nach oben

Erschienen in:

13.09.2020 | Original Paper

RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway

verfasst von: Kailiang Qiao, Yantao Liu, Zheng Xu, Haohao Zhang, Heng Zhang, Chao Zhang, Zhi Chang, Xinyan Lu, Zhongwei Li, Ce Luo, Yanrong Liu, Cheng Yang, Tao Sun

Erschienen in: Angiogenesis | Ausgabe 1/2021

Einloggen, um Zugang zu erhalten

Abstract

Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. However, the pathogenesis underlying VM is complex and has not been fully defined. m6A is a common mRNA modification and has many biological effects. However, the relationship between m6A and VM remains unclear. In this research, we found that m6A methyltransferase METTL3 in HCC tissues was positively correlated with VM. The m6A level of mRNA significantly increased in 3D cultured cells treated with VEGFa and was related to VM formation. Transcriptome sequencing analysis of 3D cultured cells with knockdown Mettl3 showed that the Hippo pathway was involved in m6A-mediated VM formation. Further mechanism research indicated that the m6A modification of YAP1 mRNA affected the translation of YAP1 mRNA. In conclusion, m6A methylation plays a key role in VM formation in HCC. METTL3 and YAP1 could be potential therapeutic targets via impairing VM formation in anti-metastatic strategies.

Nur mit Berechtigung zugänglich

Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380(15):1450–1462. https://doi.org/10.1056/NEJMra1713263CrossRefPubMed

Vogel A, Saborowski A (2020) Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev 82:101946. https://doi.org/10.1016/j.ctrv.2019.101946CrossRefPubMed

Yang W, Li Z, Qin R, Wang X, An H, Wang Y, Zhu Y, Liu Y, Cai S, Chen S, Sun T, Meng J, Yang C (2019) YY1 promotes endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma by transcriptionally activating VEGFA. Front Oncol 9:1187. https://doi.org/10.3389/fonc.2019.01187CrossRefPubMedPubMedCentral

Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan M, Wotherspoon A, Gao Z-H, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, Van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22(11):1294–1302. https://doi.org/10.1038/nm.4197CrossRefPubMedPubMedCentral

Mahase S, Rattenni RN, Wesseling P, Leenders W, Baldotto C, Jain R, Zagzag D (2017) Hypoxia-mediated mechanisms associated with antiangiogenic treatment resistance in glioblastomas. Am J Pathol 187(5):940–953. https://doi.org/10.1016/j.ajpath.2017.01.010CrossRefPubMedPubMedCentral

Wang S, Xiao Z, Hong Z, Jiao H, Zhu S, Zhao Y, Bi J, Qiu J, Zhang D, Yan J, Zhang L, Huang C, Li T, Liang L, Liao W, Ye Y, Ding Y (2018) FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA. Cancer Lett 439:78–90. https://doi.org/10.1016/j.canlet.2018.09.026CrossRefPubMed

Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155(3):739–752. https://doi.org/10.1016/S0002-9440(10)65173-5CrossRefPubMedPubMedCentral

Delgado-Bellido D, Fernandez-Cortes M, Rodriguez MI, Serrano-Saenz S, Carracedo A, Garcia-Diaz A, Oliver FJ (2019) VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression. Cell Death Differ 26(2):348–361. https://doi.org/10.1038/s41418-018-0125-4CrossRefPubMed

Liang X, Sun R, Zhao X, Zhang Y, Gu Q, Dong X, Zhang D, Sun J, Sun B (2017) Rictor regulates the vasculogenic mimicry of melanoma via the AKT-MMP-2/9 pathway. J Cell Mol Med 21(12):3579–3591. https://doi.org/10.1111/jcmm.13268CrossRefPubMedPubMedCentral

10.

Zhang W, Zhou P, Meng A, Zhang R, Zhou Y (2018) Down-regulating Myoferlin inhibits the vasculogenic mimicry of melanoma via decreasing MMP-2 and inducing mesenchymal-to-epithelial transition. J Cell Mol Med 22(3):1743–1754. https://doi.org/10.1111/jcmm.13455CrossRefPubMed

11.

