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Nuclear TEAD4 with SIX1 Overexpression is an Independent Prognostic Marker in the Stage I–III Colorectal Cancer

Authors Yu T, Song J, Zhou H, Wu T, Liang Z, Du P, Liu CY, Wang G, Cui L, Liu Y

Received 1 May 2020

Accepted for publication 8 January 2021

Published 17 February 2021 Volume 2021:13 Pages 1581—1589


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Bilikere Dwarakanath

Tong Yu,1,2,* Jinglue Song,1,2,* Hui Zhou,1,2 Tingyu Wu,1,2 Zhonglin Liang,1,2 Peng Du,1,2 Chen-Ying Liu,1,2 Guanghui Wang,3 Long Cui,1,2 Yun Liu1,2

1Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Colorectal Cancer Research Center, Shanghai, People’s Republic of China; 3Guizhou Provincial People’s Hospital, Guizhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yun Liu Tel + 86-021-25078825
Guanghui Wang Email

Introduction: Stage I–III colorectal cancer patients are under risk of tumor recurrence and metachronous metastasis after radical surgery. An increased expression of transcription factor TEAD4 is associated with epithelial-mesenchymal transition, metastasis and poor prognosis in colorectal cancer. However, the mechanistic role of TEAD4 in driving colon cancer progression and its prognostic value in early stage of CRC remains unclear.
Methods: In this study, the regulation, function and prognostic significance of TEAD4 and its new direct target gene SIX1 in CRC progression were evaluated using human tissues, molecular and cell biology.
Results: We show that TEAD4 directly upregulates the expression of SIX1 at transcriptional level in CRC cells, establishing that SIX1 is a new direct target gene of TEAD4. TEAD4 promotes EMT and cell migration of CRC cells, while SIX1 knockdown attenuates this effect and SIX1 overexpression enhances this effect, indicating that SIX1 mediates the function of TEAD4 in promoting cell migration in CRC cells. Clinically, nuclear TEAD4, overexpression of SIX1 and nuclear TEAD4 with SIX1 overexpression predict poor prognosis in CRC patients.
Discussion: Our study identifies TEAD4-SIX1-CDH1 form a novel signaling axis, which contributes to CRC progression, and its aberrant expression and activation predicts poor prognostic for CRC patients in stage I–III.

Keywords: colorectal cancer, TEAD4, SIX1, hippo pathway

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