Original contributionSex-determining region Y-box 2 expression predicts poor prognosis in human ovarian carcinoma☆,☆☆
Introduction
Ovarian cancer is the most lethal gynecologic malignancy because it was responsible for about 14 000 deaths in 2010 according to the American Cancer Society [1]. Despite continued development of surgical techniques and meticulously designed chemotherapy regimens, the overall 5-year survival rate in patients with ovarian cancer only increased from 37% to 46% for 30 years [1]. Usually, the currently used surgery techniques and/or chemotherapy regimens can mostly or partly alleviate the tumor burden, but residual therapy-resistant cancer cells may cause a relapse at the primary site and/or metastasize to secondary sites to initiate new tumors.
Over the past decade, the hypothesis that cancer arises from a small subset of cancer cells often referred to cancer stem cells (CSCs) or tumor-initiating cells that are capable of generating entire tumor has become a great interest in the cancer research community. The presence of CSCs in tumors may herald virtually unlimited proliferation, self-renewal, and high resistance to chemotherapy and/or radiotherapy [2]. Therefore, these cells are proposed to be a subpopulation of tumor cells critical to tumor development, progression, metastasis, and recurrence [3].
The transcription factor sex-determining region Y-box 2 (SOX2), which belongs to group B of the SOX family, is encoded by a single-exon gene on chromosome 3q26.3-q27 [4]. SOX2 is highly expressed in embryonic stem cells and considered a key transcription factor [5]. SOX2 can aid the reprogramming of adult cells into induced pluripotent stem cells, indicating that it has critical roles in cellular fate determination, differentiation, and proliferation [6], [7]. The known roles of SOX2 in development and cell differentiation suggest that it is relevant to the aberrant growth of tumor cells and may be related to CSCs. Researchers have found SOX2 expression in several solid tumors including melanoma [8], brain tumor [9], and digestive tract [10], [11], breast [12], liver [13], pancreatic [14], prostate [15], and lung carcinomas [16]. SOX2 is thought to maintain cellular proliferation potential via the Notch signaling pathway [17] and modulation of cyclin D1 expression [12].
In human primary ovarian cancer, the clinical role of SOX2 expression has remained unknown until recently. Because SOX2 may play an important role in tumor progression, we evaluated its expression via immunohistochemical staining of human ovarian carcinoma samples in comparison with normal fallopian tube and ovarian tissue samples using tissue microarray and analyzed the associations among SOX2 expression and clinical factors (diagnosis, tumor grade, International Federation of Gynecology and Obstetrics [FIGO] stage, and chemotherapy response), overall survival (OS), and disease-free survival (DFS).
Section snippets
Patients and clinicopathologic data
Human ovarian carcinoma samples obtained from 540 patients who underwent initial surgery at The University of Texas MD Anderson Cancer Center from January 1, 1990, to February 22, 2007, were analyzed. Relevant clinical data were obtained via retrospective review of the patients' medical files. These data included demographic information, diagnosis, tumor grade, disease stage, ascites and serum cancer antigen (CA) 125 level, chemotherapy regimen, and response to clinical treatment or
Patient characteristics
The mean age of the patients was 59 years (range, 20-92 years). At the initiation of our study, 81 patients were alive without ovarian carcinoma, 43 were alive with ovarian carcinoma, 296 had died of ovarian carcinoma, and 107 had died of an unrelated or unknown ovarian carcinoma; 13 were lost to follow-up and were excluded from the OS analysis. The median OS duration was 4.4 years (95% confidence interval [CI], 3.7-5.2 years), and the OS rate was 62% (95% CI, 60%-64%) at 3 years, 46% (95% CI,
Discussion
In the present study, we found that SOX2 expression in ovarian carcinoma tissues was associated with high-grade carcinoma (especially high-grade serous carcinoma) and FIGO stage II to IV disease. Moreover, patients with ovarian carcinoma having SOX2 expression had shorter DFS durations than did patients without this expression. These results indicated that SOX2 may be a potential marker of ovarian CSCs related to tumor recurrence, which is similar to its role in regarding embryonic stem cells.
Acknowledgments
We appreciate Donald R. Norwood's helpful editing of the manuscript.
References (34)
- et al.
Spatially precise DNA bending is an essential activity of the sox2 transcription factor
J Biol Chem
(2001) - et al.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors
Cell
(2007) - et al.
The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer
J Biol Chem
(2008) - et al.
Role of Sox2 and Oct4 in predicting survival of hepatocellular carcinoma patients after hepatectomy
Clin Biochem
(2011) - et al.
Role of Sox2 in the development of the mouse neocortex
Dev Biol
(2006) The pathological assessment of ovarian neoplasms. I: introduction to the common epithelial tumours and analysis of benign epithelial tumours
Pathology
(1979)The pathological assessment of ovarian neoplasms. II: the proliferating epithelial tumours
Pathology
(1979)The pathological assessment of ovarian neoplasms. III: the malignant epithelial tumours
Pathology
(1979)- et al.
Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study
Ann Oncol
(1996) - et al.
ALDH1 expression correlates with favorable prognosis in ovarian cancers
Mod Pathol
(2009)
SOX2 in gastric carcinoma, but not Hath1, is related to patients' clinicopathological features and prognosis
J Gastrointest Surg
SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer
Mod Pathol
Cancer statistics, 2010
CA Cancer J Clin
Stem cells, cancer, and cancer stem cells
Nature
Rac1 targeting suppresses human non-small cell lung adenocarcinoma cancer stem cell activity
PLoS One
Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells
Stem Cells
The yin and yang of Sox proteins: activation and repression in development and disease
J Neurosci Res
Cited by (54)
SOX2 in development and cancer biology
2020, Seminars in Cancer BiologyCitation Excerpt :Hence, the level of SOX2 expression in a tumor represents a prognostic factor to determine the clinical outcome for a cancer patient (Table 1). Expectedly, a great number of studies correlates high SOX2 expression in different cancer types with a poor prognosis, among them breast, oral/tongue, esophageal, lung, hepatocellular, colorectal, ovarian and prostate cancer as well as nasopharyngeal and sinonasal carcinoma [66,69,84,94,105–111]. Poor prognosis is usually associated with high migrative, invasive and consequently metastatic capacity of tumor cells.
SOX2 and SOX9 are markers of clinically aggressive disease in metastatic high-grade serous carcinoma
2019, Gynecologic OncologyCancer stem cell biomarkers and related signalling pathways
2024, Journal of Drug TargetingIsoliensinine augments the therapeutic potential of paclitaxel in multidrug-resistant colon cancer stem cells and induced mitochondria-mediated cell death
2023, Journal of Biochemical and Molecular Toxicology
- ☆
J.L. was supported by an R01 grant (R01CA131183-01A2) and ovarian cancer Specialized Programs of Research Excellence (SPORE) grant (IP50CA83638) from the National Institutes of Health and Ovarian Cancer Research Fund. This work was also supported, in part, by the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA016672). Dr D. Chang is a visiting scientist at MD Anderson Cancer Center from the Department of Obstetrics and Gynecology, Inje University Paik Hospital, Gyeonggi-do, Gyeonggi-do, Republic of Korea, and supported by the Inje Research and Scholarship Foundation in 2010.
- ☆☆
Conflicts of interest: The authors declare no conflicts of interest.