Abstract
BackgroundThe Th1 cell-specific transcription factor TBX21 functions as a regulator of expression of a Th1 cytokine, interferon gamma (IFN-γ). However, the specific function of TBX21 correlated with cancer stemness remains unclear.MethodsUsing univariate and multivariate survival analysis, TBX21was identified as an independent predictive factor and was associated with poor prognosis in 1389 patients with lung adenocarcinoma (LUAD). Its mechanism in the prognosis was explored by functional enrichment analysis and validated in bioexperiments.ResultsIn the training and test sets, TBX21 could classify 1389 LUAD patients into high and low-risk groups with significantly different prognosis (P < 0.01). Its prognostic power was independent of other clinical factors including stage, age, gender and smoking status. Functional studies indicated that downregulating TBX21 in lung cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, the study showed that TBX21 activation transduced a TBX21–IL-4 signaling cascade to promote tumor initiation, tumor growth and expression of stemness markers.ConclusionsThese data demonstrated a key role of TBX21 in the maintenance of cancer stemness and that the TBX21–IL-4 pathway is a crucial factor contributing to lung carcinogenesis.Graphical abstractTBX21 prognostic model correlated with cancer stemness via TBX21-IL-4 pathway in LUAD patients
Highlights
The Th1 cell-specific transcription factor TBX21 functions as a regulator of expression of a Th1 cytokine, interferon gamma (IFN-γ)
Upregulation of TBX21 was associated with poor prognosis of patients with lung adenocarcinoma To investigate Inflammationrelated gene (IRG)’ prognostic role in LUAD, 1027 IRGs (Additional file 1: Table S1) from others’ previous research [20] were firstly evaluated in 1389 LUAD patients from six datasets
We found that patients with high-value expression of TBX21 had significantly higher risk than those with low values (HR = 2.008, 95% Confidence interval (CI) 1.284–3.396, P = 0.003; Fig. 1a)
Summary
The Th1 cell-specific transcription factor TBX21 functions as a regulator of expression of a Th1 cytokine, interferon gamma (IFN-γ). The specific function of TBX21 correlated with cancer stemness remains unclear. Previous studies reported that stemness of cancer stem cells (CSCs) may enable CSCs to metastasize and regrow tumors [7], and can be acquired by nonstem cancer cells as they dedifferentiate in response to multiple stimuli [8, 9] including inflammatory response. Zhao et al Stem Cell Research & Therapy (2018) 9:89 promotes stemness and invasiveness of colon tumor through activation of CSC self-renewal and EMT. Zhao et al [11] reported that a three inflammatory gene model including IL-6, IL-1A and CSF3 could predict survival of diffuse large B-cell lymphoma patients, and patients with high-risk score of this signature had significantly shorter survival than those with low-risk score. The pathway analysis comprised of IRGs could determine genetic risk factors for cancers that might have an underappreciated modest inflammatory component
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