Scientists from Institute of Biophysics, Chinese Academy of Sciences, have identified a gene that negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signaling pathway. Then by maintaining the stemness of liver cancer stem cells, it can promote liver cancer cells’ chemoresistance and recurrence. This study was published on Nature Communication.
Hepatocellular carcinoma(HCC), the most common liver cancer, is the third leading cause of cancer related death. The 5-year survival rate of HCC patients remains poor, and >750,000 HCC patients die each year. The high rate of recurrence and heterogeneity are the two major features of HCC. Many studies have suggested that heterogeneity is a result of the hierarchical organization of tumour cells by a subset of cells with stem/progenitor cell features known as cancer stem cells(CSCs), which are cancer cells with stem cell features.
Like stem cells, CSCs are characterized by self-renewal and differentiation simultaneously. Not surprisingly, CSCs share core regulatory genes and developmental pathways with normal tissue stem cells. C8orf4, also called thyroid cancer 1(TC1), was originally cloned from a papillary thyroid carcinoma and its surrounding normal thyroid tissue. However, how the NOTCH signaling regulates the liver CSC self-renewal remains largely unknown.
In this study, based on analysis of several HCC transcriptome datasets and our experimental data, scientists find that C8orf4 is weakly expressed in HCC tumors and liver CSCs. C8orf4 attenuates the self-renewal capacity of liver CSCs and tumor propagation. They show that NOTCH2 is activated in liver CSCsC8orf4 is located in the cytoplasm of HCC tumour cells and associates with the NOTCH2 intracellular domain, which impedes the nuclear translocation of N2ICD. C8orf4 deletion causes the nuclear translocation of N2ICD that triggers the NOTCH2 signaling, which sustains the stemness of liver CSCs. Finally, NOTCH2 activation levels are consistent with clinical severity and prognosis of HCC patients. Altogether, C8orf4 negatively regulates the self-renewal of liver CSCs via suppression of NOTCH2 signaling.
Reference:
Zhu P, Wang Y, Du Y, et al. C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signaling[J]. Nature communications, 2015, 6.