The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma

Jing Luo,Ronghua Wang,Jinlin Wang,Si Xiong,Bin Cheng,Man Liu,Yawen Li,Peng Wang

doi:10.18632/oncotarget.6672

Abstract

CD90 has been identified as a marker for liver cancer stem cells (CSCs) that are responsible for tumorigenic activity, but it is not known how CD90+ cells contribute to tumor initiation and progression. Our data demonstrated that high expression of CD90 in Hepatocellular Carcinoma (HCC) tissues correlated with venous filtration in HCC patients. CD90+ cells isolated from HCC cell lines exhibited increased tumorigenicity, chemoresistance, tumor invasion and metastasis. Notch pathway was activated in CD90+ cells and we found that inhibition of Notch pathway in CD90+ CSCs decreased tumorigenicity, cell invasion, migration and expression of stem cell related genes. Activation of Notch pathway in CD90− cells induced self-renewal, invasion and migration. Furthermore, we observed that cancer stem cell features were facilitated by stimulating G1-S transition in the cell cycle phase and inhibiting apoptosis mediated by Notch pathway. Our findings suggested CD90 could be used as a potential biomarker for HCC CSCs, and that cancer stem cell activity was elevated through up activated Notch pathway in CD90+ CSCs.

Highlights

Liver cancer is the fifth most commonly diagnosed cancer and the second most frequent cause of cancer death in men worldwide [1]
CD90 has been identified as a marker for liver cancer stem cells (CSCs) that are responsible for tumorigenic activity, but it is not known how CD90+ cells contribute to tumor initiation and progression
Four out of five patients with high CD90 expression correlated significantly with venous infiltration (P < 0.0001, Fisher’s exact test). Two of those four patients have developed Hepatocellular Carcinoma (HCC) recurrence, of the other 26 patients with low CD90 expression only occured 5 cases of recurrence and metastasis. These results indicated that high CD90 expression which may correlate with poor prognosis of HCC patients

Summary

Introduction

Liver cancer is the fifth most commonly diagnosed cancer and the second most frequent cause of cancer death in men worldwide [1]. There is increasing evidence that resistance to HCC therapy is, at least in part, caused by inherent resistance of a subpopulation of cancer cells. This subpopulation shares many properties with stem cells and has been labeled as CSCs [2, 3]. Using a variety of stem cell markers, CSCs have been identified in solid tumors, including pancreatic cancer, colon cancer, breast cancer and HCC [4,5,6,7]. Many CSC biomarkers (e.g., CD133, CD13, CD24, EpCAM, Nanog) have been identified in HCC, it is still unclear which biomarker truly represents

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Conclusion