Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on modern management of frailty

LIVE: Thursday 17th October 2024, 18:00-19:30 (CEST)

Frailty has a significant impact on health and wellbeing, especially in older adults. Join our experts to understand the factors that contribute to the development of frailty and find out how to manage the condition and reduce the risk of disability, dependency, and mortality.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in:

Open Access 01-12-2023 | NSCLC | Research

HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

Authors: Ke Li, Quan Gong, Xu-Dong Xiang, Gang Guo, Jia Liu, Li Zhao, Jun Li, Nan Chen, Heng Li, Li-Juan Zhang, Chun-Yan Zhou, Zhi-Yong Wang, Li Zhuang

Published in: Journal of Translational Medicine | Issue 1/2023

Login to get access

Abstract

Background

Accumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “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 m6A 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 m6A modification of lncRNAs was screened by m6A-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 m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A 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 m6A 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.
Appendix
Available only for authorised users
Literature
1.
2.
Hwang I, Kim JW, Ylaya K, Chung EJ, Kitano H, Perry C, et al. Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients. J Transl Med. 2020;18(1):443.PubMedPubMedCentralCrossRef
3.
Huang H, Weng H, Chen J. m6A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270–88.PubMedPubMedCentralCrossRef
4.
5.
Jin D, Guo J, Wu Y, Du J, Yang L, Wang X, et al. m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol. 2019;12(1):135.PubMedPubMedCentralCrossRef
6.
Fan HN, Chen ZY, Chen XY, Chen M, Yi YC, Zhu JS, et al. METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Mol Cancer. 2022;21(1):51.PubMedPubMedCentralCrossRef
7.
Wang Y, Li M, Zhang L, Chen Y, Zhang S. m6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non-small cell lung cancer. Mol Ther Oncolytics. 2021;21:367–76.PubMedPubMedCentralCrossRef
8.
Sun Z, Su Z, Zhou Z, Wang S, Wang Z, Tong X, et al. RNA demethylase ALKBH5 inhibits TGF-β-induced EMT by regulating TGF-β/SMAD signaling in non-small cell lung cancer. FASEB J. 2022;36(5):e22283.PubMedCrossRef
9.
Tsuchiya K, Yoshimura K, Inoue Y, Iwashita Y, Yamada H, Kawase A, et al. YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer. Oncoimmunology. 2021;10(1):1962656.PubMedPubMedCentralCrossRef
10.
Sun S, Han Q, Liang M, Zhang Q, Zhang J, Cao J. Downregulation of m6 A reader YTHDC2 promotes tumor progression and predicts poor prognosis in non-small cell lung cancer. Thorac Cancer. 2020;11(11):3269–79.PubMedPubMedCentralCrossRef
11.
Guo H, Wang B, Xu K, Nie L, Fu Y, Wang Z, et al. m6A reader HNRNPA2B1 promotes esophageal cancer progression via up-regulation of ACLY and ACC1. Front Oncol. 2020;10:553045.PubMedPubMedCentralCrossRef
12.
Li K, Chen J, Lou X, Li Y, Qian B, Xu D, et al. HNRNPA2B1 affects the prognosis of esophageal cancer by regulating the miR-17-92 cluster. Front Cell Dev Biol. 2021;9:658642.PubMedPubMedCentralCrossRef
13.
Yang Y, Wei Q, Tang Y, Wang Yuanyuan, Luo Q, Zhao H, et al. Loss of hnRNPA2B1 inhibits malignant capability and promotes apoptosis via down-regulating Lin28B expression in ovarian cancer. Cancer Lett. 2020;475:43–52.PubMedCrossRef
14.
15.
Jiang F, Tang X, Tang C, Hua Z, Ke M, Wang C, et al. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. J Hematol Oncol. 2021;14(1):54.PubMedPubMedCentralCrossRef
16.
Zhu F, Yang T, Yao M, Shen T, Fang C. HNRNPA2B1, as a m6A reader, promotes tumorigenesis and metastasis of oral squamous cell carcinoma. Front Oncol. 2021;11:716921.PubMedPubMedCentralCrossRef
17.
Jin L, Chen C, Yao J, Yu Z, Bu L. The RNA N6-methyladenosine modulator HNRNPA2B1 is involved in the development of non-small cell lung cancer. Clin Exp Pharmacol Physiol. 2022;49(3):329–40.PubMedCrossRef
18.
Wu M, Huang Y, Chen T, Wang W, Yang S, Ye Z, et al. LncRNA MEG3 inhibits the progression of prostate cancer by modulating miR-9-5p/QKI-5 axis. J Cell Mol Med. 2019;23(1):29–38.PubMedCrossRef
19.
Dan J, Wang J, Wang Y, Zhu M, Yang X, Peng Z, et al. LncRNA-MEG3 inhibits proliferation and metastasis by regulating miRNA-21 in gastric cancer. Biomed Pharmacother. 2018;99:931–8.PubMedCrossRef
20.
Gu L, Zhang J, Shi M, Zhan Q, Shen B, Peng C. lncRNA MEG3 had anti-cancer effects to suppress pancreatic cancer activity. Biomed Pharmacother. 2017;89:1269–76.PubMedCrossRef
21.
Jin L, Cai Q, Wang S, Wang S, Mondal T, Wang J, et al. Long noncoding RNA MEG3 regulates LATS2 by promoting the ubiquitination of EZH2 and inhibits proliferation and invasion in gallbladder cancer. Cell Death Dis. 2018;9(10):1017.PubMedPubMedCentralCrossRef
22.
Zhang W, Shi S, Jiang J, Li X, Lu H, Ren F. LncRNA MEG3 inhibits cell epithelial-mesenchymal transition by sponging miR-421 targeting E-cadherin in breast cancer. Biomed Pharmacother. 2017;91:312–9.PubMedCrossRef
23.
Zhang J, Lin Z, Gao Y, Yao T. Downregulation of long noncoding RNA MEG3 is associated with poor prognosis and promoter hypermethylation in cervical cancer. J Exp Clin Cancer Res. 2017;36(1):5.PubMedPubMedCentralCrossRef