Ayala-Dominguez L, Olmedo-Nieva L, Munoz-Bello JO, Contreras-Paredes A, Manzo-Merino J, Martinez-Ramirez I, Lizano M (2019) Mechanisms of vasculogenic mimicry in ovarian cancer. Front Oncol 9:998. https://doi.org/10.3389/fonc.2019.00998CrossRefPubMedPubMedCentral

12.

Wang Y, Tong L, Wang J, Luo J, Tang J, Zhong L, Xiao Q, Niu W, Li J, Zhu J, Chen H, Li X, Wang Y (2019) cRGD-functionalized nanoparticles for combination therapy of anti-endothelium dependent vessels and anti-vasculogenic mimicry to inhibit the proliferation of ovarian cancer. Acta Biomater 94:495–504. https://doi.org/10.1016/j.actbio.2019.06.039CrossRefPubMed

13.

Li W, Zong S, Shi Q, Li H, Xu J, Hou F (2016) Hypoxia-induced vasculogenic mimicry formation in human colorectal cancer cells: involvement of HIF-1a, Claudin-4, and E-cadherin and Vimentin. Sci Rep 6:37534. https://doi.org/10.1038/srep37534CrossRefPubMedPubMedCentral

14.

Bedal KB, Grassel S, Spanier G, Reichert TE, Bauer RJ (2015) The NC11 domain of human collagen XVI induces vasculogenic mimicry in oral squamous cell carcinoma cells. Carcinogenesis 36(11):1429–1439. https://doi.org/10.1093/carcin/bgv141CrossRefPubMed

15.

Wang F, Li XK, Xu HY, Shan ZZ, Wang T, Yang ZC, He W, Wang LX, Fan QX (2015) N-cadherin participated in invasion and metastasis of human esophageal squamous cell carcinoma via taking part in the formation of vasculogenic mimicry. Med Oncol 32(2):480. https://doi.org/10.1007/s12032-014-0480-zCrossRefPubMed

16.

Schäfer KP (1982) RNA synthesis and processing reactions in a subcellular system from mouse L cells. Hoppe Seylers Z Physiol Chem 363(1):33–43. https://doi.org/10.1515/bchm2.1982.363.1.33CrossRefPubMed

17.

Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crecy-Lagard V, Ross R, Limbach PA, Kotter A, Helm M, Bujnicki JM (2018) MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46(D1):D303–D307. https://doi.org/10.1093/nar/gkx1030CrossRefPubMed

18.

Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485(7397):201–206. https://doi.org/10.1038/nature11112CrossRefPubMed

19.

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7(12):885–887. https://doi.org/10.1038/nchembio.687CrossRefPubMedPubMedCentral

20.

Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10(2):93–95. https://doi.org/10.1038/nchembio.1432CrossRefPubMed

21.

Ping X-L, Sun B-F, Wang L, Xiao W, Yang X, Wang W-J, Adhikari S, Shi Y, Lv Y, Chen Y-S, Zhao X, Li A, Yang Y, Dahal U, Lou X-M, Liu X, Huang J, Yuan W-P, Zhu X-F, Cheng T, Zhao Y-L, Wang X, Rendtlew Danielsen JM, Liu F, Yang Y-G (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24(2):177–189. https://doi.org/10.1038/cr.2014.3CrossRefPubMedPubMedCentral

22.

Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C (2014) N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505(7481):117–120. https://doi.org/10.1038/nature12730CrossRefPubMed

23.

Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell 161(6):1388–1399. https://doi.org/10.1016/j.cell.2015.05.014CrossRefPubMedPubMedCentral

24.

Bai XL, Zhang Q, Ye LY, Liang F, Sun X, Chen Y, Hu QD, Fu QH, Su W, Chen Z, Zhuang ZP, Liang TB (2015) Myocyte enhancer factor 2C regulation of hepatocellular carcinoma via vascular endothelial growth factor and Wnt/β-catenin signaling. Oncogene 34(31):4089–4097. https://doi.org/10.1038/onc.2014.337CrossRefPubMed

25.

