correlation between promoter DNA methylation and GAD1 expression in TEN was attributed to the inhibition of a Polycomb repressive complex 2 (PRC2) by the methylation of CCCTC-binding factor (CTCF) −3, with H3K27me3 levels markedly reduced at the GAD1 promoter. Through multiomic analysis of the TCGA, Yang et al reported that KIT proto-oncogene ligand (KITLG) represents a new hallmark of type A and AB thymomas by inducing aberrant alterations of mRNA, miRNA and DNA methylation [ 60 ].…”