Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, but its molecular mechanisms are not yet well characterized. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, including that of HCC. However, the role of homeobox A11 antisense (HOXA11-AS) in determining HCC stem cell characteristics remains to be explained; hence, this study aimed to investigate the effects of HOXA11-AS on HCC stem cell characteristics. Initially, the expression patterns of HOXA11-AS and HOXA11 in HCC tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. Additionally, the potential relationship and the regulatory mechanisms that link HOXA11-AS, HOXA11, and the Wnt signaling pathway were explored through treatment with Dickkopf-1 (a Wnt signaling pathway inhibitor). HCC stem cells showed high expression of HOXA11-AS and low expression of HOXA11. Both HOXA11-AS silencing and HOXA11 overexpression suppressed the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo, as evidenced by the decreased expression of cancer stem cell surface markers (CD133 and CD44) and stemness-related transcription factors (Nanog, Sox2, and Oct4). Moreover, silencing HOXA11-AS inactivated the Wnt signaling pathway by decreasing the methylation level of the HOXA11 promoter, thereby inhibiting HCC stem cell characteristics. Collectively, this study suggested that HOXA11-AS silencing exerts an antitumor effect, suppressing HCC development via Wnt signaling pathway inactivation by decreasing the methylation level of the HOXA11 promoter.
Highlights
Hepatocellular carcinoma (HCC), which is acknowledged as the primary hepatic cancer, ranks as the six most common cancer worldwide and the fourth most frequently diagnosed cancer in China
The results showed that the expression of HOXA11-AS was higher in HCC tissues than in adjacent normal tissues and was associated with the prognosis of patients with HCC (p < 0.05) (Fig. 1c, d)
The results showed that the expression of HOXA11-AS was higher in the five HCC cell lines than in the L02 cell line
Summary
Hepatocellular carcinoma (HCC), which is acknowledged as the primary hepatic cancer, ranks as the six most common cancer worldwide and the fourth most frequently diagnosed cancer in China. HCC is the third most common cause of death due to cancer, both worldwide and in China[1,2]. Multiple risk factors, including viral infections, liver cirrhosis, aflatoxin. Guo et al Experimental & Molecular Medicine (2019) 51:142 exposure, obesity, and diabetes, are related to HCC5. Hepatitis B and C viruses (HBV and HCV, respectively) account for ~80% of the viral infections linked with HCC6. Patients with liver cirrhosis arising from excessive alcohol consumption are at increased risk for HCC7. An improved understanding of molecular events involved in HCC pathogenesis can enable the understanding of mechanistic aspects and drive the potential development of novel therapeutic approaches
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