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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

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

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

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

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.

Methods

TMSB10 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.

Results

We 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.

Conclusion

TMSB10 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.
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Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
2.
Gerber B, Freund M, Reimer T. Recurrent breast cancer: treatment strategies for maintaining and prolonging good quality of life. Dtsch Arztebl Int. 2010;107(6):85–91.PubMedPubMedCentral
3.
Kast K, Rhiem K. Familial breast cancer - targeted therapy in secondary and tertiary prevention. Breast Care. 2015;10(1):27–31.CrossRefPubMed
4.
Low TL, Thurman GB, McAdoo M, McClure J, Rossio JL, Naylor PH, Goldstein AL. The chemistry and biology of thymosin. I. Isolation, characterization, and biological activities of thymosin alpha1 and polypeptide beta1 from calf thymus. J Biol Chem. 1979;254(3):981–6.PubMed
5.
Safer D, Golla R, Nachmias VT. Isolation of a 5-kilodalton actin-sequestering peptide from human blood platelets. Proc Natl Acad Sci U S A. 1990;87(7):2536–40.CrossRefPubMedPubMedCentral
6.
Lee SI, Yi JK, Bae WJ, Lee S, Cha HJ, Kim EC. Thymosin beta-4 suppresses osteoclastic differentiation and inflammatory responses in human periodontal ligament cells. PLoS One. 2016;11(1):e0146708.CrossRefPubMedPubMedCentral
7.
8.
Lee SI, Kim DS, Lee HJ, Cha HJ, Kim EC. The role of thymosin beta 4 on odontogenic differentiation in human dental pulp cells. PLoS One. 2013;8(4):e61960.CrossRefPubMedPubMedCentral
9.
Lee SJ, So IS, Park SY, Kim IS. Thymosin beta4 is involved in stabilin-2-mediated apoptotic cell engulfment. FEBS Lett. 2008;582(15):2161–6.CrossRefPubMed
10.
Gealekman O, Gurav K, Chouinard M, Straubhaar J, Thompson M, Malkani S, Hartigan C, Corvera S. Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4. J Biol Chem. 2014;289(26):18327–38.CrossRefPubMedPubMedCentral
11.
Wirsching HG, Krishnan S, Florea AM, Frei K, Krayenbuhl N, Hasenbach K, Reifenberger G, Weller M, Tabatabai G. Thymosin beta 4 gene silencing decreases stemness and invasiveness in glioblastoma. Brain. 2014;137(Pt 2):433–48.CrossRefPubMed
12.
Banyard J, Barrows C, Zetter BR. Differential regulation of human thymosin beta 15 isoforms by transforming growth factor beta 1. Genes Chromosomes Cancer. 2009;48(6):502–9.CrossRefPubMedPubMedCentral
13.
Zhang XJ, Su YR, Liu D, Xu DB, Zeng MS, Chen WK. Thymosin beta 10 correlates with lymph node metastases of papillary thyroid carcinoma. J Surg Res. 2014;192(2):487–93.CrossRefPubMed
14.
Sawanyawisuth K, Wongkham C, Araki N, Zhao Q, Riggins GJ, Wongkham S. Serial analysis of gene expression reveals promising therapeutic targets for liver fluke-associated cholangiocarcinoma. Asian Pac J Cancer Prev. 2012;13(Suppl):89–93.PubMed
15.
Lee SM, Na YK, Hong HS, Jang EJ, Yoon GS, Park JY, Kim DS. Hypomethylation of the thymosin beta(10) gene is not associated with its overexpression in non-small cell lung cancer. Mol Cells. 2011;32(4):343–8.CrossRefPubMedPubMedCentral
16.
Huang L, Zheng M, Zhou QM, Zhang MY, Jia WH, Yun JP, Wang HY. Identification of a gene-expression signature for predicting lymph node metastasis in patients with early stage cervical carcinoma. Cancer. 2011;117(15):3363–73.CrossRefPubMed
