S100A8 promotes epithelial-mesenchymal transition and metastasis under TGF-β/USF2 axis in colorectal cancer

Si Li; Jun Zhang; Senmi Qian; Xuesong Wu; Liang Sun; Tianyi Ling; Yao Jin; Wenxiao Li; Lichao Sun; Maode Lai; Fangying Xu

doi:10.1002/cac2.12130

S100A8 promotes epithelial-mesenchymal transition and metastasis under TGF-β/USF2 axis in colorectal cancer

Cancer Commun (Lond). 2021 Feb;41(2):154-170. doi: 10.1002/cac2.12130. Epub 2021 Jan 3.

Authors

Si Li^{1

2}, Jun Zhang^{1

2}, Senmi Qian^{1

2}, Xuesong Wu^{3

2}, Liang Sun^{1

2}, Tianyi Ling³, Yao Jin³, Wenxiao Li³, Lichao Sun⁴, Maode Lai^{3

2}, Fangying Xu^{1

2}

Affiliations

¹ Department of Pathology and Pathophysiology, and Department of General Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, P. R. China.
² Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, P. R. China.
³ Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, P. R. China.
⁴ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.

Abstract

Background: The transforming growth factor-β (TGF-β) pathway plays a pivotal role in inducing epithelial-mesenchymal transition (EMT), which is a key step in cancer invasion and metastasis. However, the regulatory mechanism of TGF-β in inducing EMT in colorectal cancer (CRC) has not been fully elucidated. In previous studies, it was found that S100A8 may regulate EMT. This study aimed to clarify the role of S100A8 in TGF-β-induced EMT and explore the underlying mechanism in CRC.

Methods: S100A8 and upstream transcription factor 2 (USF2) expression was detected by immunohistochemistry in 412 CRC tissues. Kaplan-Meier survival analysis was performed. In vitro, Western blot, and migration and invasion assays were performed to investigate the effects of S100A8 and USF2 on TGF-β-induced EMT. Mouse metastasis models were used to determine in vivo metastasis ability. Luciferase reporter and chromatin immunoprecipitation assay were used to explore the role of USF2 on S100A8 transcription.

Results: During TGF-β-induced EMT in CRC cells, S100A8 and the transcription factor USF2 were upregulated. S100A8 promoted cell migration and invasion and EMT. USF2 transcriptionally regulated S100A8 expression by directly binding to its promoter region. Furthermore, TGF-β enhanced the USF2/S100A8 signaling axis of CRC cells whereas extracellular S100A8 inhibited the USF2/S100A8 axis of CRC cells. S100A8 expression in tumor cells was associated with poor overall survival in CRC. USF2 expression was positively related to S100A8 expression in tumor cells but negatively related to S100A8-positive stromal cells.

Conclusions: TGF-β was found to promote EMT and metastasis through the USF2/S100A8 axis in CRC while extracellular S100A8 suppressed the USF2/S100A8 axis. USF2 was identified as an important switch on the intracellular and extracellular S100A8 feedback loop.

Keywords: S100 calcium-binding protein A8; colorectal cancer; epithelial-mesenchymal transition; metastasis; prognosis; transforming growth factor-β; upstream transcription factor 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calgranulin A / metabolism
Cell Line, Tumor
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Transforming Growth Factor beta / metabolism
Upstream Stimulatory Factors

Substances

Calgranulin A
S100A8 protein, human
S100a8 protein, mouse
Transforming Growth Factor beta
USF2 protein, human
Upstream Stimulatory Factors