The long non-coding RNA Linc-GALH promotes hepatocellular carcinoma metastasis via epigenetically regulating Gankyrin

Xiaoliang Xu,Yun Lou,Zhongming Tan,Junwei Tang,Zechuan Zhang,Yue Teng,Han Zhuo,Yin Yin

doi:10.1038/s41419-019-1348-0

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by high rate of metastasis and recurrence. Recent studies have boosted our understanding that Gankyrin contributes to both of these pathological properties, but the mechanisms underlying its aberrant regulation are poorly understood. Recently, many long noncoding RNAs (lncRNAs) have been reported to be involved in regulating the expression of oncogenes and anti-oncogenes through various mechanisms. Here, using transcriptome microarray analysis, we identified a long intergenic noncoding RNA termed Linc-GALH that was highly expressed and concordance with Gankyrin expression in HCC. In addition, we revealed that Linc-GALH was an independent unfavorable prognostic indicator for HCC, followed functional experiments showed that Linc-GALH promoted HCC cells migration and invasion in vitro, and enhanced lung metastasis ability of HCC cells in vivo. Mechanistically, we found that Linc-GALH could regulate the expression of Gankyrin through controlling the methylation status of Gankyrin by adjusting the ubiquitination status of DNMT1 in HCC. Collectively, our results demonstrated the role and functional mechanism of Linc-GALH in HCC, and indicated that Linc-GALH may act as a prognostic biomarker and potential therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is emerging as the fifth most common carcinoma and the third leading cause of cancer-associated mortality worldwide[1]
Linc-GALH expression accordance with Gankyrin is upregulated in HCC tumor tissues Previous studies revealed that Gankyrin was an oncogene in HCC6, to reconfirm this, we detected the expression level of Gankyrin in normal liver tissues (n = 12), liver cirrhosis tissues (n = 81), primary liver cancerous tissues (n = 82) and hepatocellular carcinoma with portal vein tumor thrombus (PVTT) tissues (n = 26) by using immunohistochemical assays, western blot and qRT-PCR (Figs. 1a, b, e)
Filtered by P-value and fold change (P < 0.05 and fold change >3), we identified 179 long noncoding RNAs (lncRNAs) aberrant upregulated in cirrhosis liver tissues compared with normal liver tissues, 81 lncRNAs aberrant upregulated in primary HCC tissues compared with cirrhosis liver tissues and 212 lncRNAs aberrant upregulated in tissues from HCC patients with PVTT compared with primary HCC tissues

Summary

Introduction

Hepatocellular carcinoma (HCC) is emerging as the fifth most common carcinoma and the third leading cause of cancer-associated mortality worldwide[1]. Aggressiveness, invasiveness (in particular, intrahepatic) and frequent postoperative recurrence are the most significant characteristics of HCC3. Gankyrin was illustrated to activate Akt through regulating RhoA/ROCK signaling pathway and promote tumorigenesis and metastasis of HCC5. Gankyrin could activate PI-3K/Akt/HIF1α pathway to promote the expression of Twist[1], VEGF and MMP2, accelerated the EMT transformation of hepatoma cells[6]. It has been found high expressed in other malignant tumors such as lung cancer, breast cancer, colon cancer and so on[7,8,9,10]. A study published in 2014 revealed that the expression of Gankyrin in patients with metastatic gastric cancer was significantly lower than that in patients without metastatic gastric cancer

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Results

Conclusion