Elsevier

Cellular Signalling

Volume 25, Issue 5, May 2013, Pages 1264-1271
Cellular Signalling

Review
The multiple roles for Sox2 in stem cell maintenance and tumorigenesis

https://doi.org/10.1016/j.cellsig.2013.02.013Get rights and content

Abstract

The Sry-containing protein Sox2 initially was known to regulate the self-renewal of the mouse and human embryonic stem cells (ESCs). It is also important for the maintenance of stem cells in multiple adult tissues including the brain and trachea, and it is one of the key transcription factors for establishing induced pluripotent stem cells. Recently, overexpression and gene amplification of Sox2 have been associated with the development of squamous cell carcinoma in multiple tissues such as the lung and esophagus. These different roles for Sox2 involve a complicated regulatory networks consisting of microRNAs, kinases and signaling molecules. While the levels of Sox2 are modulated transcriptionally and translationally, post-translational modification is also important for the various functions of Sox2. In clinics, high levels of Sox2 are correlated with poor prognosis and increased proliferation of cancer stem cells. Therefore targeting Sox2 can be potentially explored for a new therapeutic avenue to treat cancers. This review will focus on the different roles for Sox2 in stem cell maintenance and its oncogenic roles in the context of signal transcription and microRNA regulation. We will also review the main upstream and downstream targets of Sox2, which can be potentially used as therapeutic measures to treat cancer with abnormal levels of Sox2.

Highlights

► Variable activities of Sox2 after modifications and thereby affected its DNA-binding. ► Involvement of Sox2 in signal transduction events of cancer ► Amplified Sox2 promotes cancer progression and clinical outcome of patients.

Introduction

Sox2, a protein belonging to the family of high-mobility group transcription factors, is pivotal for early development and maintenance of undifferentiated ESCs (embryonic stem cells). It is also one of the key transcription factors initially used to derive induced pluripotent stem (iPS) cells from fibroblast cells. Interestingly, recent studies suggested that SOX2 overexpression or gene amplification has been associated with cancer development in several tissues such as the lung, esophagus and breast.

As an extremely important transcription factor, Sox2 regulates an array of gene expression involved in normal development and malignant processes, thereby plays its complicated effect in physiological network. To better understand the oncogenic roles and the corresponding signal transduction pathways involved in Sox2 protein, in this study, we not only emphasize the role of Sox2 in cancer and its correlated upstream or downstream molecules in signal transduction, but also propose some strategies for cancer therapy based on previous studies.

Section snippets

Variable activities of Sox2 protein are controlled at transcriptional, translational and post-translational level

Transcription of Sox2 could be affected through exogenous stimulus, which promoted chromosome instability and led to amplification. Although only one transcript occurred after Sox2 expression, the activities of Sox2 are also variable due to translational and post-translational modifications. At translational level, several studies reported that microRNAs could inhibit Sox2 and thus impact its role and downstream events. The level of microRNA-145 expression in self-renewing human ESCs is low,

Amplification of Sox2 gene occurred in cancer

Besides the pivotal role in maintaining stemness of cells, emerging studies showed Sox2 was closely correlated to many types of cancer and amplified in these cancers. In SCCs (squamous cell carcinomas) of the lung and esophagus, a peak of genomic amplification has been found on chromosome 3q26.33 containing Sox2 gene, which is requisite for proliferation and anchorage-independent growth of lung and esophageal cell lines. Moreover, Sox2 could cooperate with FOXE1 or FGFR2 to transform

Correlations between Sox2 and clinical outcome and its contributions to multiple processes of cancer cells

As mentioned above, amplified Sox2 in some types of cancer leads to high level of Sox2. Therefore, there might be correlations between Sox2 and clinical outcome, and the roles of Sox2 might be involved in multiple processes of cancer cells. To better elucidate the relationships between them and contributions of Sox2 in cancer progress, we explain them as following.

Relationships between Sox2 and microRNAs in cancer

As a key regulator in development and carcinogenesis, Sox2 also displayed close associations with microRNAs. As mentioned above, at translational level, activities of Sox2 were controlled by several microRNAs, namely microRNA-145, microRNA-126 and microRNA-9 [1], [2], [3], [4].

However, many microRNAs could also be regulated by Sox2 protein. To analyze the downstream targets of Sox2, integrated technologies including ChIP-seq, microarray profiling, and microRNA sequencing were utilized in this

Involvement of Sox2 in complicated signal transduction pathways

As a key transcriptional regulator, Sox2 is involved in many physiological actions including normal development and pathological processes. Previous studies demonstrated that Sox2 expression was regulated by several signal molecules, however, other evidences also showed that Sox2 was relevant to many signal pathways directly through its targets or indirectly through its interacting proteins after Sox2 overexpression and knockdown. Overall, Sox2 is closely correlated with some signal

Prospect and conclusion

As we now know, Sox2 activities are variable in different status. On one hand, Amplified SOX2 and enhanced expression level were frequently detected in many types of cancer, moreover, many modifications, including transcriptional level mediated by signal transduction and genetic environment, translational level mediated by microRNA, post-translational level such as phosphorylation, acetylation, methylation, SUMOylation and ubiquitination, affect the activities of Sox2 protein. On the other

Acknowledgments

This work was initiated in Dr. Jianwen Que's laboratory at the Department of Biomedical Genetics, University of Rochester. This work is supported by the NIH Pathway to Independence Award (K99/R00) (DK082650 to J.Que) and the National Science Foundation of China (No. 81271928 to X. Lan).

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