HNRNPA2B1-mediated m <sup>6</sup>A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

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Abstract

Background

Accumulating data indicate that N6-methyladenosine (m ⁶A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m ⁶A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m ⁶A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC).

Methods

The expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m ⁶A modification of lncRNAs was screened by m ⁶A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses.

Results

We found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m ⁶A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m ⁶A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC.

Conclusions

Our findings uncover that HNRNPA2B1-mediated m ⁶A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-04190-8.

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Most cited references 46

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

Huilin Huang, Hengyou Weng, Jianjun Chen (2020)

N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.

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The role of m 6 A RNA methylation in human cancer

Xiao-Yu Chen, Jing Zhang, Jin-Shui Zhu (2019)

N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as “writers”), reverted by the demethylases (FTO and ALKBH5, termed as “erasers”) and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as “readers”). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.

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Author and article information

Contributors

Li Zhuang: zl777120191118@163.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 12 June 2023

Publication date PMC-release: 12 June 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 382

Affiliations

[1 ]Department of Cancer Biotherapy Center, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118 Yunnan China

[2 ]Department of Rehabilitation and Palliative Medicine, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Number 519 Kunzhou Road, Kunming, 650118 Yunnan China

[3 ]Department of Thoracic Surgery, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118 Yunnan China

[4 ]GRID grid.285847.4, ISNI 0000 0000 9588 0960, Laboratory Zoology Department, , Kunming Medical University, ; Kunming, 650500 Yunnan China

[5 ]Department of Anesthesiology, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118 Yunnan China

Article

Publisher ID: 4190

DOI: 10.1186/s12967-023-04190-8

PMC ID: 10258935

PubMed ID: 37308993

SO-VID: 32d16725-c52f-45c4-aa72-be7ecd0ddb5b

License:

Open Access This 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 : 24 February 2023

Date accepted : 8 May 2023

Funding

Funded by: Our work was supported by the grants from National Natural Science Foundation of China (82260589), 2021 Anti-tumor Project of Simcere Clinical Research foundation, International Medical Exchange Foundation (Z-2014-06-2103), Beijing Xisike Clinical Oncology

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: m6a,hnrnpa2b1,lncrna meg3,mir-21-5p,nsclc,proliferation

Data availability:

ScienceOpen disciplines: Medicine

Keywords: m6a, hnrnpa2b1, lncrna meg3, mir-21-5p, nsclc, proliferation

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