Abstract
The TBX2 subfamily (TBXs 2, 3, 4 and 5) transactivates or represses genes involved in lung organogenesis. Yet TBX2 subfamily expression in pathogenesis of non-small cell lung cancer (NSCLC), the most common lung malignancy, remains elusive. We sought to probe the expression profile of the TBX2 subfamily in early phases of NSCLC. Expression of TBX2 subfamily was analyzed in datasets of pan-normal specimens as well as NSCLCs and normal lung tissues. TBX2 subfamily expression in matched normal lungs, premalignant hyperplasias and NSCLCs was profiled by transcriptome sequencing. TBX2 subfamily expression was evaluated in the cancerization field consisting of matched NSCLCs and adjacent cytologically-normal airways relative to distant normal lungs and in a dataset of normal bronchial samples from smokers with indeterminate nodules suspicious for malignancy. Statistical analysis was performed using R. TBX2 subfamily expression was markedly elevated in normal lungs relative to other organ-specific normal tissues. Expression of the TBXs was significantly suppressed in NSCLCs relative to normal lungs (P < 10−9). TBX2 subfamily was significantly progressively decreased across premalignant lesions and NSCLCs relative to normal lungs (P < 10−4). The subfamily was significantly suppressed in NSCLCs and adjacent normal-appearing airways relative to distant normal lung tissues (P < 10−15). Further, suppressed TBX2 subfamily expression in normal bronchi was associated with lung cancer status (P < 10−5) in smokers. Our findings suggest that the TBX2 subfamily is notably suppressed in human NSCLC pathogenesis and may serve as a high-potential biomarker for early lung cancer detection in high-risk smokers.
Highlights
Lung cancer is the leading cause of cancer deaths in the United States and worldwide [1]
We interrogated the expression of the TBX2 subfamily of transcription factors in early phases of human non-small cell lung cancer (NSCLC) pathogenesis
We first found that the four members of the subfamily were preferentially up-regulated in human normal lung tissues as well as consistently suppressed in human lung NSCLCs concomitant with aberrant modulation of various downstream TBX target canonical cancer-associated markers
Summary
Lung cancer is the leading cause of cancer deaths in the United States and worldwide [1]. While screening by low-dose computed tomography was shown to reduce lung cancer mortality, this approach exhibits substantial false positive rates warranting new or complimentary strategies [6]. Limitations in achieving these advances are, in part, due to our lagging knowledge of early (e.g., premalignant) molecular alterations in NSCLC pathogenesis. Earlier studies have pinpointed molecular changes in cytologicallynormal airway epithelium that are shared with the lung tumor itself, a phenomenon referred to as “airway field of injury” [8,9,10] Since they manifest in normal-appearing epithelium, airway field of injury changes are suggested to be highly pertinent to the pathobiology and early clinical management of NSCLC [10]
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