The Emerging Role of SOX2 in Cell Proliferation and Survival and Its Crosstalk with Oncogenic Signaling in Lung Cancer

Abstract

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer. STEM CELLS

Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity

“…Functional analyses by gene knockdown and a chemical inhibitor revealed that ALDH and SOX2 are essential for the proliferation of ovarian CSCs. Of note, both ALDH1A and SOX2 expression contribute to chemo-resistance of ovarian cancer cell lines (35,(43)(44)(45). Therefore, SOX2 and ALDH may mediate its capability to confer chemo-resistance to ovarian CSCs as well as stem cell-related features.…”

Downregulation of miR‐638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC

“…In lung cancer, SOX2 could regulate cancer cells apoptosis through MAP4K4-Survivin signaling pathway [27]. The emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling was identified as a prognosis marker and a therapeutic target [28]. Wnt signaling substantially could impact NSCLC tumorigenesis, prognosis, and resistance to therapy [29].…”

“…In various cancers, SOX2 has been indentified to promote proliferation and invasion [16,17]. Here, we explored whether the functional effect of miR-638 on NSCLC cell lines was dependent on SOX2.…”

Clinicopathological significance of cancer stem-like cell markers in high-grade neuroendocrine carcinoma of the lung

“…Tissue sections were stained overnight at 4 °C with each CSLC marker anti-human antibody (Table 1). We used seven markers that have been reported to be CSLC markers for lung or other solid malignant tumors (Caveolin, Notch, CD44, CD166, SOX2, Aldehyde dehydrogenase 1 [ALDH1], and Musashi1) (Chou et al 2013;Fischer et al 2011;Jiang et al 2009;Kuang et al 2013;Leung et al 2010;Palaniyandi et al 2012;Zhang et al 2012). The slides were subsequently incubated with EnVision™ (DAKO, Glostrup, Denmark) for 1 h at room temperature, and the color reaction developed.…”