Abstract
CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and is the most prevalent subtype of primary liver cancer, which accounts for about 30,000 deaths each year in Japan [1]
It is noteworthy that these cancer stem cell (CSC) markers showed a cell line-preferential expression pattern while the expression levels of Nuclear enriched abundant transcript 1 (NEAT1) were almost similar among the cell lines (Figure S1B)
These results indicate that NEAT1 expression is upregulated in CSCs
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and is the most prevalent subtype of primary liver cancer, which accounts for about 30,000 deaths each year in Japan [1]. The features of CSCs, such as tumorigenicity and resistance to conventional chemo- and radiotherapy, contribute to their survival, eventually causing recurrence and metastasis, even after these therapies have eliminated non-CSCs [5,6]. CSCs were first reported in acute myeloid leukemia [7], various tumors such as those of the brain, breast, lung, colon, and liver have been proven to harbor them [8,9,10,11,12]. It has been reported that CSCs significantly contribute to development, recurrence, and metastasis in many cancers [5,6]. The removal of CSCs is essential to completely eradicate cancer
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