Abstract
Roles for SOX2 have been extensively studied in several types of cancer, including colorectal cancer, glioblastoma and breast cancer, with particular emphasis placed on the roles of SOX2 in cancer stem cell. Our previous study identified SOX2 as a marker in cervical cancer stem cells driven by a full promoter element of SOX2 EGFP reporter. Here, dual-luciferase reporter and mutagenesis analyses were employed, identifying key cis-elements in the SOX2 promoter, including binding sites for SOX2, OCT4 and NF-YA factors in SOX2 promoter. Mutagenesis analysis provided additional evidence to show that one high affinity-binding domain CCAAT box was precisely recognized and bound by the transcription factor NF-YA. Furthermore, overexpression of NF-YA in primitive cervical cancer cells SiHa and C33A significantly activated the transcription and the protein expression of SOX2. Collectively, our data identified NF-YA box CCAAT as a key cis-element in the SOX2 promoter, suggesting that NF-YA is a potent cellular regulator in the maintenance of SOX2-positive cervical cancer stem cell by specific transcriptional activation of SOX2.
Highlights
Tumor growth, metastasis and recurrence are driven by a small sub-population of cancer stem cells (CSCs)[1]
The optimized response element was determined by dual-luciferase reporter assay in SOX2-positive and -negative cervical cells from SiHa isolated by pSOX2/enhanced green fluorescent protein (EGFP) plasmid, and we found that the luciferase activity of reporters containing -1185bp region in SOX2-EGFP + cells was significantly higher than that in SOX2-EGFP- cells regardless of whether there was -1828 downstream or not (Fig 2C, p < 0.05)
We hypothesized that the -1185bp to +1828bp region of the SOX2 promoter may be necessary for transcriptional activation of SOX2 in cervical CSCs
Summary
Metastasis and recurrence are driven by a small sub-population of cancer stem cells (CSCs)[1]. Most CSCs assays have far depended on a variety of different cell surface markers, including CD133, CD44, CD166, CD24 and so on[2]. Surface markers can only be used to isolate the most common CSCs and these markers are often unstable in many somatic cancers[3]. The results obtained with CSCs isolated using the same surface marker are not consistent among laboratories. Due to the instability and scarcity of surface markers in solid tumors, other methodological strategies have been widely explored to identify and isolate CSCs, including nuclear markers[4], side population phenotype[5], sphere formation, and aldehyde dehydrogenase (ALDH) activity assays[6].
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