Abstract
A high-fat diet is responsible for hepatic fat accumulation that sustains chronic liver damage and increases the risks of steatosis and hepatocellular carcinoma (HCC). MicroRNA-29a (miR-29a), a key regulator of cellular behaviors, is present in anti-fibrosis and modulator tumorigenesis. However, the increased transparency of the correlation between miR-29a and the progression of human HCC is still further investigated. In this study, we predicted HIF-1α and ANGPT2 as regulators of HCC by the OncoMir cancer database and showed a strong positive correlation with HIF-1α and ANGPT2 gene expression in HCC patients. Mice fed the western diet (WD) while administered CCl4 for 25 weeks induced chronic liver damage and higher HCC incidence than without fed WD mice. HCC section staining revealed signaling upregulation in ki67, severe fibrosis, and steatosis in WD and CCl4 mice and detected Col3a1 gene expressions. HCC tissues significantly attenuated miR-29a but increased in HIF-1α, ANGPT2, Lox, Loxl2, and VEGFA expression. Luciferase activity analysis confirms that miR-29a specific binding 3′UTR of HIF-1α and ANGPT2 to repress expression. In summary, miR-29a control HIF-1α and ANGPT2 signaling in HCC formation. This study insight into a novel molecular pathway by which miR-29a targeting HIF-1α and ANGPT2 counteracts the incidence of HCC development.
Highlights
Hepatocellular carcinoma (HCC) is considered the sixth most common cancer and the second principal detriment of cancer-related deaths worldwide, accounting for approximately 841,000 new cases and 782,000 deaths every year [1,2]
We demonstrate that miR-29a regulates the expression of hypoxia-inducible factors (HIFs)-1α and ANGPT2 in vivo and in vitro, offering novel insights into the miR-29a involved chronic liver disease in the developing of a practical diagnostic/prognostic panel for hepatocellular carcinoma (HCC)
We uncovered that liver tissue of mice treated with western diet (WD)/CCl4 upregulated the expression of HIF-1α and Angpt2 (Figure 4B,C)
Summary
Hepatocellular carcinoma (HCC) is considered the sixth most common cancer and the second principal detriment of cancer-related deaths worldwide, accounting for approximately 841,000 new cases and 782,000 deaths every year [1,2]. HCC exhibited upregulation of hypoxia-inducible factors (HIFs) and mediated neovascular and lymphatic vessel formation process to create an appropriate niche, allowing tumor progress, multiplying, and disorganized architecture. We have previously uncovered an anti-HCC effect of miR-29a via comprehensively suppressing the expression of lysyl oxidase family members, Lox, Loxl, and vascular endothelial growth factor A (VEGFA) [16]. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) has been characterized as the master regulator of cellular adaption to hypoxia in tumorigenesis microenvironment [18], which acts to promote various gene expressions, including angiogenic inducer VEGFs, VEGFRs, and ANGPTs [19]. We demonstrate that miR-29a regulates the expression of HIF-1α and ANGPT2 in vivo and in vitro, offering novel insights into the miR-29a involved chronic liver disease in the developing of a practical diagnostic/prognostic panel for HCC
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