SOX2 Gene Regulates the Transcriptional Network of Oncogenes and Affects Tumorigenesis of Human Lung Cancer Cells

Abstract

Recent studies demonstrated that cancer stem cells (CSCs) have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP) cells than in non-side population (NSP) cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.

Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer

“…This result is in contrast with the previously reported frequency of high-level SOX2 amplification which has previously been found in 27% (15/56) SCLC 27. The presence of SOX2 expression does not appear to relate to prognosis or survival in patients with SCLC 28. There are currently no therapies available to directly target SOX2 amplification in cancer.…”

An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2

“…Other proteins expressed at higher levels in TTF1-negative cohorts including c-Myc, 4EBP1 and EGFR are downstream targets of the transcription factor sex determining region Y-box 2 (SOX2) (39). SOX2 has previously been characterized as both a marker (40) and driver (41, 42) of lung squamous carcinoma where SOX2 amplification is commonly observed and results in increased tumor formation, migration and proliferation through the activation of hedgehog signaling (23).…”

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

“…The expression levels of these transcription factors were quantified in terms of EI and ER, which reflect the level of protein expression and the number of cells expressing a protein, respectively. As high expression levels of CSC-related transcription factors may promote tumorigenesis (31,32), EI may also be a measure of tumor invasiveness and local metastasis. Similarly, as large numbers of CSCs increase the chance that some will maintain stemness when they disseminate to other sites (33), ER may be a measure of the likelihood of distant metastasis.…”