PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination

Wen, Jie; Xiong, Kai; Aili, Abudureyimujiang; Wang, Hao; Zhu, Yu; Yu, Zhengquan; Yao, Xueyan; Jiang, Ping; Xue, Lixiang; Wang, Junjie

doi:10.7150/thno.42371

Cited by 36 publications

(30 citation statements)

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“…Alteration of PEX3, PEX10, AGPS, and FAR1 showed no connection with ACSL4 and LPCAT3 ( Zou et al, 2020 ). In our previous work, PEX5 was found to be involved in radioresistance in hepatocellular carcinoma (HCC) ( Wen et al, 2020 ). However, the functions of peroxisomes in regulating ferroptosis sensitivity are dispensable given that the alkenyl-ether group is not critical to ferroptosis sensitivity.…”

Section: Fatty Acid Metabolism and Ferroptosismentioning

confidence: 99%

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

Yuan

Liu

Wang

et al. 2021

Front. Cell Dev. Biol.

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Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.

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Section: Fatty Acid Metabolism and Ferroptosismentioning

confidence: 99%

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

Yuan

Liu

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…MicroRNAs (miRNAs) are small (around 22 nucleotides), non-coding RNA gene products existing in many organisms and play crucial post-transcriptional regulatory roles in mRNA translation and degradation by binding to the 3′-untranslated region (3′-UTR) of target genes 4 . Aberrant expression of miRNAs alters numerous aspects of cellular function such as differentiation, apoptosis, and survival signaling, linking miRNAs to disease pathology 5 , 6 . Several miRNAs have demonstrated to be associated with sorafenib resistance and to function as predictive biomarkers for sorafenib responses in HCC patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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, LXRα, 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 LXRα 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 (LXRα), 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. LXRα 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.

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“…miR-31-5p is a well-known tumor-associated microRNA and participates in the progression of various tumors, including lung cancer, colorectal cancer, and hepatocellular carcinoma [ 16 , 17 ]. Emerging studies indicate that miR-31-5p also plays indispensable roles in maintaining the pathophysiological homeostasis in noncancerous tissues.…”

Section: Discussionmentioning

confidence: 99%

“…A number of researches have proved the necessity of microRNAs in modulating sepsis-induced inflammation, oxidative stress, and ALI [ 14 , 15 ]. miR-31-5p is well accepted as an oncogenic microRNA and participates in the proliferation, migration, invasion, and chemosensitivity of cancer cells [ 16 , 17 ]. Yet, Kim et al found that miR-31-5p was elevated in TNF- α -treated human endothelial cells and defined it as a NF- κ B-responsive microRNA with inflammation-modulating actions [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Results from Toyonaga et al indicated that miR-31-5p was upregulated in inflammatory bowel disease and was associated with colonic epithelial cell integrity and function [ 19 ]. Besides, a recent study reported the role of miR-31-5p on ROS accumulation in hepatocellular carcinoma [ 16 ]. Based on these data, we supposed that miR-31-5p might be involved in the pathogenesis of LPS-induced ALI.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway

Jiang

Zhao

Wen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Acute lung injury (ALI) and the subsequent acute respiratory distress syndrome remain devastating diseases with high mortality rates and poor prognoses among patients in intensive care units. The present study is aimed at investigating the role and underlying mechanisms of microRNA-31-5p (miR-31-5p) on lipopolysaccharide- (LPS-) induced ALI. Mice were pretreated with miR-31-5p agomir, antagomir, and their negative controls at indicated doses for 3 consecutive days, and then they received a single intratracheal injection of LPS (5 mg/kg) for 12 h to induce ALI. MH-S murine alveolar macrophage cell lines were cultured to further verify the role of miR-31-5p in vitro. For AMP-activated protein kinase α (AMPKα) and calcium-binding protein 39 (Cab39) inhibition, compound C or lentiviral vectors were used in vivo and in vitro. We observed an upregulation of miR-31-5p in lung tissue upon LPS injection. miR-31-5p antagomir alleviated, while miR-31-5p agomir exacerbated LPS-induced inflammation, oxidative damage, and pulmonary dysfunction in vivo and in vitro. Mechanistically, miR-31-5p antagomir activated AMPKα to exert the protective effects that were abrogated by AMPKα inhibition. Further studies revealed that Cab39 was required for AMPKα activation and pulmonary protection by miR-31-5p antagomir. We provide the evidence that endogenous miR-31-5p is a key pathogenic factor for inflammation and oxidative damage during LPS-induced ALI, which is related to Cab39-dependent inhibition of AMPKα.

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PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination

Cited by 36 publications

References 0 publications

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

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

MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKα Pathway

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