Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma.
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.
National Institute of Cancer Research, NHRI, Zhunan, Taiwan.
Wen-Tsen
WT
Fang
Chi-Chen
CC
Fan
Shih-Miao
SM
Li
Te-Hsuan
TH
Jang
Hsiu-Ping
HP
Lin
Neng-Yao
NY
Shih
Chung-Hsing
CH
Chen
Tao-Yeuen
TY
Wang
Shiu-Feng
SF
Huang
Alan Yueh-Luen
AY
Lee
Ying-Lan
YL
Liu
Fang-Yu
FY
Tsai
Chih-Ting
CT
Huang
Su Jing
SJ
Yang
Lin-Ju
LJ
Yen
Chih-Pin
CP
Chuu
Chih-Yi
CY
Chen
Chao A
CA
Hsiung
Jang-Yang
JY
Chang
Lu-Hai
LH
Wang
I-Shou
IS
Chang
Shih Sheng
SS
Jiang
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
BMP4; SOX2; lung cancer; lung squamous cell carcinoma