MiR-182-5p and its target HOXA9 in non-small cell lung cancer: a clinical and in-silico exploration with the combination of RT-qPCR, miRNA-seq and miRNA-chip

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Abstract

Background

MiR-182-5p, a cancer-related microRNA (miRNA), modulates tumorigenesis and patient outcomes in various human malignances. This study interroted the clinicopathological significance and molecular mechanisms of miR-182-5p in non-small cell lung cancer (NSCLC).

Methods

The clinical significance of miR-182-5p in NSCLC subtypes was determined based on an analysis of 124 samples (lung adenocarcinomas [LUADs], n = 101; lung squamous cell carcinomas [LUSCs], n = 23) obtained from NSCLC patients and paired noncancer tissues and an analysis of data obtained from public miRNA-seq database, miRNA-chip database, and the scientific literature. The NSCLC samples ( n = 124) were analyzed using the real-time quantitative polymerase chain reaction (RT-qPCR). Potential targets of miR-182-5p were identified using lists generated by miRWalk v.2.0, a comprehensive atlas of predicted and validated targets of miRNA-target interactions. Molecular events of miR-182-5p in NSCLC were unveiled based on a functional analysis of candidate targets. The association of miR-182-5p with one of the candidate target genes, homeobox A9 ( HOXA9), was validated using in-house RT-qPCR and dual-luciferase reporter assays.

Results

The results of the in-house RT-qPCR assays analysis of data obtained from public miRNA-seq databases, miRNA-chip databases, and the scientific literature all supported upregulation of the expression level of miR-182-5p level in NSCLC. Moreover, the in-house RT-qPCR data supported the influence of upregulated miR-182-5p on malignant progression of NSCLC. In total, 774 prospective targets of miR-182-5p were identified. These targets were mainly clustered in pathways associated with biological processes, such as axonogenesis, axonal development, and Ras protein signal transduction, as well as pathways involved in axonal guidance, melanogenesis, and longevity regulation, in multiple species. Correlation analysis of the in-house RT-qPCR data and dual-luciferase reporter assays confirmed that HOXA9 was a direct target of miR-182-5p in NSCLC.

Conclusions

The miR-182-5p expression level was upregulated in NSCLC tissues. MiR-182-5p may exert oncogenic influence on NSCLC through regulating target genes such as HOXA9.

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Most cited references 49

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HOX genes and their role in the development of human cancers.

Seema Bhatlekar, Jeremy Fields, Bruce M. Boman (2014)

In this review, we summarize published findings on the involvement of HOX genes in oncogenesis. HOX genes are developmental genes--they code for proteins that function as critical master regulatory transcription factors during embryogenesis. Many reports have shown that the protein products of HOX genes also play key roles in the development of cancers. Based on our review of the literature, we found that the expression of HOX genes is not only up- or downregulated in most solid tumors but also that the expression of specific HOX genes in cancers tends to differ based on tissue type and tumor site. It was also observed that HOXC family gene expression is upregulated in most solid tumor types, including colon, lung, and prostate cancer. The two HOX genes that were reported to be most commonly altered in solid tumors were HOXA9 and HOXB13. HOXA were often reported to have altered expression in breast and ovarian cancers, HOXB genes in colon cancers, HOXC genes in prostate and lung cancers, and HOXD genes in colon and breast cancers. It was found that HOX genes are also regulated at the nuclear-cytoplasmic transport level in carcinomas. Tumors arising from tissue having similar embryonic origin (endodermal), including colon, prostate, and lung, showed relatively similar HOXA and HOXB family gene expression patterns compared to breast tumors arising from mammary tissue, which originates from the ectoderm. The differential expression of HOX genes in various solid tumors thus provides an opportunity to advance our understanding of cancer development and to develop new therapeutic agents.

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miR-146a Inhibits Cell Growth, Cell Migration and Induces Apoptosis in Non-Small Cell Lung Cancer Cells

Gang Chen, Ijeoma Umelo, Shasha Lv … (2013)

Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-κB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC.

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RISC assembly: Coordination between small RNAs and Argonaute proteins.

