Thymosin beta 10 is a key regulator of tumorigenesis and metastasis and a novel serum marker in breast cancer

Xin Zhang,Ling Guo,Lan Wang,Liping Ye,Libing Song,Shu Wu,Chuyong Lin,Huanxin Lin,Jun Li,Jinrong Zhu,Dong Ren,Zhenyu He

doi:10.1186/s13058-016-0785-2

Abstract

BackgroundThymosin beta 10 (TMSB10) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to determine the biological roles and clinical significance of TMSB10 in breast cancer and to identify whether TMSB10 might be used as a serum marker for the diagnosis of breast cancer.MethodsTMSB10 expression was evaluated by immunohistochemical analysis (IHC) of 253 breast tumors and ELISA of serum from 80 patients with breast cancer. Statistical analysis was performed to explore the correlation between TMSB10 expression and clinicopathological features in breast cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between TMSB10 expression and overall survival and metastatic status. In vitro and in vivo assays were performed to assess the biological roles of TMSB10 in breast cancer. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the tumor-promoting role of TMSB10.ResultsWe found TMSB10 was upregulated in breast cancer cells and tissues. Univariate and multivariate analysis demonstrated that high TMSB10 expression significantly correlated with clinicopathological features, poor prognosis and distant metastases in patients with breast cancer. Overexpression of TMSB10 promotes, while silencing of TMSB10 inhibits, proliferation, invasion and migration of breast cancer cells in vitro and in vivo. Our results further reveal that TMSB10 promotes the proliferation, invasion and migration of breast cancer cells via AKT/FOXO signaling, which is antagonized by the AKT kinase inhibitor perifosine. Importantly, the expression of TMSB10 is significantly elevated in the serum of patients with breast cancer and is positively associated with clinical stages of breast cancer.ConclusionTMSB10 may hold promise as a minimally invasive serum cancer biomarker for the diagnosis of breast cancer and a potential therapeutic target which will facilitate the development of a novel therapeutic strategy against breast cancer.

Highlights

Thymosin beta 10 (TMSB10) has been demonstrated to be involved in the malignant process of many cancers
TMSB10 is upregulated in breast cancer cell lines and tissues We first analyzed expression levels of primary thymosinassociated proteins in the RNA sequencing data from E-GEOD-58135 and The Cancer Genome Atlas (TCGA) datasets, including thymosin beta 4 (TMSB4), TMSB10, TMSB15, prothymosin, alpha (PTMA) and parathymosin (PTMS), which have been reported to be implicated in the development and progression of different types of cancer, including breast cancer [11,12,13, 17, 22, 23] and found that expression levels of TMSB10, PTMS and PTMA were upregulated to varying degrees in breast cancer tissues compared with normal tissues, TMSB10 at the highest level (2.03-fold and 1.45-fold change, respectively) (Fig. 1a and Additional file 3: Figure S1a)
Subsequent analysis of TMSB10 expression in breast cancer datasets revealed that TMSB10 was upregulated in breast cancer tissues and breast cancer cells compared with normal breast tissue samples and epithelium cells (Fig. 1b, c and Additional file 3: Figure S1b)

Summary

Introduction

Thymosin beta 10 (TMSB10) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to determine the biological roles and clinical significance of TMSB10 in breast cancer and to identify whether TMSB10 might be used as a serum marker for the diagnosis of breast cancer. Recent studies have focused on the biological roles of beta-thymosins in the progression and metastasis of various types of cancer. TMSB4 overexpression correlates with advanced stages of cancer and shorter overall survival by regulating invasiveness and stemness in glioma cells [11]; TMSB15A is upregulated in transforming growth factor beta 1-treated breast cancer cells, and TMSB15B is involved in epidermal growth factor-induced migration of prostate cancer cells [12]. It is worth noting that Bouchal et al report that TMSB10 is positively associated with highgrade aggressive breast cancer [17], but the underlying mechanism by which TMSB10 promotes breast cancer progression and metastasis remains unclear, which is yet to be further elucidated

Objectives

Methods

Results

Discussion

Conclusion