Oncotarget

Research Papers:

Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma

Jing-Jing Wang, Qing-Yun Chong, Xin-Bao Sun, Ming-Liang You, Vijay Pandey, Yi-Jun Chen, Qiu-Shi Zhuang, Dong-Xu Liu, Lan Ma, Zheng-Sheng Wu, Tao Zhu and Peter E. Lobie _

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Oncotarget. 2017; 8:103900-103918. https://doi.org/10.18632/oncotarget.21812

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Abstract

Jing-Jing Wang1,*, Qing-Yun Chong1,*, Xin-Bao Sun2,3, Ming-Liang You1, Vijay Pandey1, Yi-Jun Chen1, Qiu-Shi Zhuang1, Dong-Xu Liu4, Lan Ma5, Zheng-Sheng Wu6, Tao Zhu2,3 and Peter E. Lobie1,5,7

1Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore

2Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China

3The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China

4School of Science, Auckland University of Technology, Auckland, New Zealand

5Tsinghua Berkeley Shenzhen Institute, Tsinghua University Graduate School at Shenzhen, Shenzhen, China

6Department of Pathology, Anhui Medical University, Hefei, China

7National University Cancer Institute, Singapore, Singapore

*These authors have contributed equally to this work

Correspondence to:

Peter E. Lobie, email: [email protected]

Tao Zhu, email: [email protected]

Keywords: growth hormone, ERK, epithelial-mesenchymal transition, cancer stem cell, colorectal carcinoma

Received: June 06, 2017     Accepted: September 08, 2017     Published: October 10, 2017

ABSTRACT

Tumor derived human growth hormone (hGH) has been implicated in cancer development and progression. However, the specific functional role of autocrine/paracrine hGH in colorectal cancer (CRC) remains largely to be determined. Herein, we demonstrated a crucial oncogenic role of autocrine hGH in CRC progression. Elevated hGH expression was detected in CRC compared to normal colorectal tissue, and hGH expression in CRC was positively associated with tumor size and lymph node metastasis. Forced expression of hGH stimulated cell proliferation, survival, oncogenicity and epithelial to mesenchymal transition (EMT) of CRC cells, and promoted xenograft growth and local invasion in vivo. Autocrine hGH expression in CRC cells stimulated the activation of the ERK1/2 pathway, which in turn resulted in increased transcription of the mesenchymal marker FIBRONECTIN 1 and transcriptional repression of the epithelial marker E-CADHERIN. The autocrine hGH-stimulated increase in CRC cell proliferation, cell survival and EMT was abrogated upon ERK1/2 inhibition. Furthermore, autocrine hGH-stimulated CRC cell migration and invasion was dependent on the ERK1/2-mediated increase in FIBRONECTIN 1 expression and decrease in E-CADHERIN expression. Forced expression of hGH also enhanced CSC-like behavior of CRC cells, as characterized by increased colonosphere formation, ALDH-positive population and CSC marker expression. Autocrine hGH-enhanced cancer stem cell (CSC)-like behavior in CRC cells was also observed to be E-CADHERIN-dependent. Thus, autocrine hGH plays a critical role in CRC progression, and inhibition of hGH could be a promising targeted therapeutic approach to limit disease progression in metastatic CRC patients.


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