Transcriptional factor OCT4 promotes esophageal cancer metastasis by inducing epithelial-mesenchymal transition through VEGF-C/VEGFR-3 signaling pathway.

Chunguang Li,Maoling Zhu,Zhigang Li,Xuejing Lin,Chunying Liu,Xiaoli Lou,Changqing Su,Hezhong Chen,Weidan Ji

doi:10.18632/oncotarget.18035

Abstract

The octamer-binding transcription factor 4 (OCT4) can promote cancer proliferation and metastasis. Esophageal carcinoma (ECC) harbors different quantities of OCT4-positive cancer cells. These cells are highly malignant and prone to metastasis; however, the mechanism remains unknown. In this study, we found that OCT4 enhances vascular endothelial growth factor C (VEGF-C) promoter activity to promote VEGF-C expression and activates VEGF receptor 3 (VEGFR-3) in ECC cells, thereby inducing cancer cell epithelial-mesenchymal transition (EMT). Studies using xenograft models showed that OCT4 promoted xenograft growth and intraperitoneal implantation metastasis of ECC cells. Downregulation of OCT4 expression could inhibit cancer metastasis. OCT4- and VEGF-C-positive ECC presented more malignant biological behaviors and the corresponding patients exhibited a poor prognosis. The study confirmed that the OCT4/VEGF-C/VEGFR-3/EMT signaling plays a role in the progression of ECC. Understanding of how OCT4 regulates EMT and how ECC metastasis occurs will provide useful targets for the biological treatment of ECC.

Highlights

Esophageal carcinoma (ECC) is a malignant gastrointestinal cancer with morbidity second only to gastric cancer
We found that octamer-binding transcription factor 4 (OCT4) enhances vascular endothelial growth factor C (VEGF-C) promoter activity to promote VEGF-C expression and activates VEGF receptor 3 (VEGFR-3) in ECC cells, thereby inducing cancer cell epithelial-mesenchymal transition (EMT)
Our preliminary studies indicated that a small population of octamer-binding transcription factor 4 (OCT4)-positive cancer cells was present in ECC tissues and that ECC with a high percentage of OCT4-positive cells displayed rapid progression, high incidence of lymph node metastasis, and short tumor-free survival and overall survival [2]

Summary

Introduction

Esophageal carcinoma (ECC) is a malignant gastrointestinal cancer with morbidity second only to gastric cancer. Recent studies showed that OCT4 is expressed in human solid tumors, including lung cancer [4], breast cancer [5], and head and neck cancer [6], and especially in germ cell tumors, such as embryonal carcinoma and seminoma, and is closely related to tumor proliferation, metastasis and prognosis [7]. OCT4 expression in solid tumors supported the theory of cancer stem cells (CSCs) and became a highly sensitive and highly specific marker and a treatment target for malignant tumors. OCT4 can be regarded as an oncogene with complex mechanisms in its role in tumor development and progression; besides its role in regulating survivin and CCND1-related signaling pathways (as our study showed), OCT4 may promote the malignant progression of tumors by regulating the Wnt, Hedgehog, and transforming growth factor (TGF)-β signaling pathways [9]

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