Hepatocellular carcinoma (HCC) treatment is a major challenge. Although andrographolide (Andro) has an anti-proliferation effect on HCC, its underlying mechanism is not yet elucidated, and whether Andro can inhibit HCC metastasis has not been reported. The present study aimed to clarify whether Andro inhibits SK-Hep-1 cell proliferation and HCC metastasis, and the mechanisms. The results showed that Andro significantly reduced the survival of HCC cells and tumor weight and volume in tumor-bearing nude mice. Andro also triggered apoptosis of HCC cells and upregulated MIR22HG, Cleaved Caspase 9/7/3 expression levels, and downregulated BCL-2 mRNA, BCL-2 expression levels. Knockdown of MIR22HG or overexpression of HuR attenuated the effects of Andro on the signal transduction of mitochondrial apoptotic pathway and proliferation ability in HCC cells. Moreover, Andro significantly reduced the invasive ability of the cells and the level of HCC cell lung metastasis, upregulated miR-22-3p expression level and downregulated HMGB1 and MMP-9 expression levels. MIR22HG or miR-22-3p knockdown attenuated the effects of Andro on the signaling of HMGB1/MMP-9 pathway and invasive ability in HCC cells, while the overexpression of HMGB1 attenuated the inhibitory effects of Andro on the MMP-9 expression level and invasive ability in HCC cells. Thus, the regulation of MIR22HG-HuR/BCL-2 and MIR22HG/HMGB1 signaling pathways is involved in the anti-HCC proliferation and metastasis effects of Andro. This study provided a new pharmacological basis for Andro in HCC treatment and, for the first time, identified a natural product molecule capable of positively regulating MIR22HG, which has a robust biological function.

Graphical abstract

中文翻译：

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穿心莲内酯通过LncRNA MIR22HG调控抗肝癌增殖和转移

肝细胞癌（HCC）治疗是一个重大挑战。尽管穿心莲内酯（Andro）对HCC具有抗增殖作用，但其潜在机制尚未阐明，且Andro是否能抑制HCC转移尚未见报道。本研究旨在阐明Andro是否抑制SK-Hep-1细胞增殖和HCC转移及其机制。结果显示，Andro显着降低了荷瘤裸鼠中HCC细胞的存活率以及肿瘤重量和体积。Andro 还引发 HCC 细胞凋亡，上调 MIR22HG、Cleaved Caspase 9/7/3 表达水平，下调 BCL-2 mRNA、BCL-2 表达水平。MIR22HG 的敲低或 HuR 的过表达减弱了 Andro 对肝癌细胞线粒体凋亡途径信号转导和增殖能力的影响。此外，Andro显着降低细胞的侵袭能力和HCC细胞肺转移水平，上调miR-22-3p表达水平，下调HMGB1和MMP-9表达水平。MIR22HG或miR-22-3p敲低减弱了Andro对HCC细胞中HMGB1/MMP-9通路信号传导和侵袭能力的影响，而HMGB1的过表达减弱了Andro对MMP-9表达水平和侵袭能力的抑制作用HCC 细胞的能力。因此，MIR22HG-HuR/BCL-2和MIR22HG/HMGB1信号通路的调节参与了Andro的抗HCC增殖和转移作用。该研究为Andro治疗HCC提供了新的药理学基础，并首次鉴定出一种能够正向调节MIR22HG的天然产物分子，该分子具有强大的生物学功能。

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