SERPINB2 Is a Novel Indicator of Cancer Stem Cell Tumorigenicity in Multiple Cancer Types.

Na-Hee Lee,Soyi Lim,Jin Woo Lee,Seung Yeon Hah,Hwa-Yong Lee,Dong Young Kim,In-Sun Hong,Se-Ra Park,Seung-Ho Lee,Seungyoon Nam

doi:10.3390/cancers11040499

Abstract

Drug resistance is one of the major characteristics of cancer stem cells (CSCs) and a mechanism of tumor recurrence. Therefore, selectively targeting CSCs may be an effective therapeutic strategy to overcome cancer recurrence. In the present study, we found that exposure to tumorigenic compounds significantly increased the growth potential and stem-cell-like properties of various CSCs. Early-response genes involved in tumorigenesis can be used as specific markers to predict potential tumorigenicity. Importantly, for the first time we identified, a labile tumorigenic response gene—SERPINB2—and showed that tumorigenic compound exposure more profoundly affected its expression in CSCs than in non-stem cancer cells, although both cells exhibit basal expression of SERPINB2 in multiple cancer types. Our data also revealed a strong relationship between the significantly enhanced expression of SERPINB2 and metastatic progression in multiple cancer types. To the best of our knowledge, this is the first study to focus on the functions of SERPINB2 in the tumorigenicity of various CSCs and these findings will facilitate the development of promising tumorigenicity test platforms.

Highlights

It has been proposed that a small population of cancer cells—cancer stem cells (CSCs) or cancer-initiating cell—within a tumor are one of the critical factors for drug resistance and tumorCancers 2019, 11, 499; doi:10.3390/cancers11040499 www.mdpi.com/journal/cancersCancers 2019, 11, 499 recurrence [1,2,3]
The relative percentages of cells expressing each CSC marker were significantly increased in the TCDD-treated CSCs in multiple cancer types (Figure 2D–F) compared to those in the untreated CSCs. These results suggest that tumorigenic compound exposure profoundly stimulates the clonogenic abilities and stem cell-like properties of multiple CSC types
Large-scale data analysis (Figure 5D–F) and our immunocytochemical analysis (Figure 6A–D) revealed a strong relationship between the significantly increased expression of both SERPINB2 itself and constituents in its related signaling pathways and metastatic progression or recurrence in breast, colorectal and liver cancers. These results suggest that the stimulatory effects of tumorigenic materials on the self-renewal and stem cell-like properties of CSCs can be achieved by maintaining SERPINB2 expression

Summary

Introduction

It has been proposed that a small population of cancer cells—cancer stem cells (CSCs) or cancer-initiating cell—within a tumor are one of the critical factors for drug resistance and tumorCancers 2019, 11, 499; doi:10.3390/cancers11040499 www.mdpi.com/journal/cancersCancers 2019, 11, 499 recurrence [1,2,3]. CSC populations have recently been identified in most human cancers, including leukemia [4], breast cancer [5], colon cancer [6] and liver cancer [7] Due to their varying states of tumorigenicity, CSCs and non-stem cancer cells respond differently to the same carcinogen exposure; differential tumorigenic effects might be expected. Compared to non-stem cancer cells, CSCs responded differently to the same stimuli with distinct gene expression patterns [8,9]. In this context, CSC-based screening platforms can provide valuable tumorigenic information of chemicals because their tumorigenicity is not normally detected by other non-stem cancer cell-based screening platforms

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Discussion

Conclusion