SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer

Lundberg, Ida; Edin, Sofia; Eklöf, Vincy; Öberg, Åke; Palmqvist, Richard; Wikberg, Maria L.

doi:10.1186/s12885-016-2509-5

Cited by 86 publications

(72 citation statements)

References 55 publications

(65 reference statements)

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“…Similarly, activation of EGFR also results in overexpression of SNAIL, most likely regulated by the p38 MAPK, ERK1/2 and the AKT/GSK-3b pathways (38). Interestingly, it has been reported that SOX2 and SNAIL play an essential role in the regulation of self-renewal, expansion of CSCs and metastasis in several cancers, including CRC (43,44). Here, we found that ginsenoside Rd inhibited the CSCs maintenance and cell mobility through downregulation of SOX2 and SNAIL as the downstream of EGFR/pAKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis

et al. 2018

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Ginsenoside Rd is a saponin from ginseng and has been reported to have various biological activities. However, the effect of ginsenoside Rd on the metastasis of colorectal cancer (CRC) remains unknown. Here, we found that ginsenoside Rd decreased the colony‐forming ability, migration, invasion, and wound‐healing abilities of CRC cells, although it did not affect cell proliferation. In addition, using an inverse‐docking assay, we found that ginsenoside Rd bound to epidermal growth factor receptor (EGFR) with a high binding affinity, inducing the downregulation of stemness‐ and epithelial‐mesenchymal transition‐related genes; these were partially rescued by either exogenous EGF treatment or ectopic expression of SOX2. Furthermore, ginsenoside Rd significantly decreased the number and size of tumor metastasis nodules in the livers, lungs, and kidneys of mouse model of metastasis. © 2018 IUBMB Life, 71(5):601–610, 2019

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis

et al. 2018

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“…Several studies have shown that CD24 and SOX2 are associated with a more undifferentiated and more cancer stem cell-like phenotype. 7,36,37 Both SOX2 and CD24 have also been linked to an increased therapy resistance. [38][39][40][41] This is in line with our data demonstrating that in melanoma cells an increased expression level of SOX2 or CD24 resulted in a higher tolerance toward BRAFis, while the depletion of SOX2 via KD showed higher sensitivity.…”

Section: Discussionmentioning

confidence: 99%

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

Hüser

Sachindra

Granados

et al. 2018

Intl Journal of Cancer

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Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock-down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock-down or Src/STAT3 inhibition in resistant SOX2-overexpressing cells, the sensitivity toward BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors.

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“…Among them, transcription factor SRY (sexdetermining region Y)-box 2 (Sox2) is a key regulator of the self-renewing capability of CSCs (Boumahdi et al, 2014). Sox2 is overexpressed in various cancers and is associated with cancer progression and poor prognosis Lundberg et al, 2016). In particular, Sox2 is a pivotal prognostic marker that is correlated with the clinical-pathologic characteristics in lung cancer (Chou et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cancer Stem Cell–Suppressing Activity of Chrysotoxine, a Bibenzyl fromDendrobium pulchellum

Bhummaphan

Pongrakhananon

Sritularak

et al. 2017

J Pharmacol Exp Ther

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Cancer stem cells (CSCs) have been recognized as rare populations driving cancer progression, metastasis, and drug resistance in leading cancers. Attempts have been made toward identifying compounds that specifically target these CSCs. Therefore, investigations of novel therapeutic strategies for CSC targeting are required. The cytotoxic effects of chrysotoxine on human non-small cell lung cancer-derived H460 and H23 cells were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of chrysotoxine suppression of CSC-like phenotypes were determined in CSC-rich populations and primary CSCs in three-dimensional (3D) culture and in an extreme limiting dilution assay. Expression of CSC markers and associated proteins was determined by Western blot analyse and flow cytometry. We have reported herein the CSC-suppressing activity of chrysotoxine, a bibenzyl compound isolated from We have shown, to our knowledge for the first time, that chrysotoxine dramatically suppresses CSC-like phenotypes of H460 and H23 cells. Treatment with chrysotoxine significantly reduced the viability of 3D CSC-rich populations and concomitantly decreased known CSC markers. Chrysotoxine suppressed CSC phenotypes through downregulation of Src/protein kinase B (Akt) signaling. Active (phosphorylated Y416) Src was shown to regulate cancer stemness, since ectopic overexpression of Src strongly activated Akt and subsequently enhanced pluripotency transcription factor SRY (sex-determining region Y)-box 2 (Sox2)- mediating CSC phenotypes, whereas the short hairpin RNA of Src and an Src inhibitor (dasatinib) suppressed Akt, Sox2, and CSC properties. Importantly, chrysotoxine was shown to suppress active Src/Akt signaling and in turn depleted Sox2-mediated CSCs. Our findings indicate a novel CSC-targeted role of chrysotoxine and its regulation by Src/Akt and Sox2, which may be exploited for cancer treatment.

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SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer

Cited by 86 publications

References 55 publications

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

Cancer Stem Cell–Suppressing Activity of Chrysotoxine, a Bibenzyl fromDendrobium pulchellum

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