Abstract
BackgroundAmplifications of the transcription factor, SRY (sex determining region Y)-box 2 (SOX2), are common in non-small cell lung cancer (NSCLC). SOX2 signaling is important in maintaining the stem cell-like phenotype of cancer cells and contributes to the pathogenesis of lung cancer. TP53 is known to inhibit gene amplifications and to repress many stem cell-associated genes following DNA damage. The aim of this study was to investigate if TP53 mutational status affected SOX2 copy number variation and gene expression in early-stage NSCLC patients; moreover, to assess if TP53 regulates SOX2 expression in human lung cancer cells.Methods258 early-stage lung cancer patients were included in the study. Exons 4–9 in the TP53 gene were sequenced for mutations in tumor tissues. SOX2 copy number as well as TP53 and SOX2 gene expression were analyzed in tumor and in adjacent non-tumorous tissues by qPCR. TP53 and SOX2 were silenced using gene-specific siRNAs in human lung adenocarcinoma A427 cells, and the expression of TP53, SOX2 and subset of selected miRNAs was analyzed by qPCR. The odds ratios (ORs) for associations between copy number variation and lung cancer were estimated by conditional logistic regression, and the correlation between gene status and clinicopathological characteristics was assessed by Chi-square or Fisher’s exact test. Gene expression data was analyzed using nonparametric Mann–Whitney test.ResultsTP53 mutations were associated with an increased risk of acquiring a SOX2 copy number alteration (OR = 2.08, 95 % CI: 1.14–3.79, p = 0.017), which was more frequently occurring in tumor tissues (34 %) than in adjacent non-tumorous tissues (3 %). Moreover, SOX2 and TP53 expression levels were strongly correlated in tumor tissues. In vitro studies showed that a reduction in TP53 was associated with decreased SOX2 expression in A427 cells. Furthermore, TP53 knockdown reduced the miRNA hsa-miR-145, which has previously been shown to regulate SOX2 expression.ConclusionsTP53 signaling may be important in the regulation of SOX2 copy number and expression in NSCLC tumors, and the miRNA hsa-miR-145-5p may be one potential driver. This prompts for further studies on the mechanisms behind the TP53-induced regulation of SOX2 expression and the possible importance of hsa-miR-145 in lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2061-3) contains supplementary material, which is available to authorized users.
Highlights
Amplifications of the transcription factor, SRY-box 2 (SOX2), are common in non-small cell lung cancer (NSCLC)
Amplifications of >5 copies were observed in 15 of 81 tumors with a SOX2 amplification (Fig. 1b), and SOX2 copy number alterations were most frequent in squamous cell carcinoma (Fig. 1c)
We suggest a possible role of hsa-miR-145 as an inducer of SOX2 expression in NSCLC
Summary
Amplifications of the transcription factor, SRY (sex determining region Y)-box 2 (SOX2), are common in non-small cell lung cancer (NSCLC). The aim of this study was to investigate if TP53 mutational status affected SOX2 copy number variation and gene expression in early-stage NSCLC patients; to assess if TP53 regulates SOX2 expression in human lung cancer cells. Alterations in the TP53 gene are among the most significant genetic events in lung cancers [6], often occurring as a response to DNA damage caused by exposure to a variety of genotoxic agents such as polycyclic aromatic hydrocarbons (PAHs) [7]. Mutations in the TP53 gene increase the risk for chromosomal rearrangements, such as copy number alterations, which are involved in the development and progression of many human malignancies including lung cancer [8]. Amplifications or deletions in the fragile sites harboring important transcription factors may further advance the process of carcinogenesis [9]
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