Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2021 | Hepatocellular Carcinoma | Research

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

Authors: Xueqiang Peng, Xinyu Li, Shuo Yang, Mingyao Huang, Shibo Wei, Yingbo Ma, Yan Li, Bo Wu, Hongyuan Jin, Bowen Li, Shilei Tang, Qing Fan, Jingang Liu, Liang Yang, Hangyu Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Abnormally expressed long noncoding RNAs (lncRNAs) have been confirmed to regulate multiple processes associated with tumor progression. However, the mechanism by which lncRNAs affect exosome secretion remains unclear.

Methods

The underlying mechanisms of long noncoding RNA LINC00511 (LINC00511) regulation of multivesicular body (MVB) trafficking, exosome secretion, invadopodia formation, and tumor invasion were determined through gene set enrichment analysis (GSEA), immunoblotting, nanoparticle tracking analysis, confocal colocalization analysis, electron microscopy, and invasion experiments.

Results

We revealed that the tumorigenesis process is associated with a significant increase in vesicle secretion in hepatocellular carcinoma (HCC). Additionally, LINC00511 was significantly more highly expressed in HCC tissues and is related to vesicle trafficking and MVB distribution. We also found that in addition to the formation of invadopodia in HCC progression, abnormal LINC00511 induces invadopodia formation in HCC cells by regulating the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23) to induce the invadopodia formation, which are key secretion sites for MVBs and control exosome secretion. Finally, we revealed that LINC0051-induced invadopodia and exosome secretion were involved in tumor progression.

Conclusions

Our experiments revealed novel findings on the relationship between LINC00511 dysregulation in HCC and invadopodia production and exosome secretion. This is a novel mechanism by which LINC00511 regulates invadopodia biogenesis and exosome secretion to further promote cancer progression.

Available only for authorised users

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37. https://doi.org/10.1038/nm.3394.CrossRefPubMedPubMedCentral

Fan Q, Yang L, Zhang X, Peng X, Wei S, Su D, et al. The emerging role of exosome-derived non-coding RNAs in cancer biology. Cancer Lett. 2018;414:107–15. https://doi.org/10.1016/j.canlet.2017.10.040.CrossRefPubMed

Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88(1):487–514. https://doi.org/10.1146/annurev-biochem-013118-111902.CrossRefPubMed

Zhang S, Wang C, Ma B, Xu M, Xu S, Liu J, et al. Mutant p53 drives Cancer metastasis via RCP-mediated Hsp90α secretion. Cell Rep. 2020;32(1):107879. https://doi.org/10.1016/j.celrep.2020.107879.CrossRefPubMed

Peng X, Yang L, Ma Y, Li Y, Li H. Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies. Cell Commun Signal. 2020;18(1):122. https://doi.org/10.1186/s12964-020-00619-5.CrossRefPubMedPubMedCentral

Ghoroghi S, Mary B, Larnicol A, Asokan N, Klein A, Osmani N, et al. Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes. eLife. 2021;10. https://doi.org/10.7554/eLife.61539.

Li Y, Zhang X, Zheng Q, Zhang Y, Ma Y, Zhu C, et al. YAP1 inhibition in HUVECs is associated with released Exosomes and increased Hepatocarcinoma invasion and metastasis. Mol Ther Nucleic Acids. 2020;21:86–97. https://doi.org/10.1016/j.omtn.2020.05.021.CrossRefPubMedPubMedCentral

Dai W, Wang Y, Yang T, Wang J, Wu W, Gu J. Downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMPK and VEGF signals. Cell Commun Signal. 2019;17(1):113. https://doi.org/10.1186/s12964-019-0423-6.CrossRefPubMedPubMedCentral

Chen R, Xu X, Tao Y, Qian Z, Yu Y. Exosomes in hepatocellular carcinoma: a new horizon. Cell Commun Signal. 2019;17(1):1. https://doi.org/10.1186/s12964-018-0315-1.CrossRefPubMedPubMedCentral

10.

Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977. https://doi.org/10.1126/science.aau6977.

11.

Frankel EB, Audhya A. ESCRT-dependent cargo sorting at multivesicular endosomes. Semin Cell Dev Biol. 2018;74:4–10. https://doi.org/10.1016/j.semcdb.2017.08.020.CrossRefPubMed

12.

Heisler FF, Pechmann Y, Wieser I, Altmeppen HC, Veenendaal L, Muhia M, et al. Muskelin coordinates PrP(C) lysosome versus exosome targeting and impacts prion disease progression. Neuron. 2018;99(6):1155–69.e9.CrossRef

13.

Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R, et al. Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J Natl Cancer Inst. 2010;102(12):866–80. https://doi.org/10.1093/jnci/djq153.CrossRefPubMedPubMedCentral

14.

Mughees M, Chugh H, Wajid S. Vesicular trafficking-related proteins as the potential therapeutic target for breast cancer. Protoplasma. 2020;257(2):345–52. https://doi.org/10.1007/s00709-019-01462-3.CrossRefPubMed

15.

Gu H, Chen C, Hao X, Wang C, Zhang X, Li Z, et al. Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. J Clin Invest. 2016;126(12):4537–53. https://doi.org/10.1172/JCI87105.CrossRefPubMedPubMedCentral

16.

Yang L, Peng X, Li Y, Zhang X, Ma Y, Wu C, et al. Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma. Mol Cancer. 2019;18(1):78. https://doi.org/10.1186/s12943-019-0990-6.CrossRefPubMedPubMedCentral

17.

Hong W, Lev S. Tethering the assembly of SNARE complexes. Trends Cell Biol. 2014;24(1):35–43. https://doi.org/10.1016/j.tcb.2013.09.006.CrossRefPubMed

18.

Manmi K, Wang Q. Acoustic microbubble dynamics with viscous effects. Ultrason Sonochem. 2017;36:427–36. https://doi.org/10.1016/j.ultsonch.2016.11.032.CrossRefPubMed

19.

Augoff K, Hryniewicz-Jankowska A, Tabola R. Invadopodia: clearing the way for cancer cell invasion. Ann Transl Med. 2020;8(14):902. https://doi.org/10.21037/atm.2020.02.157.CrossRefPubMedPubMedCentral

20.

Hoshino D, Kirkbride KC, Costello K, Clark ES, Sinha S, Grega-Larson N, et al. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5(5):1159–68. https://doi.org/10.1016/j.celrep.2013.10.050.CrossRefPubMed

21.

Sinha S, Hoshino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, et al. Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol. 2016;214(2):197–213. https://doi.org/10.1083/jcb.201601025.CrossRefPubMedPubMedCentral

22.

Sharma P, Parveen S, Shah LV, Mukherjee M, Kalaidzidis Y, Kozielski AJ, et al. SNX27-retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis. J Cell Biol. 2020;219(1):e201812098. https://doi.org/10.1083/jcb.201812098.

23.

Steffen A, Le Dez G, Poincloux R, Recchi C, Nassoy P, Rottner K, et al. MT1-MMP-dependent invasion is regulated by TI-VAMP/VAMP7. Curr Biol. 2008;18(12):926–31. https://doi.org/10.1016/j.cub.2008.05.044.CrossRefPubMed

24.

Liu Y, Lu LL, Wen D, Liu DL, Dong LL, Gao DM, et al. MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming. J Hematol Oncol. 2020;13(1):12. https://doi.org/10.1186/s13045-019-0841-3.CrossRefPubMedPubMedCentral

25.

Wu B, Yuan Y, Han X, Wang Q, Shang H, Liang X, et al. Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer. FASEB J. 2020;34(7):9713–26. https://doi.org/10.1096/fj.202000481R.CrossRefPubMed

26.

Sun CC, Li SJ, Li G, Hua RX, Zhou XH, Li DJ. Long Intergenic noncoding RNA 00511 acts as an oncogene in non-small-cell lung Cancer by binding to EZH2 and suppressing p57. Mol Ther Nucleic Acids. 2016;5(11):e385. https://doi.org/10.1038/mtna.2016.94.CrossRefPubMedPubMedCentral

27.

Shi G, Cheng Y, Zhang Y, Guo R, Li S, Hong X. Long non-coding RNA LINC00511/miR-150/MMP13 axis promotes breast cancer proliferation, migration and invasion. Biochim Biophys Acta Mol Basis Dis. 2021;1867(3):165957. https://doi.org/10.1016/j.bbadis.2020.165957.

28.

Peng X, Yang L, Ma Y, Li X, Yang S, Li Y, et al. IKKβ activation promotes amphisome formation and extracellular vesicle secretion in tumor cells. Biochim Biophys Mol Cell Res. 1868;2021(1):118857.

29.

Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10(8):513–25. https://doi.org/10.1038/nrm2728.CrossRefPubMed

30.

Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biol. 2010;12(1):19–30 sup pp 1–13.CrossRef

31.

Arora A, Olkkonen VM. Protrudin in protrudinG invadopodia: Membrane contact sites and cell invasion. J Cell Biol. 2020;219(8):e202006146. https://doi.org/10.1083/jcb.202006146.

32.

