Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma

Abstract

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells.

Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells From Multiple Myeloma Patients By Targeting BMP4 Transcription

“…E) ( p < .01). In accordance with the negative correlation between SOX2 and BMP4 in lung squamous cell carcinoma cells , knockdown of the SOX2 increased BMP4 transcription in MM‐MSCs (Fig. F, 7G) ( p < .01).…”

“…Previous studies revealed that SOX2 could negatively regulate BMP4 promoter activity through binding to the promoter . To elucidate the role of SOX2 in the osteogenic differentiation of MSCs, we determined SOX2 expression during the osteogenic differentiation of MSCs by qPCR.…”

“…The SOX2‐responsive element is resided within the +2,832 to +2,900 region of BMP4 promoter , which bound the same site with MEG3. To examine whether SOX2 is involved in the MEG3‐mediated interaction, we performed ChIP assay.…”

Integration of genomic data analysis for demonstrating potential targets in the subgroup populations of squamous cell lung cancer patients

“…Increased expression of SOX2 has been proposed to maintain some characteristics of cancer cells [33,34]. Knocking-down or downregulation of SOX2 inhibits cancer cell growth and metastatic potential [35][36][37]. The expression of SOX2 is critical to maintain the selfrenewal in embryonic stem cells and neural progenitor cells [38][39][40].…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…Öte yandan, akciğerin skuamöz hücreli karsinomunda, Sox2'nin BMP4 promotoruna bağlaranak onu negatif şekilde düzenlediği ve Sox2 inhibisyonunun, BMP4 protein ifadesini arttırarak, hücre proliferasyonunu arttırdığı gösterilmiştir (62).…”