24.
Zheng Q, Lin Z, Xu J, Lu Y, Meng Q, Wang C, et al. Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN. Cell Death Dis. 2018;9(3):253.PubMedPubMedCentralCrossRef
25.
Lu KH, Li W, Liu XH, Sun M, Zhang ML, Wu WQ, et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer. 2013;13:461.PubMedPubMedCentralCrossRef
26.
Wu J, Pang R, Li M, Chen B, Huang J, Zhu Y. m6A-induced LncRNA MEG3 suppresses the proliferation, migration and invasion of hepatocellular carcinoma cell through miR-544b/BTG2 signaling. Onco Targets Ther. 2021;14:3745–55.PubMedPubMedCentralCrossRef
27.
Klinge CM, Piell KM, Tooley CS, Rouchka EC. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Sci Rep. 2019;9(1):9430.PubMedPubMedCentralCrossRef
28.
Jin Y, Wang Z, He D, Zhu Y, Hu X, Gong L, et al. Analysis of m6A-related signatures in the tumor immune microenvironment and identification of clinical prognostic regulators in adrenocortical carcinoma. Front Immunol. 2021;12:637933.PubMedPubMedCentralCrossRef
29.
Du Y, Geng G, Zhao C, Gao T, Wei B. LncRNA MEG3 promotes cisplatin sensitivity of cervical cancer cells by regulating the miR-21/PTEN axis. BMC Cancer. 2022;22(1):1145.PubMedPubMedCentralCrossRef
30.
Li Z, Yang L, Liu X, Nie Z, Luo J. Long noncoding RNA MEG3 inhibits proliferation of chronic myeloid leukemia cells by sponging microRNA21. Biomed Pharmacother. 2018;104:181–92.PubMedCrossRef
31.
Tian C, Su J, Ma Z, Wu Y, Ma H. lncRNA NBAT1 inhibits cell metastasis and promotes apoptosis in endometrial cancer by sponging miR-21-5p to regulate PTEN. Comput Math Methods Med. 2022;2022:9304392.PubMedPubMedCentralCrossRef
32.
Zhang Z, Hu J, Ishihara M, Sharrow AC, Flora K, He Y, et al. The miRNA-21-5p payload in exosomes from m2 macrophages drives tumor cell aggression via PTEN/Akt signaling in renal cell carcinoma. Int J Mol Sci. 2022;23(6):3005.PubMedPubMedCentralCrossRef
33.
Cong M, Shen M, Wu X, Li Y, Wang L, He Q, et al. Improvement of sensory neuron growth and survival via negatively regulating PTEN by miR-21-5p-contained small extracellular vesicles from skin precursor-derived Schwann cells. Stem Cell Res Ther. 2021;12(1):80.PubMedPubMedCentralCrossRef
34.
Xuan Y, Wang J, Ban L, Lu JJ, Yi C, Li Z, et al. hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers. Mol Oncol. 2016;10(4):610–24.PubMedCrossRef
35.
Li C, Qin F, Wang W, Ni Y, Gao M, Guo M, et al. hnRNPA2B1-mediated extracellular vesicles sorting of miR-122-5p potentially promotes lung cancer progression. Int J Mol Sci. 2021;22(23):12866.PubMedPubMedCentralCrossRef
36.
Yang Z, Liao B, Xiang X, Ke S. miR-21-5p promotes cell proliferation and G1/S transition in melanoma by targeting CDKN2C. FEBS Open Bio. 2020;10(5):752–60.PubMedPubMedCentralCrossRef
37.
Zhong J, Ren X, Chen Z, Zhang H, Zhou L, Yuan J, et al. miR-21-5p promotes lung adenocarcinoma progression partially through targeting SET/TAF-Iα. Life Sci. 2019;231:116539.PubMedCrossRef
38.
Li Q, Li B, Li Q, Wei S, He Z, Huang X, et al. Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition. Cell Death Dis. 2018;9(9):854.PubMedPubMedCentralCrossRef
39.
Gao Y, Zou T, Liang W, Zhang Z, Qie M. Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis. Cancer Gene Ther. 2021;28(6):619–33.PubMedCrossRef
40.
Zhu Y, Bo H, Chen Z, Li J, He D, Xiao M, et al. LINC00968 can inhibit the progression of lung adenocarcinoma through the miR-21-5p/SMAD7 signal axis. Aging (Albany NY). 2020;12(21):21904–22.PubMedCrossRef
41.
Zhang J, Yao T, Wang Y, Yu J, Liu Y, Lin Z. Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21. Cancer Biol Ther. 2016;17(1):104–13.PubMedCrossRef
42.
Perumal E, So Youn K, Sun S, Seung-Hyun J, Suji M, Jieying L, et al. PTEN inactivation induces epithelial-mesenchymal transition and metastasis by intranuclear translocation of β-catenin and snail/slug in non-small cell lung carcinoma cells. Lung Cancer. 2019;130:25–34.PubMedCrossRef
43.
Liu Y, Lei J, Ji X, Li C, Chen X, Wang J, et al. Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway. Genes Genomics. 2023;45(4):507–17.PubMedCrossRef
44.
Zhu S, Hou J, Gao H, Hu Q, Kloeber JA, Huang J, et al. SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses. Mol Cell. 2023;83(4):539-555.e7.PubMedCrossRef
45.
Chodari L, Dilsiz Aytemir M, Vahedi P, Alipour M, Vahed SZ, Khatibi SMH, et al. Targeting mitochondrial biogenesis with polyphenol compounds. Oxid Med Cell Longev. 2021;2021:4946711.PubMedPubMedCentralCrossRef
46.
Rosales-Pérez KE, Elizalde-Velázquez GA, Gómez-Oliván LM, Orozco-Hernández JM, Cardoso-Vera JD, Heredia-García G, et al. Response to letter to the editor about Rosales-Pérez et al., 2022 (https://​doi.​org/​10.​1016/​j.​chemosphere.​2022.​133791) instigating reflections on methodological and anstigating reflections on methodological and analytical rigor in ecotoxicological studies based on the research by Rosales-Pérez et al. (2022) by Guilherme Malafaia. Chemosphere. 2023;312:137128.PubMedCrossRef
Metadata
Title
HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis
Authors
Ke Li
Quan Gong
Xu-Dong Xiang
Gang Guo
Jia Liu
Li Zhao
Jun Li
Nan Chen
Heng Li
Li-Juan Zhang
Chun-Yan Zhou
Zhi-Yong Wang
Li Zhuang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-023-04190-8