Huang H, Weng H, Zhou K, Wu T, Zhao BS, Sun M, Chen Z, Deng X, Xiao G, Auer F, Klemm L, Wu H, Zuo Z, Qin X, Dong Y, Zhou Y, Qin H, Tao S, Du J, Liu J, Lu Z, Yin H, Mesquita A, Yuan CL, Hu YC, Sun W, Su R, Dong L, Shen C, Li C, Qing Y, Jiang X, Wu X, Sun M, Guan JL, Qu L, Wei M, Muschen M, Huang G, He C, Yang J, Chen J (2019) Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature 567(7748):414–419. https://doi.org/10.1038/s41586-019-1016-7CrossRefPubMedPubMedCentral

26.

Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, Schinzel AC, Sood S, Rosenbluh J, Kim JW, Zwang Y, Roberts TM, Root DE, Jacks T, Hahn WC (2014) KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158(1):171–184. https://doi.org/10.1016/j.cell.2014.06.004CrossRefPubMedPubMedCentral

27.

Moon H, Ju HL, Chung SI, Cho KJ, Eun JW, Nam SW, Han KH, Calvisi DF, Ro SW (2017) Transforming growth factor-beta promotes liver tumorigenesis in mice via up-regulation of snail. Gastroenterology 153(5):1378–1391. https://doi.org/10.1053/j.gastro.2017.07.014CrossRefPubMed

28.

Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18(2):128–134. https://doi.org/10.1038/nrc.2017.118CrossRefPubMed

29.

Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z, Zhao G (2019) METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer 18(1):142–142. https://doi.org/10.1186/s12943-019-1065-4CrossRefPubMedPubMedCentral

30.

Lin X, Chai G, Wu Y, Li J, Chen F, Liu J, Luo G, Tauler J, Du J, Lin S, He C, Wang H (2019) RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun 10(1):2065–2065. https://doi.org/10.1038/s41467-019-09865-9CrossRefPubMedPubMedCentral

31.

He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P, Liu D, Tian L, Yin J, Jiang K, Miao Y (2018) ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cell Physiol Biochem 48(2):838–846. https://doi.org/10.1159/000491915CrossRefPubMed

32.

Lin S, Choe J, Du P, Triboulet R, Gregory RI (2016) The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell 62(3):335–345. https://doi.org/10.1016/j.molcel.2016.03.021CrossRefPubMedPubMedCentral

33.

Kwok C-T, Marshall AD, Rasko JEJ, Wong JJL (2017) Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia. J Hematol Oncol 10(1):39–39. https://doi.org/10.1186/s13045-017-0410-6CrossRefPubMedPubMedCentral

34.

Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C, Yu M, Skibbe J, Dai Q, Zou D, Wu T, Yu K, Weng H, Huang H, Ferchen K, Qin X, Zhang B, Qi J, Sasaki AT, Plas DR, Bradner JE, Wei M, Marcucci G, Jiang X, Mulloy JC, Jin J, He C, Chen J (2018) R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell 172(1–2):90–105.e123. https://doi.org/10.1016/j.cell.2017.11.031CrossRefPubMed

35.

Li T, Hu P-S, Zuo Z, Lin J-F, Li X, Wu Q-N, Chen Z-H, Zeng Z-L, Wang F, Zheng J, Chen D, Li B, Kang T-B, Xie D, Lin D, Ju H-Q, Xu R-H (2019) METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer 18(1):112–112. https://doi.org/10.1186/s12943-019-1038-7CrossRefPubMedPubMedCentral

36.

Meng Y, Li S, Gu D, Xu K, Du M, Zhu L, Chu H, Zhang Z, Wu Y, Fu Z, Wang M (2019) Genetic variants in m6A modification genes are associated with colorectal cancer risk. Carcinogenesis. https://doi.org/10.1093/carcin/bgz165CrossRefPubMed

37.

Zhu L, Zhu Y, Han S, Chen M, Song P, Dai D, Xu W, Jiang T, Feng L, Shin VY, Wang X, Jin H (2019) Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis 10(6):383–383. https://doi.org/10.1038/s41419-019-1585-2CrossRefPubMedPubMedCentral

38.

Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K (2018) Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37(4):522–533. https://doi.org/10.1038/onc.2017.351CrossRefPubMed

39.

Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M, Liang Y, Zhu F, Zhang Y, Zhang X, Yuan Q, Li Y (2019) The m(6)A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene 38(19):3667–3680. https://doi.org/10.1038/s41388-019-0683-zCrossRefPubMed

40.

Zhang P, He Q, Lei Y, Li Y, Wen X, Hong M, Zhang J, Ren X, Wang Y, Yang X, He Q, Ma J, Liu N (2018) m(6)A-mediated ZNF750 repression facilitates nasopharyngeal carcinoma progression. Cell Death Dis 9(12):1169–1169. https://doi.org/10.1038/s41419-018-1224-3CrossRefPubMedPubMedCentral

41.

Sun T, Zhao N, Zhao XL, Gu Q, Zhang SW, Che N, Wang XH, Du J, Liu YX, Sun BC (2010) Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology 51(2):545–556. https://doi.org/10.1002/hep.23311CrossRefPubMed

42.

Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong G-M, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J (2017) FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell 31(1):127–141. https://doi.org/10.1016/j.ccell.2016.11.017CrossRefPubMed

43.

Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H (2013) RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155(4):793–806. https://doi.org/10.1016/j.cell.2013.10.026CrossRefPubMed

44.

Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF (2015) HNRNPA2B1 Is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 162(6):1299–1308. https://doi.org/10.1016/j.cell.2015.08.011CrossRefPubMedPubMedCentral

45.

Tatomer DC, Wilusz JE (2017) An unchartered journey for ribosomes: circumnavigating circular RNAs to produce proteins. Mol Cell 66(1):1–2. https://doi.org/10.1016/j.molcel.2017.03.011CrossRefPubMed

46.

Yang X, Liu Q-L, Xu W, Zhang Y-C, Yang Y, Ju L-F, Chen J, Chen Y-S, Li K, Ren J, Sun Q, Yang Y-G (2019) m6A promotes R-loop formation to facilitate transcription termination. Cell Res. https://doi.org/10.1038/s41422-019-0235-7CrossRefPubMedPubMedCentral

47.

Ou H, Chen Z, Xiang L, Fang Y, Xu Y, Liu Q, Hu Z, Li X, Huang Y, Yang D (2019) Frizzled 2-induced epithelial-mesenchymal transition correlates with vasculogenic mimicry, stemness, and Hippo signaling in hepatocellular carcinoma. Cancer Sci 110(4):1169–1182. https://doi.org/10.1111/cas.13949CrossRefPubMedPubMedCentral

48.

Wei H, Wang F, Wang Y, Li T, Xiu P, Zhong J, Sun X, Li J (2017) Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex. Cancer Sci 108(3):478–487. https://doi.org/10.1111/cas.13138CrossRefPubMedPubMedCentral

Titel: RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway
verfasst von: Kailiang Qiao
Yantao Liu
Zheng Xu
Haohao Zhang
Heng Zhang
Chao Zhang
Zhi Chang
Xinyan Lu
Zhongwei Li
Ce Luo
Yanrong Liu
Cheng Yang
Tao Sun
Publikationsdatum: 13.09.2020
Verlag: Springer Netherlands
Erschienen in: Angiogenesis / Ausgabe 1/2021
Print ISSN: 0969-6970
Elektronische ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-020-09744-8

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

27.05.2024 Blut im Stuhl Nachrichten

Immunchemischer Stuhltest positiv, Koloskopie negativ – in solchen Fällen kann die Blutungsquelle auch weiter proximal sitzen. Ein Forschungsteam hat nachgesehen, wie häufig und in welchen Lokalisationen das der Fall ist.

GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

24.05.2024 Diabetische Retinopathie Nachrichten

Möglicherweise hängt es von der Art der Diabetesmedikamente ab, wie hoch das Risiko der Betroffenen ist, dass sich sehkraftgefährdende Komplikationen verschlimmern.

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2021

Vessel tech: a high-accuracy pipeline for comprehensive mouse retinal vasculature characterization

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors

Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis

3D analysis of microvasculature in murine liver fibrosis models using synchrotron radiation-based microtomography