ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway

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Abstract

Background

ATP binding cassette subfamily A member 8 (ABCA8) belongs to the ATP binding cassette (ABC) transporter superfamily. ABCA8 is a transmembrane transporter responsible for the transport of organics, such as cholesterol, and drug efflux. Some members of the ABC subfamily, such as ABCA1, may inhibit cancer development. However, the mechanism of ABCA8 in the process of cancer activation is still ambiguous.

Methods

The expression of ABCA8 in human hepatocellular carcinoma (HCC) tissues and cell lines was examined using qPCR, immunoblotting, and immunohistochemical staining. The effects of ABCA8 on the proliferation and metastasis of HCC were examined using in vitro and in vivo functional tests. A luciferase reporter assay was performed to explore the binding between microRNA-374b-5p (miR-374b-5p) and the ABCA8 3′-untranslated region (UTR).

Results

ABCA8 was frequently down-regulated in HCC and this down-regulation was negatively correlated with prognosis. The overexpression of ABCA8 inhibited growth and metastasis in HCC, whereas the knockdown of ABCA8 exerted the antithetical effects both in vivo and in vitro. ABCA8 was down-regulated by miR-374b-5p; this down-regulation can induce epithelial transformation to mesenchyme via the ERK/ZEB1 signaling pathway and promote HCC progression.

Conclusion

We exposed the prognostic value of ABCA8 in HCC, and illuminated a novel pathway in ABCA8-regulated inhibition of HCC tumorigenesis and metastasis. These findings may lead to a new targeted therapy for HCC through the regulation of ABCA8, and miR-374b-5p.

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Most cited references 25

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Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.

Erick Morris, Sharda Jha, Clifford R Restaino … (2013)

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.

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Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer

Eric Cheung, Gina M. DeNicola, Colin Nixon … (2020)

Summary The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.

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ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition.

Matthew J. Lazzara, Janine Buonato (2014)

Overcoming cellular mechanisms of de novo and acquired resistance to drug therapy remains a central challenge in the clinical management of many cancers, including non-small cell lung cancer (NSCLC). Although much work has linked the epithelial-mesenchymal transition (EMT) in cancer cells to the emergence of drug resistance, it is less clear where tractable routes may exist to reverse or inhibit EMT as a strategy for drug sensitization. Here, we demonstrate that extracellular signal-regulated kinase (ERK) 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) signaling plays a key role in directing the mesenchymal character of NSCLC cells and that blocking ERK signaling is sufficient to heighten therapeutic responses to EGF receptor (EGFR) inhibitors. MEK1/2 (MAPKK1/2) inhibition promoted an epithelial phenotype in NSCLC cells, preventing induction of EMT by exogenous TGF-β. Moreover, in cells exhibiting de novo or acquired resistance to the EGFR inhibitor gefitinib, MEK inhibition enhanced the sensitivity to gefitinib and slowed cell migration. These effects only occurred, however, if MEK was inhibited for a period sufficient to trigger changes in EMT marker expression. Consistent with these findings, changes in EMT phenotypes and markers were also induced by the expression of mutant KRAS in a MEK-dependent manner. Our results suggest that prolonged exposure to MEK or ERK inhibitors may not only restrain EMT but also overcome naïve or acquired resistance of NSCLC to EGFR-targeted therapy in the clinic.

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Author and article information

Contributors

Zhaoyang Lu: lzy76772005@163.com

Lianxin Liu: LiuLX@ems.hrbmu.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 19 May 2020

Publication date PMC-release: 19 May 2020

Publication date Collection: 2020

Volume: 39

Electronic Location Identifier: 90

Affiliations

[1 ]GRID grid.412596.d, ISNI 0000 0004 1797 9737, Department of Hepatic Surgery, , The First Affiliated Hospital of Harbin Medical University, ; Harbin, Heilongjiang China

[2 ]GRID grid.419897.a, ISNI 0000 0004 0369 313X, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, ; Harbin, Heilongjiang China

[3 ]GRID grid.59053.3a, ISNI 0000000121679639, Department of Hepatobiliary Surgery, , The First Affiliated Hospital of University of Science and Technology of China, ; Hefei, Anhui China

[4 ]GRID grid.412651.5, ISNI 0000 0004 1808 3502, Department of Colorectal Surgery, , Harbin Medical University Cancer Hospital, ; Harbin, Heilongjiang China

Article

Publisher ID: 1591

DOI: 10.1186/s13046-020-01591-1

PMC ID: 7236190

PubMed ID: 32430024

SO-VID: afdeff5b-8d3b-492e-9d4c-9ecf66362dc6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 12 November 2019

Date accepted : 6 May 2020

Funding

Funded by: Changjiang Scholars and Innovative Research Team in University

Award ID: IRT1122

Award Recipient : Lianxin Liu

Funded by: National Natural Scientific Foundation of China

Award ID: 81602058

Award ID: 81301807

Award ID: 81772588

Award ID: 81972230

Award Recipient : Zhaoyang Lu Lianxin Liu

Funded by: National Natural Scientific Foundation of China

Award ID: 81773194

Award ID: 81902954

Award Recipient : Jihua Han Lianxin Liu

Funded by: FundRef http://dx.doi.org/10.13039/501100010009, Heilongjiang Provincial Postdoctoral Science Foundation;

Award ID: LBH-Z18132

Award ID: LBH-Z19182

Award Recipient : Xirui Liu Yan Wang

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma,atp binding cassette subfamily a member 8,epithelial to mesenchymal transition,therapeutic target

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma, atp binding cassette subfamily a member 8, epithelial to mesenchymal transition, therapeutic target

ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway

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Karger: Oncology

Most cited references 25

Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.

Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer

ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition.

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