LINC00963 Promotes the Malignancy and Metastasis of Lung Adenocarcinoma by Stabilizing Zeb1 and Exosomes-induced M2 Macrophage Polarization

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2023 Jan 5

PMID 36604626

Authors

Ronghang Hu

Baobin Xu

Jiajun Ma

Linfeng Li

Liming Zhang

Li Wang

Jiebo Zhu

Tao Guo

Heng Zhang

Shaoqiang Wang

Affiliations

Soon will be listed here.

Abstract

Background: Long intergenic non-coding RNA 00963 (LINC00963) is an oncogenic lncRNA in human cancers. However, little is known on how it impacts the pathogenesis of lung adenocarcinoma (LUAD).

Methods: Biological effects on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were examined by CCK-8, colony formation, EdU incorporation, transwell, and immunofluorescence assays, respectively. Macrophage polarization was evaluated by flow cytometry. Ubiquitination of Zeb1 was examined by co-immunoprecipitation. The location of LINC00963 in LUAD tissues and cell lines was tested by FISH assay. The LINC00963/HNRNPA2B1/Siah1 mRNA complex interaction was verified using RNA pull-down and immunoprecipitation assays. The exact roles of LINC00963 were further validated in metastasis and xenograft models.

Results: Higher LINC00963 expression in LUAD patients positively correlated with shorter overall survival, higher stages, and metastasis. LINC00963 mainly localized in the cytoplasm and aggravated malignant phenotypes of LUAD cells in vitro and metastasis in vivo. Mechanistically, LINC00963 directly interacted HNRNPA2B1 protein to trigger the degradation of Siah1 mRNA, which inhibited the ubiquitination and degradation of Zeb1. Moreover, exosomal LINC00963 derived from LUAD cells induced M2 macrophage polarization and promoted LUAD growth and metastasis.

Conclusion: By stabilizing Zeb1 in cancer cells and delivering exosomes to induce M2 macrophage polarization, LINC00963 promoted the malignancy and metastasis of LUAD. Targeting LINC00963 may become a valuable therapeutic target for LUAD.

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References

Nielsen S, Schmid M . Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediators Inflamm. 2017; 2017:9624760. PMC: 5292164. DOI: 10.1155/2017/9624760. View

Yu T, Zhao Y, Hu Z, Li J, Chu D, Zhang J . MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway. Cancer Res. 2017; 77(21):5782-5794. DOI: 10.1158/0008-5472.CAN-17-0671. View

Sun Z, Yang S, Zhou Q, Wang G, Song J, Li Z . Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment. Mol Cancer. 2018; 17(1):82. PMC: 5909226. DOI: 10.1186/s12943-018-0831-z. View

Sun F, Wu K, Yao Z, Mu X, Zheng Z, Sun M . Long noncoding RNA LINC00963 induces NOP2 expression by sponging tumor suppressor miR-542-3p to promote metastasis in prostate cancer. Aging (Albany NY). 2020; 12(12):11500-11516. PMC: 7343457. DOI: 10.18632/aging.103236. View

Baig M, Roy A, Rajpoot S, Liu D, Savai R, Banerjee S . Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res. 2020; 69(5):435-451. DOI: 10.1007/s00011-020-01318-0. View

Zheng K, Zhang T . LncRNA LINC00963 promotes proliferation and migration through the miR-124-3p/FZD4 pathway in colorectal cancer. Eur Rev Med Pharmacol Sci. 2020; 24(14):7634-7644. DOI: 10.26355/eurrev_202007_22264. View

Carlevaro-Fita J, Johnson R . Global Positioning System: Understanding Long Noncoding RNAs through Subcellular Localization. Mol Cell. 2019; 73(5):869-883. DOI: 10.1016/j.molcel.2019.02.008. View

Liu W, Yang Y, An Q . Promotes Ovarian Cancer Proliferation, Migration and EMT via the miR-378g / Axis. Cancer Manag Res. 2020; 12:463-473. PMC: 6982455. DOI: 10.2147/CMAR.S229083. View

Jiao H, Jiang S, Wang H, Li Y, Zhang W . Upregulation of LINC00963 facilitates melanoma progression through miR-608/NACC1 pathway and predicts poor prognosis. Biochem Biophys Res Commun. 2018; 504(1):34-39. DOI: 10.1016/j.bbrc.2018.08.115. View

10.

Zhang N, Zeng X, Sun C, Guo H, Wang T, Wei L . LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression. Mol Ther Nucleic Acids. 2019; 18:871-881. PMC: 6881674. DOI: 10.1016/j.omtn.2019.09.033. View

11.

Wu J, Tian X, An Q, Guan X, Hao C . LINC00963 promotes hepatocellular carcinoma progression by activating PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018; 22(6):1645-1652. DOI: 10.26355/eurrev_201803_14574. View

12.

Davalos V, Esteller M . Disruption of Long Noncoding RNAs Targets Cancer Hallmark Pathways in Lung Tumorigenesis. Cancer Res. 2019; 79(12):3028-3030. DOI: 10.1158/0008-5472.CAN-19-0910. View

13.

Kao S, Wang W, Chen C, Chang Y, Wu Y, Wang Y . Analysis of Protein Stability by the Cycloheximide Chase Assay. Bio Protoc. 2017; 5(1). PMC: 5659619. DOI: 10.21769/BioProtoc.1374. View

14.

Zhang L, Yang Z, Trottier J, Barbier O, Wang L . Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. Hepatology. 2016; 65(2):604-615. PMC: 5258819. DOI: 10.1002/hep.28882. View

15.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

16.

Ye F, Xu R, Ge Y, Zheng Y, Liu X, Deng P . LINC00963 Confers Oncogenic Properties in Glioma by Regulating the miR-506/BCAT1 Axis. Cancer Manag Res. 2020; 12:2339-2351. PMC: 7108718. DOI: 10.2147/CMAR.S246332. View

17.

Wu Z, Wang W, Wang Y, Wang X, Sun S, Yao Y . Long noncoding RNA promotes breast cancer progression by functioning as a molecular sponge for microRNA-625 and thereby upregulating HMGA1. Cell Cycle. 2020; 19(5):610-624. PMC: 7100992. DOI: 10.1080/15384101.2020.1728024. View

18.

Xu M, Zhu C, Zhao X, Chen C, Zhang H, Yuan H . Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors. Oncotarget. 2014; 6(2):979-94. PMC: 4359269. DOI: 10.18632/oncotarget.2825. View

19.

Ruf H, Georgalis Y, Grell E . Dynamic laser light scattering to determine size distributions of vesicles. Methods Enzymol. 1989; 172:364-90. DOI: 10.1016/s0076-6879(89)72024-3. View

20.

Wang J, Li C, Xu L, Yang C, Zhang X . MiR-1193 was sponged by LINC00963 and inhibited cutaneous squamous cell carcinoma progression by targeting SOX4. Pathol Res Pract. 2019; 215(10):152600. DOI: 10.1016/j.prp.2019.152600. View