17.
Bouchal P, Dvorakova M, Roumeliotis T, Bortlicek Z, Ihnatova I, Prochazkova I, Ho JT, Maryas J, Imrichova H, Budinska E, et al. Combined proteomics and transcriptomics identifies carboxypeptidase B1 and nuclear factor kappaB (NF-kappaB) associated proteins as putative biomarkers of metastasis in low grade breast cancer. Mol Cell Proteomics. 2015;14(7):1814–30.CrossRefPubMedPubMedCentral
18.
Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol. 2002;22(7):2111–23.CrossRefPubMedPubMedCentral
19.
Tang ED, Nunez G, Barr FG, Guan KL. Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem. 1999;274(24):16741–6.CrossRefPubMed
20.
Carey LA, Metzger R, Dees EC, Collichio F, Sartor CI, Ollila DW, Klauber-DeMore N, Halle J, Sawyer L, Moore DT, et al. American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst. 2005;97(15):1137–42.CrossRefPubMed
21.
Takata M, Yamanaka N, Tanaka T, Yamanaka J, Maeda S, Okamoto E, Yasojima H, Uematsu K, Watanabe H, Uragari Y. What patients can survive disease free after complete resection for hepatocellular carcinoma? A multivariate analysis. Jpn J Clin Oncol. 2000;30(2):75–81.CrossRefPubMed
22.
Lin YT, Lu HP, Chao CC. Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis. Biochem Pharmacol. 2015;93(1):110–24.CrossRefPubMed
23.
Tsitsiloni OE, Stiakakis J, Koutselinis A, Gogas J, Markopoulos C, Yialouris P, Bekris S, Panoussopoulos D, Kiortsis V, Voelter W, et al. Expression of alpha-thymosins in human tissues in normal and abnormal growth. Proc Natl Acad Sci U S A. 1993;90(20):9504–7.CrossRefPubMedPubMedCentral
24.
Inzitari R, Cabras T, Pisano E, Fanali C, Manconi B, Scarano E, Fiorita A, Paludetti G, Manni A, Nemolato S, et al. HPLC-ESI-MS analysis of oral human fluids reveals that gingival crevicular fluid is the main source of oral thymosins beta(4) and beta(10). J Sep Sci. 2009;32(1):57–63.CrossRefPubMed
25.
Cabras T, Iavarone F, Martelli C, Delfino D, Rossetti DV, Inserra I, Manconi B, Desiderio C, Messana I, Hannappel E, et al. High-resolution mass spectrometry for thymosins detection and characterization. Expert Opin Biol Ther. 2015;15 Suppl 1:S191–201.CrossRefPubMed
26.
Nemolato S, Messana I, Cabras T, Manconi B, Inzitari R, Fanali C, Vento G, Tirone C, Romagnoli C, Riva A, et al. Thymosin beta(4) and beta(10) levels in pre-term newborn oral cavity and foetal salivary glands evidence a switch of secretion during foetal development. PLoS One. 2009;4(4):e5109.CrossRefPubMedPubMedCentral
27.
Desiderio C, Martelli C, Rossetti DV, Di Rocco C, D'Angelo L, Caldarelli M, Tamburrini G, Iavarone F, Castagnola M, Messana I, et al. Identification of thymosins beta4 and beta 10 in paediatric craniopharyngioma cystic fluid. Childs Nerv Syst. 2013;29(6):951–60.CrossRefPubMed
28.
Huang CM, Wang CC, Barnes S, Elmets CA. In vivo detection of secreted proteins from wounded skin using capillary ultrafiltration probes and mass spectrometric proteomics. Proteomics. 2006;6(21):5805–14.CrossRefPubMed
29.
Hannappel E, van Kampen M. Determination of thymosin beta 4 in human blood cells and serum. J Chromatogr. 1987;397:279–85.CrossRefPubMed
30.
Weller FE, Mutchnick MG, Goldstein AL, Naylor PH. Enzyme immunoassay measurement of thymosin beta 4 in human serum. J Biol Response Mod. 1988;7(1):91–6.PubMed
31.
