Sox2 Gene Amplification Significantly Impacts Overall Survival in Serous Epithelial Ovarian Cancer

Belotte, J; Fletcher, N.M.; Alexis, Mitchell; Morris, Robert T.; Munkarah, Adnan; Diamond, Michael P.; Saed, Ghassan M.

doi:10.1177/1933719114542021

Cited by 33 publications

(30 citation statements)

References 80 publications

(113 reference statements)

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“…We investigated whether current clinical data in the TCGA database could corroborate this finding and we found that indeed, SOX2, but not OCT4 or NANOG, is significantly higher in tumors that were recurrent. These data are also in alignment with other studies showing that SOX2 is associated with worse overall survival of serous epithelial ovarian cancer [54][55][56]. Although additional studies are required to confirm SOX2 as a bona-fide TIC marker, our data confirms previous studies establishing SOX2 in spheroid formation and tumor initiation [19,24] and indicates SOX2 is strongly correlated with a TIC phenotype and may serve as a more reliable marker of ovarian TICS with high relapse potential.…”

Section: Discussionsupporting

confidence: 91%

Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Robinson

Gilbert

Waters

et al. 2020

Preprint

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Identification of tumor initiating cells (TICs) has traditionally relied on expression of surface markers such as CD133, CD44, and CD117 and enzymes such as aldehyde dehydrogenase (ALDH). Unfortunately, these markers are often cell type specific and not reproducible across patient samples. A more reliable indication of TICs may include elevated expression of stem cell transcription factors such as SOX2, OCT4, and NANOG that function to support long-term self-renewal, multipotency, and quiescence. RNA-sequencing studies presented here highlight a potential role for SOX2 in cell cycle progression in cells grown as 3-D spheroids, which are more tumorigenic and contain higher numbers of TICs than their 2-D monolayer cultured counterparts. SOX2, OCT4, and NANOG have not been comprehensively evaluated in ovarian cancer cell lines, although their expression is often associated with tumorigenic cells. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and will correlate with chemotherapy resistance, tumor initiation, and expression of traditional TIC markers. To investigate this hypothesis, we evaluated SOX2, OCT4, and NANOG in a panel of eight ovarian cancer cell lines grown as a monolayer in standard 2-D culture or as spheroids in TIC-enriching 3-D culture. Our data show that the high-grade serous ovarian cancer (HGSOC) lines CAOV3, CAOV4, OVCAR4, and OVCAR8 had longer doubling-times, greater resistance to chemotherapies, and significantly increased expression of SOX2, OCT4, and NANOG in TIC-enriching 3-D culture conditions. We also found that in vitro chemotherapy treatment enriches for cells with significantly higher expression of SOX2. We further show that the traditional TIC marker, CD117 identifies ovarian cancer cells with enhanced SOX2, OCT4, and NANOG expression. Tumor-initiation studies and analysis of The Cancer Genome Atlas (TCGA) suggest a stronger role for SOX2 in ovarian cancer relapse compared with OCT4 or NANOG. Overall, our study clarifies the expression of SOX2, OCT4, and NANOG in TICs from a variety of ovarian cancer cell lines. Our findings suggest that SOX2 expression is a stronger indicator of ovarian TICs with enhanced tumor-initiation capacity and potential for relapse. Improved identification of ovarian TICs will advance our understanding of TIC biology and facilitate the design of better therapies to eliminate TICs and overcome chemotherapy resistance and disease relapse.

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Section: Discussionsupporting

confidence: 91%

Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Robinson

Gilbert

Waters

et al. 2020

Preprint

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“…Knockdown of SOX2 in cell lines accordingly decreased chemoresistance to cisplatin via down-regulating expression of ABCB1 , ABCG2 , and ABCC6 31 . These results were accordance with those of researches on the roles of SOX2 based on OC cell lines, but not with researches based on patients’ samples in other cases 9,31,34,38,39 . Further simultaneous in vitro and in vivo researches into SOX2 are therefore needed to develop its role as a promising new therapeutic target for patients with OC.…”

Section: Sox Genes In Gcssupporting

confidence: 69%

“…On the other hand, Pham et al 38 demonstrated that high expression level of SOX2 was a favorable biomarker indicating longer DFS and overall survival (OS) in patients with stage II–IV high-grade serous OC among 215 cases of OC. Other researchers also affirmed the good prognostic effects of SOX2 in 570 samples from patients with ovarian serous cystadenocarcinoma 39 . The mechanisms responsible for these different effects of SOX2 may be due to various factors, such as feedback mechanisms of SOX2 expression, interactions between SOX2 in the cytoplasm and nucleus, or differences between patient spectra and measuring methods.…”

Section: Sox Genes In Gcsmentioning

confidence: 83%

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

et al. 2019

Cancer Biol Med

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Sex-determining region Y box-containing genes are transcription factors with roles in multiple biological processes, including cell differentiation, proliferation, and apoptosis. Sex-determining region Y box-containing genes have also been shown to act as regulators and biomarkers in the progression of many different cancers, including gynecological cancers such as ovarian, cervical, and endometrial cancer. In this review, we summarize the contrasting regulatory roles of Sex-determining region Y box-containing genes in different gynecological cancers, as promotors with high expression levels or as suppressors with low expression levels. Expression levels of Sex-determining region Y box-containing genes were also identified as biomarkers of clinical features, including International Federation of Gynecology and Obstetrics stage, histopathologic grade together with disease-free survival, and treatment efficacy in patients with gynecological cancers. An understanding of the mechanisms whereby Sex-determining region Y box-containing genes regulate the progression of gynecological cancers will aid in the development of novel diagnostic and therapeutic strategies, while analysis of Sex-determining region Y box-containing expression levels will help to predict the prognosis of patients with gynecological cancers.

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“…In this regard, the SOX2 gene is amplified in several cancers, [41, 54–56] and high levels of SOX2 correlate with poor prognosis in many cancers [24, 57–60]. As shown previously, SOX2 protein levels vary considerably between different PDAC cell lines [23].…”

Section: Discussionmentioning

confidence: 77%

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.

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Sox2 Gene Amplification Significantly Impacts Overall Survival in Serous Epithelial Ovarian Cancer

Cited by 33 publications

References 80 publications

Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

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