The Long Noncoding RNA lncTCF7 Promotes Self-Renewal of Human Liver Cancer Stem Cells through Activation of Wnt Signaling

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (lncRNA) termed lncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, lncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that lncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an lncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that lncRNAs can play in tumor growth and propagation.

ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

“…CD13 and CD133 are widely used as liver CSC markers (6,28 (29).We analyzed differential noncoding RNA transcripts in liver CSCs compared with non-CSCs and showed that lncTCF7 is highly expressed in liver CSCs, playing a critical role in the maintenance of liver CSC self-renewal (29).…”

Upregulated GAPLINC predicts a poor prognosis in bladder cancer patients and promotes tumor proliferation and invasion

“…An increasing amount of evidence has indicated that certain lncRNAs exhibit crucial roles in human cancers, acting as oncogenes or tumor suppressors (20,21). The lncRNA GAPLINC was previously reported to be overexpressed in gastric cancer and colorectal cancer.…”

Long Non-coding RNAs and their Role in Metastasis

“…In addition, NBAT-1 inhibits invasion and proliferation of breast cancer cells due to activation of Wnt signaling through inactivation of dickkopf Wnt signaling inhibitor 1 (DKK1) via recruitment of PRC2 (153). The last lncRNA to be discussed is lncTCF-7, which has been studied in HCC and shown to be involved in renewal of human liver cancer stem cells (CSCs) and HCC aggressiveness through promotion of EMT (154,155). Self-renewal of liver CSCs is mediated through recruitment of the SWI/SNF chromatin remodeling complex resulting in activation of Wnt signaling through lncTCF-7 (154).…”

“…The last lncRNA to be discussed is lncTCF-7, which has been studied in HCC and shown to be involved in renewal of human liver cancer stem cells (CSCs) and HCC aggressiveness through promotion of EMT (154,155). Self-renewal of liver CSCs is mediated through recruitment of the SWI/SNF chromatin remodeling complex resulting in activation of Wnt signaling through lncTCF-7 (154). Activation of EMT in HCC cells is initiated by inflammatory cytokine IL6 which activates lncTCF7 expression through binding of STAT3 to the lncTCF7 promoter (155).…”