Santelli G, Califano D, Chiappetta G, Vento MT, Bartoli PC, Zullo F, Trapasso F, Viglietto G, Fusco A. Thymosin beta-10 gene overexpression is a general event in human carcinogenesis. Am J Pathol. 1999;155(3):799–804.CrossRefPubMedPubMedCentral
32.
Gu Y, Wang C, Wang Y, Qiu X, Wang E. Expression of thymosin beta10 and its role in non-small cell lung cancer. Hum Pathol. 2009;40(1):117–24.CrossRefPubMed
33.
Hall AK. Differential expression of thymosin genes in human tumors and in the developing human kidney. Int J Cancer. 1991;48(5):672–7.CrossRefPubMed
34.
Kim YC, Kim BG, Lee JH. Thymosin beta10 expression driven by the human TERT promoter induces ovarian cancer-specific apoptosis through ROS production. PLoS One. 2012;7(5):e35399.CrossRefPubMedPubMedCentral
35.
Lee SH, Son MJ, Oh SH, Rho SB, Park K, Kim YJ, Park MS, Lee JH. Thymosin {beta}(10) inhibits angiogenesis and tumor growth by interfering with Ras function. Cancer Res. 2005;65(1):137–48.PubMed
36.
Verghese-Nikolakaki S, Apostolikas N, Livaniou E, Ithakissios DS, Evangelatos GP. Preliminary findings on the expression of thymosin beta-10 in human breast cancer. Br J Cancer. 1996;74(9):1441–4.CrossRefPubMedPubMedCentral
37.
Sribenja S, Sawanyawisuth K, Kraiklang R, Wongkham C, Vaeteewoottacharn K, Obchoei S, Yao Q, Wongkham S, Chen C. Suppression of thymosin beta10 increases cell migration and metastasis of cholangiocarcinoma. BMC Cancer. 2013;13:430.CrossRefPubMedPubMedCentral
38.
Maelan AE, Rasmussen TK, Larsson LI. Localization of thymosin beta10 in breast cancer cells: relationship to actin cytoskeletal remodeling and cell motility. Histochem Cell Biol. 2007;127(1):109–13.CrossRefPubMed
39.
40.
Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG. Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol. 2000;149(4):775–82.CrossRefPubMedPubMedCentral
41.
O'Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, Yurchenco P, Mostov KE. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. 2001;3(9):831–8.CrossRefPubMed
42.
Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114(Pt 15):2713–22.PubMed
43.
Bertucci F, Finetti P, Roche H, Le Doussal JM, Marisa L, Martin AL, Lacroix-Triki M, Blanc-Fournier C, Jacquemier J, Peyro-Saint-Paul H, et al. Comparison of the prognostic value of genomic grade index, Ki67 expression and mitotic activity index in early node-positive breast cancer patients. Ann Oncol. 2013;24(3):625–32.CrossRefPubMed
44.
Alba E, Lluch A, Ribelles N, Anton-Torres A, Sanchez-Rovira P, Albanell J, Calvo L, Garcia-Asenjo JA, Palacios J, Chacon JI, et al. High proliferation predicts pathological complete response to neoadjuvant chemotherapy in early breast cancer. Oncologist. 2016;21(6):778.CrossRefPubMedPubMedCentral
45.
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8.CrossRefPubMedPubMedCentral
46.
Kallioniemi OP, Kallioniemi A, Kurisu W, Thor A, Chen LC, Smith HS, Waldman FM, Pinkel D, Gray JW. ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci U S A. 1992;89(12):5321–5.CrossRefPubMedPubMedCentral
47.
Callender T, el-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG. PRAD-1 (CCND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma. Cancer. 1994;74(1):152–8.
Metadata
Title
Thymosin beta 10 is a key regulator of tumorigenesis and metastasis and a novel serum marker in breast cancer
Authors
Xin Zhang
Dong Ren
Ling Guo
Lan Wang
Shu Wu
Chuyong Lin
Liping Ye
Jinrong Zhu
Jun Li
Libing Song
Huanxin Lin
Zhenyu He
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0785-2

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