Tenascin C Promotes Glioma Cell Malignant Behavior and Inhibits Chemosensitivity to Paclitaxel via Activation of the PI3K/AKT Signaling Pathway

Qingping Zhang,Qinghua Zhang,Fulan Hu,Xinmin Liu,Xianjin Chen,You Zuo,Binchu Xu

doi:10.1007/s12031-021-01832-8

Abstract

The present study aimed to detect the effect of tenascin C (TNC) on cell function and chemosensitivity to paclitaxel and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling in glioma cells.Human glioma cells U87, LN-229, T98G and U251 and normal human astrocytes were obtained, in which TNC expression was detected. The U87 cells and U251 cells were chosen and infected with lentivirus of control overexpression, TNC overexpression, control knockdown, and TNC knockdown for functional experiments. Rescue experiments were then performed to evaluate the effect of PI3K/AKT activator 740 Y-P on cell function and chemosensitivity to paclitaxel in TNC knockdown U251 cells. TNC mRNA and protein expression was elevated in glioma cells, including U87, LN-229, U251 and T98G cells, compared to normal human astrocytes. In U87 and U251 cells, TNC promoted proliferation while inhibiting apoptosis. In addition, TNC upregulated PI3K and p-AKT protein expression in U87 and U251 cells. As for chemosensitivity, TNC increased relative viability in U251 cells treated with 400 ng/mL and 800 ng/mL paclitaxel. In terms of stemness, TNC increased the sphere number per 1000 cells, CD44+CD133+ cell percentage and 1/stem cell frequency (assessed by extreme limiting dilution analysis) in U251 cells. In rescue experiments, 740 Y-P reduced the effect of TNC on proliferation, apoptosis, chemosensitivity to paclitaxel, and stemness in U251 cells. TNC acts as an oncogenic factor by promoting cancer cell proliferation and stemness while inhibiting apoptosis and chemosensitivity to paclitaxel in glioma via modulation of PI3K/AKT signaling.

Highlights

Tenascin C (TNC), a glycoprotein with a multi-modular structure that is mainly expressed in tendons and embryos, is a crucial regulator in embryonic development, predominantly via interaction with motile cells (Brosicke and Faissner 2015)
TNC mRNA was overexpressed in the human glioma cells, including U87 (P < 0.001), LN-229 (P < 0.001), U251 (P < 0.01) and T98G (P < 0.001) cells, compared to the normal human astrocytes (Fig. 1a), and TNC protein expression was upregulated in U87, LN-229, U251 and T89G cells compared to normal human astrocytes (Fig. 1b)
Further experiments revealed that TNC positively regulated cell proliferation at 48 h and 72 h post-transfection (Fig. 3a) but negatively modulated cell apoptosis in U251 cells (Fig. 3b, c)

Summary

Introduction

Tenascin C (TNC), a glycoprotein with a multi-modular structure that is mainly expressed in tendons and embryos, is a crucial regulator in embryonic development, predominantly via interaction with motile cells (Brosicke and Faissner 2015). TNC is expressed at very low levels in adult tissues compared with that in embryos, it is expressed most abundantly in stem cells, sites of inflammation or tissue trauma, and solid tumors in adults (Uenishi et al 2014; Ning et al 2019; Zhao et al 2017; Leppanen et al 2019). Since the first discovery regarding the role of TNC in cancers, over two decades have passed. Findings such as the involvement of TNC in tumor growth, metastasis and stemness have rejuvenated the research area of oncology (Sun et al 2018; Sun et al 2019; Yang et al 2019)

Objectives

Methods

Results

Conclusion