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Exposure to ambient particular matters (PM) has been associated with the development of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study aimed to explore the role of miRNA-mRNA regulation underlying abnormal lipid metabolism triggered by PM 2.5 liposoluble extracts. We confirmed that 72-h exposure to liposoluble extracts of PM 2.5 from Nanjing at 25 μg/cm2 induced lipid accumulation in HepG2 cells by promoting uptake of free fatty acids (FFAs). Notably, lipid accumulation induced by PM 2.5 liposoluble extracts was associated with decreased expression of miR-26a and consequent upregulation of fatty acid translocase (FAT, also known as CD36). Using gain- and loss-of-function assays, we demonstrated that miR-26a negatively regulated CD36 to mediate lipid accumulation in HepG2 cells. We further confirmed that miR-26a directly acted on the 3′ untranslated region (3′UTR) of CD36. Furthermore, overexpression of miR-26a abolished steatosis in HepG2 cells treated with PM 2.5 liposoluble extracts by suppressing CD36. In addition, we demonstrated that PM 2.5 liposoluble extracts caused inflammation in HepG2 cells by raising p65 phosphorylation, thereby fuelling the transition from simple non-alcoholic fatty liver to non-alcoholic steatohepatitis. In conclusion, this study demonstrated a novel mechanism by which miR-26a-CD36 pathway mediated lipid accumulation induced by PM 2.5 liposoluble extracts in hepatocytes. Lipid accumulation and inflammation induced by PM 2.5 liposoluble extracts implied the potential role of PM 2.5 in developing NAFLD. Image 1 • PM 2.5 liposoluble extracts induced inflammation and lipid accumulation in HepG2 cells. • PM 2.5 liposoluble extracts induced miR-26a deficiency to raise CD36, thus promoting uptake of FFAs. • CD36 is a direct target of miR-26a. • MiR-26a overexpression abolished steatosis in HepG2 cells by suppressing CD36. This study demonstrated novel molecular mechanisms by which PM 2.5 liposoluble extracts contributed to the development of non-alcoholic fatty liver disease (NAFLD). [ABSTRACT FROM AUTHOR]

Abstract Background Our previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). The direct roles of miR-26a on tumor cell invasion remain poorly understood. In this study, we aim to explore the mechanism of miR-26a in modulating epithelial-mesenchymal transition (EMT) in HCC. Methods In vitro cell morphology and cell migration were compared between the hepatoma cell lines HCCLM3 and HepG2, which were established in the previous study. Overexpression and down-regulation of miR-26a were induced in these cell lines, and Western blot and immunofluorescence assays were used to detect the expression of EMT markers. Xenograft nude mouse models were used to observe tumor growth and pulmonary metastasis. Immunohistochemical assays were conducted to study the relationships between miR-26a expression and enhancer of zeste homolog 2 (EZH2) and E-cadherin expression in human HCC samples. Results Down-regulation of miR-26a in HCCLM3 and HepG2 cells resulted in an EMT-like cell morphology and high motility in vitro and increased in tumor growth and pulmonary metastasis in vivo. Through down-regulation of EZH2 expression and up-regulation of E-cadherin expression, miR-26a inhibited the EMT process in vitro and in vivo. Luciferase reporter assay showed that miR-26a directly interacted with EZH2 messenger RNA (mRNA). Furthermore, the expression of miR-26a was positively correlated with E-cadherin expression and inversely correlated with EZH2 expression in human HCC tissue. Conclusions miR-26a inhibited the EMT process in HCC by down-regulating EZH2 expression.

Background: Literatures have confirmed role of inflammatory mediators like interleukin-2 (IL-2) in non-small cell lung cancer (NSCLC). microRNA-26a (miR-26a) is involved in variety of signaling pathways and functions as tumor suppressor and regulating the responsible genes at posttranscriptional level. The aim of study was to study the correlation of IL-2 and miR-26a in lung cancer (LC) cells., Methods: For the study we selected 32 subjects reported for NSCLC and 20 with chronic obstructive pulmonary disease (COPD) as control in the present study. For in vitro analysis, H-460 and H-226 cell lines were selected and received treatment of varying dose of IL-2 to study the effect of IL-2 on expression of miR-26a and vascular cell adhesion molecule-1 (VCAM-1). miR-26a mimic and miR-26a inhibitor were transfected to study the effect on progression and migration of tumor cell as well as on levels of VCAM-1., Results: We evidenced that, expression of miR-26a was suppressed, whereas levels of IL-2 and VCAM-1 were increased in NSCLC tissues. IL-2 down-regulated the levels of miR-26a but upregulated the levels of VCAM-1 in H-460 and H-226 cells. miR-26a modulated the expression level of VCAM-1 via binding the 3'-UTR region. We found that miR-26a attenuated the migration and proliferation of H-460 and H-226 cells. IL-2 modulated the levels of miR-26a via activating p65 but not STAT-3., Conclusions: All together, the finding of our study show that miR-26a blocks IL-2 mediated proliferation and migration of NSCLC via targeting VCAM-1., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.02.36). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Exposure to ambient particular matters (PM) has been associated with the development of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study aimed to explore the role of miRNA-mRNA regulation underlying abnormal lipid metabolism triggered by PM 2.5 liposoluble extracts. We confirmed that 72-h exposure to liposoluble extracts of PM 2.5 from Nanjing at 25 μg/cm 2 induced lipid accumulation in HepG2 cells by promoting uptake of free fatty acids (FFAs). Notably, lipid accumulation induced by PM 2.5 liposoluble extracts was associated with decreased expression of miR-26a and consequent upregulation of fatty acid translocase (FAT, also known as CD36). Using gain- and loss-of-function assays, we demonstrated that miR-26a negatively regulated CD36 to mediate lipid accumulation in HepG2 cells. We further confirmed that miR-26a directly acted on the 3' untranslated region (3'UTR) of CD36. Furthermore, overexpression of miR-26a abolished steatosis in HepG2 cells treated with PM 2.5 liposoluble extracts by suppressing CD36. In addition, we demonstrated that PM 2.5 liposoluble extracts caused inflammation in HepG2 cells by raising p65 phosphorylation, thereby fuelling the transition from simple non-alcoholic fatty liver to non-alcoholic steatohepatitis. In conclusion, this study demonstrated a novel mechanism by which miR-26a-CD36 pathway mediated lipid accumulation induced by PM 2.5 liposoluble extracts in hepatocytes. Lipid accumulation and inflammation induced by PM 2.5 liposoluble extracts implied the potential role of PM 2.5 in developing NAFLD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)