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LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

ABSTRACT: Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods: A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. Interactions among miR-378a-3p, LXR?, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXR? and its downstream miR-378a-3p. Results: miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXR?), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo. Conclusions: Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXR? was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.

SUBMITTER: Lin Z

PROVIDER: S-EPMC7392029 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

Lin Zhongjie Z Xia Shunjie S Liang Yuelong Y Ji Lin L Pan Yu Y Jiang Shi S Wan Zhe Z Tao Liye L Chen Jiang J Lin Chengping C Liang Xiao X Xu Junjie J Cai Xiujun X

Theranostics 20200711 19

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the under ...[more]

PMID: 32754282

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Project description:Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann-Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

Project description:Rationale: Hyperlipidemia is a major risk factor of atherosclerosis and cardiovascular diseases (CVD). As a standard-of-care approach for hyperlipidemia, statins only reduce the risk of coronary artery disease by 20-40%, underscoring the importance of identifying molecular pathways for the design of drugs against this disorder. Alterations in microRNA (miRNA) expression have been reported in patients with hyperlipidemia and CVD. This study was designed to determine the mechanism of dysregulated miR-378a-3p under the status of hyperlipidemia and evaluate how miR-378a-3p regulates hepatic secretion of VLDL. Methods: Wild-type mice kept on a high fat diet were injected with miR-378a-3p inhibitor or a mini-circle expression system containing miR-378a precursor to study loss and gain-of functions of miR-378a-3p. Mice were treated with Triton WR1339 and 35S-methionine/cysteine to determine the effect of miR-378a-3p on hepatic secretion of VLDL. Database mining, luciferase assay, and ChIP (chromatin immunoprecipitation) were used to study the mechanism of dysregulated miR-378a-3p biogenesis. Results: miR-378a-3p expression is significantly increased in livers of hyperlipidemic mice. Sort1 (sortilin 1) was identified as a direct target of miR-378a-3p. By inhibiting the function of sortilin 1 as a transmembrane trafficking receptor, miR-378a-3p stabilized ApoB100 and promoted ApoB100 secretion in vitro. Liver-specific expression of miR-378a-3p stabilized ApoB100 and facilitated hepatic secretion of VLDL, which subsequently increased levels of VLDL/LDL cholesterol as well as triglycerides. In contrast, antagonizing miR-378a-3p using its inhibitor increased hepatic expression of Sort1 and reduced hepatic export of VLDL with its consequent effects of serum lipid levels. Additional knockdown of up-regulated Sort1 in livers of mice offset the effects of miR-378a-3p inhibitor, suggesting that Sort1 was indispensable for miR-378a-3p to promote secretion of VLDL and thereby high levels of circulating VLDL/LDL cholesterol and triglycerides. Furthermore, oncogenic E2F1 (E2F transcription factor 1) was identified as a transcriptional activator of miR-378a-3p. E2f1 knockdown, through reducing miR-378a-3p, impaired secretion of VLDL and reduced levels of VLDL/LDL cholesterol and triglycerides. Conclusions: This study defines a novel pathway of E2F1-miR-378a-3p-SORT1-ApoB100 that controls levels of circulating VLDL/LDL cholesterol and triglycerides by modulating degradation and secretion of ApoB100, and suggests the use of miR-378a-3p as a potential therapeutic target for dyslipidemia.

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LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

Publications

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

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