Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway

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Abstract

Background

KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that Kir2.1 may be associated with SCLC multidrug resistance (MDR). However, whether Kir2.1 can regulate MDR and its underlying mechanisms remain poorly understood in SCLC.

Methods

KCNJ2/Kir2.1 expression was examined in tissues from fifty-two SCLC cases by immunohistochemistry. Overexpression or knockdown of KCNJ2/Kir21 was performed in multidrug-resistant SCLC cell lines (H69AR and H446AR) and their parental cell lines (H69 and H446) to assess its influence on cell growth, apoptosis, the cell cycle and chemoresistance.

Results

KCNJ2/Kir2.1 was expressed in 44.23% (23/52) of SCLC tissues. Overexpression of KCNJ2/Kir2.1 was correlated with the clinical stage and chemotherapy response in SCLC patients. Knockdown of KCNJ2/Kir2.1 expression using KCNJ2/Kir2.1 shRNA in H69AR and H446AR cells inhibited cell growth and sensitized the cancer cells to chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest. Forced KCNJ2/Kir2.1 expression in H69 and H446 cells promoted cell growth and enhanced multidrug resistance via reduced drug-induced apoptosis accompanied by cell cycle arrest. KCNJ2/Kir2.1 expression was also influenced by PKC and MEK inhibitors. In addition, multidrug resistance protein 1 (MRP1/ABCC1) was confirmed to interact with KCNJ2/Kir2.1 by Co-IP assays.

Conclusions

KCNJ2/Kir2.1 modulates cell growth and drug resistance by regulating MRP1/ABCC1 expression and is simultaneously regulated by the Ras/MAPK pathway and miR-7. KCNJ2/Kir2.1 may be a prognostic predictor and a potentially novel target for interfering with chemoresistance in SCLC.

Electronic supplementary material

The online version of this article (doi:10.1186/s12943-015-0298-0) contains supplementary material, which is available to authorized users.

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Most cited references 33

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microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma.

Benjamin Kefas, Jakub Godlewski, Laurey Comeau … (2008)

microRNAs are noncoding RNAs inhibiting expression of numerous target genes, and a few have been shown to act as oncogenes or tumor suppressors. We show that microRNA-7 (miR-7) is a potential tumor suppressor in glioblastoma targeting critical cancer pathways. miR-7 potently suppressed epidermal growth factor receptor expression, and furthermore it independently inhibited the Akt pathway via targeting upstream regulators. miR-7 expression was down-regulated in glioblastoma versus surrounding brain, with a mechanism involving impaired processing. Importantly, transfection with miR-7 decreased viability and invasiveness of primary glioblastoma lines. This study establishes miR-7 as a regulator of major cancer pathways and suggests that it has therapeutic potential for glioblastoma.

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MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma.

YuXiang Fang, Jing-Lun Xue, Qi Shen … (2012)

MicroRNAs (miRNAs) are known to be involved in carcinogenesis and tumor progression in hepatocellular carcinoma (HCC). Recently, microRNA-7 (miR-7) has been proven to play a substantial role in glioblastoma and breast cancer, but its functions in the context of HCC remain unknown. Here, we demonstrate that miR-7 inhibits HCC cell growth and metastasis in vitro and in vivo. We first screened and identified a novel miR-7 target, phosphoinositide 3-kinase catalytic subunit delta (PIK3CD). Overexpression of miR-7 would specifically and markedly down-regulate its expression. miR-7-overexpressing subclones showed significant cell growth inhibition by G(0) /G(1) -phase cell-cycle arrest and significant impairment of cell migration in vitro. To identify the mechanisms, we investigated the phosphoinositide 3-kinase (PI3K)/Akt pathway and found that Akt, mammalian target of rapamycin (mTOR), and p70S6K were down-regulated, whereas 4EBP1 was up-regulated in miR-7-overexpressing subclones. We also identified two novel, putative miR-7 target genes, mTOR and p70S6K, which further suggests that miR-7 may be a key regulator of the PI3K/Akt pathway. In xenograft animal experiments, we found that overexpressed miR-7 effectively repressed tumor growth (3.5-fold decrease in mean tumor volume; n = 5) and abolished extrahepatic migration from liver to lung in a nude mouse model of metastasis (n = 5). The number of visible nodules on the lung surface was reduced by 32-fold. A correlation between miR-7 and PIK3CD expression was also confirmed in clinical samples of HCC. These findings indicate that miR-7 functions as a tumor suppressor and plays a substantial role in inhibiting the tumorigenesis and reversing the metastasis of HCC through the PI3K/Akt/mTOR-signaling pathway in vitro and in vivo. By targeting PIK3CD, mTOR, and p70S6K, miR-7 efficiently regulates the PI3K/Akt pathway. Given these results, miR-7 may be a potential therapeutic or diagnostic/prognostic target for treating HCC. Copyright © 2012 American Association for the Study of Liver Diseases.

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Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

Nikki Plaster, Rabi Tawil, Martin Tristani-Firouzi … (2001)

Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.

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Author and article information

Contributors

Huanxin Liu: liuhuanxin@smu.edu.cn

Jie Huang: h_jie2008@aliyun.com

Juan Peng: 185881427@qq.com

Xiaoxia Wu: 1013054401@qq.com

Yan Zhang: 35507531@qq.com

Weiliang Zhu: 754640115@qq.com

Linlang Guo: linlangg@yahoo.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 12 March 2015

Publication date PMC-release: 12 March 2015

Publication date Collection: 2015

Volume: 14

Electronic Location Identifier: 59

Affiliations

[ ]Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

[ ]Department of Pathology, Guangdong Provincial Corps Hospital of Chinese People’s Armed Police Forces, Guangzhou Medical College, Guangzhou, China

[ ]Department of Pathology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

[ ]Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Article

Publisher ID: 298

DOI: 10.1186/s12943-015-0298-0

PMC ID: 4373128

PubMed ID: 25777558

SO-VID: fc294ea5-6363-4aba-b5bf-eb8a04be109d

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

History

Date received : 6 September 2014

Date accepted : 15 January 2015

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: sclc,kcnj2/kir2.1,chemoresistance,mrp1/abcc1,mir-7,ras/mapk pathway

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: sclc, kcnj2/kir2.1, chemoresistance, mrp1/abcc1, mir-7, ras/mapk pathway

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Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway

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Most cited references 33

microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma.

MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma.

Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

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