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Inhibitor of DNA binding 1 (Id1) mediates stemness of colorectal cancer cells through the Id1-c-Myc-PLAC8 axis via the Wnt/β-catenin and Shh signaling pathways

Authors Sun Y, Lai X, Yu Y, Li J, Cao L, Lin W, Huang C, Liao J, Chen W, Li C, Yang C, Ying M, Chen Q, Ye Y

Received 28 February 2019

Accepted for publication 15 June 2019

Published 23 July 2019 Volume 2019:11 Pages 6855—6869

DOI https://doi.org/10.2147/CMAR.S207167

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Ahmet Emre Eskazan


Yanxia Sun,*,1,2 Xiaolan Lai,*,3 Yue Yu,1,2 Jieyu Li,2,4 Lei Cao,3 Wansong Lin,2,4 Chuanzhong Huang,2,4 Jinrong Liao,2,4 Wei Chen,1,2 Chao Li,5 Chunkang Yang,6 Mingang Ying,6 Qiang Chen,3 Yunbin Ye2,4

1School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian Province, People’s Republic of China; 2Laboratory of Immuno-Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 3Department of Medical Oncology, Union Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People’s Republic of China; 4Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, People’s Republic of China; 5Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 6Department of Abdominal Surgery, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China

*These authors contributed equally to this work

Background: Inhibitor of DNA binding 1 (Id1) is upregulated in multiple cancers, and Id1overexpression correlates with cancer aggressiveness and poor clinical outcomes in cancer patients. However, its roles in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) are still elusive.
Purpose: This study aimed to examine the role of Id1 on the mediation of CRC stemness and explore the underlying mechanisms.
Methods: Id1 and CD133 expression was detected by qPCR assay and immunohistochemistry (IHC) in normal mucosal and primary colorectal cancer (CRC) specimens. Id1 was stably knocked down (KD) in human CRC cell lines. Spheres forming assay and tumorigenic assay were performed to evaluate self-renewal capacity and tumor initiation. Expression of CSC- and EMT-related markers and TCF/LEF activity were assessed in HCT116 cells after Id1 KD.
Results: qPCR assay showed higher Id1 and CD133 expression in CRC specimens than in normal mucosal specimens (P<0.05). IHC detected high cytoplasmic Id1 expression in 35 CRC specimens (46.7%), and high CD133 expression in 22 CRC specimens (29.3%) and negative expression in 18 normal mucosal specimens. High Id1 expression positively correlated with poor differentiation (P=0.034), and CD133 expression correlated with T category in CRC patients (P=0.002). Spearman correlation analysis revealed a positive correlation between Id1 and CD133 expression in CRC patients (P<0.05). Id1 KD resulted in suppression of proliferation, cell-colony formation, self-renewal capability and CSC-like features in HCT116 cells, and impaired the tumor-initiating capability in CRC cells. In addition, Id1 maintained the stemness of CRC cells via the Id1-c-Myc-PLAC8 axis through activating the Wnt/β-catenin and Shh signaling pathways.
Conclusions: Id1 expression significantly correlates with CD133 expression in CRC patients, and Id1 KD impairs CSC-like capacity and reverses EMT traits, partially via the Wnt/β-catenin signaling. Id1 may be a promising therapeutic target against colon CSCs.

Keywords: inhibitor of DNA binding 1, Id1, self-renewal, stemness, epithelial-mesenchymal transition, colon cancer, Wnt/β-catenin signaling pathway

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