Tenascin-C predicts poor outcomes for patients with colorectal cancer and drives cancer stemness via Hedgehog signaling pathway

Zhaoting Yang,Ying Feng,Yan Cui,Chengye Zhang,Mingji Quan,Yanhua Xuan

doi:10.1186/s12935-020-01188-w

Zhaoting Yang, Ying Feng + Show 4 more

Open Access

https://doi.org/10.1186/s12935-020-01188-w

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Abstract

BackgroundTenascin-C (TNC) is an extracellular matrix protein that is widely expressed in the stromal fibroblasts of various cancers. However, the roles of TNC in colorectal cancer (CRC) cells remain unclear.MethodsThe expression of TNC, cancer stem cell-like (CSC) and cell cycle markers, and Hedgehog (HH) signaling pathway genes were assessed in 100 paraffin embedded clinical CRC patient tissues using immunohistochemistry. The interaction between TNC and CSC marker or HH related genes in CRC cells were detected by immunofluorescence. Cell cycle distribution was measured by flow cytometry. Migration and invasion were evaluated by transwell assays. The expressions of TNC, CSC marker, and HH related proteins were analyzed by western blot.ResultsTNC expression was markedly upregulated in CRC tissues, and was associated with worse clinical outcomes. TNC overexpression was positively associated with CSC marker LSD1, cell cycle markers CDK4 and p16, and HH signaling pathway related genes SMO and GLI1 in clinical CRC tissue samples. TNC silencing downregulated the expression of the CSC marker LSD1, and the proliferation, migration, and invasion of CRC cells. Interestingly, the GLI1 inhibitor GANT61 strongly inhibited the expression of TNC in CRC cells.ConclusionsTNC may drive tumor progression and is involved in CSC properties via the HH signaling pathway. TNC has potential value in the evaluation of poor prognosis in CRC.

Highlights

Tenascin-C (TNC) is an extracellular matrix protein that is widely expressed in the stromal fibroblasts of various cancers
TNC regulates cancer stem cell-like (CSC) marker LSD1 in CRCTo determine whether TNC regulates the stemness for colorectal cancer (CRC) cells, we studied the association between TNC and the hallmark CSC genes CD133, CD44, LSD1, SOX2, and SOX9
Kaplan–Meier survival analysis revealed that CRC patients with high TNC expression had significantly shorter 5-year Overall survival (OS) (P = 0.007, Fig. 1e) and disease free survival (DFS) (P = 0.004, Fig. 1f )

Summary

Introduction

Tenascin-C (TNC) is an extracellular matrix protein that is widely expressed in the stromal fibroblasts of various cancers. The roles of TNC in colorectal cancer (CRC) cells remain unclear. Colorectal cancer (CRC) is the third leading cause of gastrointestinal cancer-related deaths in the industrialized world [1]. The occurrence of CRC has begun to decline in the wealthiest countries, the rate of incidence is still sharply increasing in the developing world [2]. A. Hedgehog (HH) signaling starts with the secretion of HH ligand; this is followed by the secretion of Patched (PTC), transmembrane protein Smoothened (SMO), and three GLI zinc finger transcription factors [3]. The HH/GLI1 pathway plays an important role in promoting carcinoma growth, stem cell self-renewal, and metastatic behavior in advanced colon cancers [4].

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