Other articles of this Issue 1/2023

Journal of Translational Medicine 1/2023 Go to the issue

Research

Phenylpropanoid-enriched broccoli seedling extract can reduce inflammatory markers and pain behavior

Research

Association between Chinese visceral adiposity index and risk of stroke incidence in middle-aged and elderly Chinese population: evidence from a large national cohort study

Research

Preoperative fluorescence in situ hybridization analysis as a predictor of tumor recurrence in patients with non-muscle invasive bladder cancer: a bi-institutional study

Research

The comprehensive study on the role of POSTN in fetal congenital heart disease and clinical applications

Review

Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions

Research

Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment

EASD 2024

‘Noninferior’ reduction of type 1 diabetes HbA1c by weekly insulin efsitora alfa

Weekly treatment with insulin efsitora is noninferior to daily insulin degludec for the reduction of HbA1c in adults with type 1 diabetes, show the findings of the QWINT-5 trial.

Read more

Weight loss with new obesity drug amycretin

Tirzepatide significantly reduces UACR in individuals with obesity and type 2 diabetes

Liraglutide reduces BMI for young children with obesity

» View more highlights on the EASD 2024 hub page

2024 ESC Congress

Noise pollution dangerous for heart health

Two studies underscore the adverse impact of noise pollution on the risk for and prognosis after myocardial infarction.

Read more

Post-TAVI follow up: deploying virtual assistants

Antihypertensives: more effective at morning or night?

Low Lp(a) levels unlikely to increase the risk of diabetes

» View more highlights on the 2024 ESC Congress hub page

A quick guide to ECGs

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date. 

PD Dr. Carsten W. Israel
Developed by: Springer Medizin
Start the cases

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Read more
Image Credits