Zagryazhskaya-Masson A, Monteiro P, Macé AS, Castagnino A, Ferrari R, Infante E, et al. Intersection of TKS5 and FGD1/CDC42 signaling cascades directs the formation of invadopodia. J Cell Biol. 2020;219(9):e201910132. https://doi.org/10.1083/jcb.201910132.

33.

Hyenne V, Apaydin A, Rodriguez D, Spiegelhalter C, Hoff-Yoessle S, Diem M, et al. RAL-1 controls multivesicular body biogenesis and exosome secretion. J Cell Biol. 2015;211(1):27–37. https://doi.org/10.1083/jcb.201504136.CrossRefPubMedPubMedCentral

34.

Wei Y, Wang D, Jin F, Bian Z, Li L, Liang H, et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun. 2017;8(1):14041. https://doi.org/10.1038/ncomms14041.CrossRefPubMedPubMedCentral

35.

Röhl J, West ZE, Rudolph M, Zaharia A, Van Lonkhuyzen D, Hickey DK, et al. Invasion by activated macrophages requires delivery of nascent membrane-type-1 matrix metalloproteinase through late endosomes/lysosomes to the cell surface. Traffic. 2019;20(9):661–73.PubMed

36.

Williams KC, McNeilly RE, Coppolino MG. SNAP23, Syntaxin4, and vesicle-associated membrane protein 7 (VAMP7) mediate trafficking of membrane type 1-matrix metalloproteinase (MT1-MMP) during invadopodium formation and tumor cell invasion. Mol Biol Cell. 2014;25(13):2061–70. https://doi.org/10.1091/mbc.e13-10-0582.CrossRefPubMedPubMedCentral

37.

Urabe F, Kosaka N, Sawa Y, Yamamoto Y, Ito K, Yamamoto T, et al. miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1. Sci Adva. 2020;6(18):eaay3051.CrossRef

38.

Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet. 2004;36(4):400–4. https://doi.org/10.1038/ng1325.CrossRefPubMed

39.

Xia X, Wang S, Ni B, Xing S, Cao H, Zhang Z, et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene. 2020;39(39):6231–44. https://doi.org/10.1038/s41388-020-01425-6.CrossRefPubMed

40.

Guo H, Chitiprolu M, Roncevic L, Javalet C, Hemming FJ, Trung MT, et al. Atg5 disassociates the V(1)V(0)-ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy. Dev Cell. 2017;43(6):716–30.e7.CrossRef

41.

Guo F, Su Z, Wang G, Sun L, Tigabu M, Yang X, et al. Understanding fire drivers and relative impacts in different Chinese forest ecosystems. Sci Total Environ. 2017;605–606:411–25.CrossRef

42.

Tsuruda M, Yoshino H, Okamura S, Kuroshima K, Osako Y, Sakaguchi T, et al. Oncogenic effects of RAB27B through exosome independent function in renal cell carcinoma including sunitinib-resistant. PLoS One. 2020;15(5):e0232545. https://doi.org/10.1371/journal.pone.0232545.CrossRefPubMedPubMedCentral

43.

Zhu JJ, Liu YF, Zhang YP, Zhao CR, Yao WJ, Li YS, et al. VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia. Proc Natl Acad Sci U S A. 2017;114(31):8271–6. https://doi.org/10.1073/pnas.1700561114.CrossRefPubMedPubMedCentral

44.

Williams KC, Cepeda MA, Javed S, Searle K, Parkins KM, Makela AV, et al. Invadopodia are chemosensing protrusions that guide cancer cell extravasation to promote brain tropism in metastasis. Oncogene. 2019;38(19):3598–615. https://doi.org/10.1038/s41388-018-0667-4.CrossRefPubMedPubMedCentral

Title: LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation
Authors: Xueqiang Peng
Xinyu Li
Shuo Yang
Mingyao Huang
Shibo Wei
Yingbo Ma
Yan Li
Bo Wu
Hongyuan Jin
Bowen Li
Shilei Tang
Qing Fan
Jingang Liu
Liang Yang
Hangyu Li
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01990-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Long non‐coding RNA NORAD promotes the prostate cancer cell extracellular vesicle release via microRNA-541-3p-regulated PKM2 to induce bone metastasis of prostate cancer

ChrXq27.3 miRNA cluster functions in cancer development

HOXA10 promotion of HDAC1 underpins the development of lung adenocarcinoma through the DNMT1-KLF4 axis

Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer

Correction to: microRNA-193a stimulates pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings

The role of patient-derived ovarian cancer organoids in the study of PARP inhibitors sensitivity and resistance: from genomic analysis to functional testing

Keynote webinar | Spotlight on antibody–drug conjugates in cancer