Hotaka Kobayashi, Yukihide Tomari (2016)

Non-coding RNAs generally form ribonucleoprotein (RNP) complexes with their partner proteins to exert their functions. Small RNAs, including microRNAs, small interfering RNAs, and PIWI-interacting RNAs, assemble with Argonaute (Ago) family proteins into the effector complex called RNA-induced silencing complex (RISC), which mediates sequence-specific target gene silencing. RISC assembly is not a simple binding between a small RNA and Ago; rather, it follows an ordered multi-step pathway that requires specific accessory factors. Some steps of RISC assembly and RISC-mediated gene silencing are dependent on or facilitated by particular intracellular platforms, suggesting their spatial regulation. In this review, we summarize the currently known mechanisms for RISC assembly of each small RNA class and propose a revised model for the role of the chaperone machinery in the duplex-initiated RISC assembly pathway. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.

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Author and article information

Contributors

Li Gao: 2339352006@qq.com

Shi-bai Yan: 522937211@qq.com

Jie Yang: yanglz2005@126.com

Jin-liang Kong: kjl071@126.com

Ke Shi: 529057611@qq.com

Fu-chao Ma: mafuchao@live.cn

Lin-zhen Huang: 944354533@qq.com

Jie Luo: 1164524563@qq.com

Shu-ya Yin: 349230442@qq.com

Rong-quan He: herongquan@gxmu.edu.cn

Xiao-hua Hu: huxiaohua@gxmu.edu.cn

Gang Chen: chengang@gxmu.edu.cn

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8794

Publication date (Electronic): 6 January 2020

Publication date PMC-release: 6 January 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 3

Affiliations

[1 ]GRID grid.412594.f, Department of Pathology, , the First Affiliated Hospital of Guangxi Medical University, ; Zhuang Autonomous Region, Nanning, 530021 Guangxi China

[2 ]GRID grid.412594.f, Department of Medical Oncology, , the First Affiliated Hospital of Guangxi Medical University, ; Zhuang Autonomous Region, Nanning, 530021 Guangxi China

[3 ]ISNI 0000 0004 1798 2653, GRID grid.256607.0, Department of Pharmacology, , School of Pharmacy, Guangxi Medical University, ; Zhuang Autonomous Region, Nanning, 530021 Guangxi China

[4 ]GRID grid.412594.f, Department of Respiratory and Critical Care Medicine, , the First Affiliated Hospital of Guangxi Medical University, ; Zhuang Autonomous Region, Nanning, 530021 Guangxi China

[5 ]GRID grid.412594.f, Department of Medical Oncology, , the Second Affiliated Hospital of Guangxi Medical University, ; Zhuang Autonomous Region, Nanning, 530021 Guangxi China

Article

Publisher ID: 648

DOI: 10.1186/s12920-019-0648-7

PMC ID: 6945423

PubMed ID: 31906958

SO-VID: 265449b7-275a-43e2-9b22-8426595bd581

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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 : 2 May 2019

Date accepted : 19 December 2019

Funding

Funded by: National Natural Science Foundation of China

Award ID: NSFC81560469, NSFC81360327

Funded by: Natural Science Foundation of Guangxi, China

Award ID: 2015GXNSFCA139009, 2017GXNSFAA198016

Funded by: Guangxi Medical University Training Program for Distinguished Young Scholars (2017) and Innovation Project of Guangxi Graduate Education

Award ID: 201710598080

Funded by: Guangxi Degree and Postgraduate Education Reform and Development Research Projects, China

Award ID: JGY2019050

Funded by: Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University

Funded by: Science and Technology Innovation Training Program for College Students in the First Clinical Medical College of Guangxi Medical University in 2018

Award ID: 1

Award Recipient : Li Gao

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: mir-182-5p,non-small cell lung cancer,rt-qpcr,mirna-seq,mirna-chips,hoxa9

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ScienceOpen disciplines: Genetics

Keywords: mir-182-5p, non-small cell lung cancer, rt-qpcr, mirna-seq, mirna-chips, hoxa9

MiR-182-5p and its target HOXA9 in non-small cell lung cancer: a clinical and in-silico exploration with the combination of RT-qPCR, miRNA-seq and miRNA-chip

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Abstract

Background

Methods

Results

Conclusions

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RNA drug delivery

Most cited references 49

HOX genes and their role in the development of human cancers.

miR-146a Inhibits Cell Growth, Cell Migration and Induces Apoptosis in Non-Small Cell Lung Cancer Cells

RISC assembly: Coordination between small RNAs and Argonaute proteins.

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