Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

Sun Young Yoon, Ha Reum Lee, Yoorim Park, Joo Heon Kim, Soo Young Kim, Suk Ran Yoon, Wang Jae Lee, Byung Joo Cho, Hyeyoung Min, Jung Wook Bang, Hyunjeong Park, Sa Ik Bang, Dae Ho Cho

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We examined HIF-1α HIF-2 and Tβ4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1-α and HIF-2-α strongly correlates with Tβ4 expression (P≤0.0001) and overexpression of Tβ4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activities were reduced by interference of Tβ4 expression using Tβ4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.

Original languageEnglish
Pages (from-to)23-31
Number of pages9
JournalOncology Reports
Volume25
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1
Externally publishedYes

Fingerprint

Thymosin
Lymph Nodes
Breast Neoplasms
Neoplasm Metastasis
Hypoxia-Inducible Factor 1
Epidermal Growth Factor
Blood Vessels
Hypoxia
Lentivirus
Small Interfering RNA
Neoplasms

Keywords

  • Breast carcinoma
  • HIF-α
  • Lymph node metastasis
  • Thymosin β4
  • VEGF-A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer. / Yoon, Sun Young; Lee, Ha Reum; Park, Yoorim; Kim, Joo Heon; Kim, Soo Young; Yoon, Suk Ran; Lee, Wang Jae; Cho, Byung Joo; Min, Hyeyoung; Bang, Jung Wook; Park, Hyunjeong; Bang, Sa Ik; Cho, Dae Ho.

In: Oncology Reports, Vol. 25, No. 1, 01.01.2011, p. 23-31.

Research output: Contribution to journalArticle

Yoon, SY, Lee, HR, Park, Y, Kim, JH, Kim, SY, Yoon, SR, Lee, WJ, Cho, BJ, Min, H, Bang, JW, Park, H, Bang, SI & Cho, DH 2011, 'Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer', Oncology Reports, vol. 25, no. 1, pp. 23-31. https://doi.org/10.3892/or-00001037
Yoon, Sun Young ; Lee, Ha Reum ; Park, Yoorim ; Kim, Joo Heon ; Kim, Soo Young ; Yoon, Suk Ran ; Lee, Wang Jae ; Cho, Byung Joo ; Min, Hyeyoung ; Bang, Jung Wook ; Park, Hyunjeong ; Bang, Sa Ik ; Cho, Dae Ho. / Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer. In: Oncology Reports. 2011 ; Vol. 25, No. 1. pp. 23-31.
@article{00be03aae5ee4aa6900379a7caf41597,
title = "Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer",
abstract = "Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We examined HIF-1α HIF-2 and Tβ4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1-α and HIF-2-α strongly correlates with Tβ4 expression (P≤0.0001) and overexpression of Tβ4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activities were reduced by interference of Tβ4 expression using Tβ4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.",
keywords = "Breast carcinoma, HIF-α, Lymph node metastasis, Thymosin β4, VEGF-A",
author = "Yoon, {Sun Young} and Lee, {Ha Reum} and Yoorim Park and Kim, {Joo Heon} and Kim, {Soo Young} and Yoon, {Suk Ran} and Lee, {Wang Jae} and Cho, {Byung Joo} and Hyeyoung Min and Bang, {Jung Wook} and Hyunjeong Park and Bang, {Sa Ik} and Cho, {Dae Ho}",
year = "2011",
month = "1",
day = "1",
doi = "10.3892/or-00001037",
language = "English",
volume = "25",
pages = "23--31",
journal = "Oncology Reports",
issn = "1021-335X",
publisher = "Spandidos Publications",
number = "1",

}

TY - JOUR

T1 - Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

AU - Yoon, Sun Young

AU - Lee, Ha Reum

AU - Park, Yoorim

AU - Kim, Joo Heon

AU - Kim, Soo Young

AU - Yoon, Suk Ran

AU - Lee, Wang Jae

AU - Cho, Byung Joo

AU - Min, Hyeyoung

AU - Bang, Jung Wook

AU - Park, Hyunjeong

AU - Bang, Sa Ik

AU - Cho, Dae Ho

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We examined HIF-1α HIF-2 and Tβ4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1-α and HIF-2-α strongly correlates with Tβ4 expression (P≤0.0001) and overexpression of Tβ4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activities were reduced by interference of Tβ4 expression using Tβ4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.

AB - Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We examined HIF-1α HIF-2 and Tβ4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1-α and HIF-2-α strongly correlates with Tβ4 expression (P≤0.0001) and overexpression of Tβ4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activities were reduced by interference of Tβ4 expression using Tβ4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.

KW - Breast carcinoma

KW - HIF-α

KW - Lymph node metastasis

KW - Thymosin β4

KW - VEGF-A

UR - http://www.scopus.com/inward/record.url?scp=78650742217&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650742217&partnerID=8YFLogxK

U2 - 10.3892/or-00001037

DO - 10.3892/or-00001037

M3 - Article

C2 - 21109953

AN - SCOPUS:78650742217

VL - 25

SP - 23

EP - 31

JO - Oncology Reports

JF - Oncology Reports

SN - 1021-335X

IS - 1

ER -