Top

Gastric Cancer

Published in:

Open Access 28-10-2023 | Gastric Cancer | Original Article

N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Authors: Rongjun Xie, Longfei Liu, Xianzhou Lu, Chengjian He, Hongyi Yao, Guoxin Li

Published in: Gastric Cancer | Issue 1/2024

Abstract

Background

Opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) has been demonstrated to play vital roles in development and progression of tumors such as gastric cancer (GC). However, the detailed molecular mechanism of OIP5-AS1 has not been completely elucidated. Our study aimed to investigate the role and the epigenetic regulation mechanism of OIP5-AS1 in GC.

Methods

OIP5-AS1 expression in GC tissues was detected by RT-qPCR. Loss- and gain-of-function experiments were conducted to assess the biological function of OIP5-AS1 in vitro and in vivo. The interaction of OIP5-AS1 with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) or heterogeneous nuclear nucleoprotein A1 (hnRNPA1) was verified by bioinformatics analysis, RNA pull-down assays, and RNA immunoprecipitation assays.

Results

In this study, we identified that OIP5-AS1 is specifically overexpressed in GC tumor tissues and cell lines and correlated with a poor prognosis. The loss of OIP5-AS1 suppressed the proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and glycolysis of GC cells, but the ectopic expression of OIP5-AS1 had the opposite impact. Meanwhile, knockdown of OIP5-AS1 inhibited tumor growth in patient-derived xenograft models, as well as repressed tumor metastasis. Mechanistically, IGF2BP3 could bind to OIP5-AS1 by N6-methyladenosine (m6A) modification sites on OIP5-AS1, thereby stabilizing OIP5-AS1. Moreover, OIP5-AS1 prevented Trim21-mediated ubiquitination and degradation of hnRNPA1, stabilizing hnRNPA1 protein and promoting the malignant progression of GC by regulating PKM2 signaling pathway.

Conclusions

In conclusion, this study highlighted that OIP5-AS1 is an oncogenic m6A-modified long non-coding RNA (lncRNA) in GC and that IGF2BP3/OIP5-AS1/hnRNPA1 axis may provide a potential diagnostic or prognostic target for GC.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. https://doi.org/10.3322/caac.21262.CrossRefPubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. https://doi.org/10.3322/caac.21442.CrossRefPubMed

Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396:635–48. https://doi.org/10.1016/S0140-6736(20)31288-5.CrossRefPubMed

Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8. https://doi.org/10.1038/nature11233.CrossRefPubMedPubMedCentral

Lan T, Yuan K, Yan X, et al. LncRNA SNHG10 facilitates hepatocarcinogenesis and metastasis by modulating its homolog SCARNA13 via a positive feedback loop. Cancer Res. 2019;79:3220–34. https://doi.org/10.1158/0008-5472.CAN-18-4044.CrossRefPubMed

Song H, Liu Y, Li X, et al. Long noncoding RNA CASC11 promotes hepatocarcinogenesis and HCC progression through EIF4A3-mediated E2F1 activation. Clin Transl Med. 2020;10: e220. https://doi.org/10.1002/ctm2.220.CrossRefPubMedPubMedCentral

Zhang X, Li D, Jia C, Cai H, Lv Z, Wu B. METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer. Cell Death Dis. 2021;12:617. https://doi.org/10.1038/s41419-021-03891-6.CrossRefPubMedPubMedCentral

Khorkova O, Hsiao J, Wahlestedt C. Basic biology and therapeutic implications of lncRNA. Adv Drug Deliv Rev. 2015;87:15–24. https://doi.org/10.1016/j.addr.2015.05.012.CrossRefPubMedPubMedCentral

10.

Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46. https://doi.org/10.1016/j.cell.2013.06.020.CrossRefPubMedPubMedCentral

11.

Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307. https://doi.org/10.1016/j.cell.2013.02.012.CrossRefPubMedPubMedCentral

12.

Li H, Yao G, Zhai J, Hu D, Fan Y. LncRNA FTX promotes proliferation and invasion of gastric cancer via miR-144/ZFX Axis. Onco Targets Ther. 2019;12:11701–13. https://doi.org/10.2147/OTT.S220998.CrossRefPubMedPubMedCentral

13.

Wang H, Wu M, Lu Y, et al. LncRNA MIR4435-2HG targets desmoplakin and promotes growth and metastasis of gastric cancer by activating Wnt/beta-catenin signaling. Aging (Albany NY). 2019;11:6657–73. https://doi.org/10.18632/aging.102164.CrossRefPubMed

14.

Zhuo W, Liu Y, Li S, et al. Long noncoding RNA GMAN, up-regulated in gastric cancer tissues, is associated with metastasis in patients and promotes translation of Ephrin A1 by competitively binding GMAN-AS. Gastroenterology. 2019;156(676–691): e611. https://doi.org/10.1053/j.gastro.2018.10.054.CrossRef

15.

He X, Wang J, Chen J, et al. lncRNA UCA1 predicts a poor prognosis and regulates cell proliferation and migration by repressing p21 and SPRY1 expression in GC. Mol Ther Nucleic Acids. 2019;18:605–16. https://doi.org/10.1016/j.omtn.2019.09.024.CrossRefPubMedPubMedCentral

16.

Wang X, Li X, Zhou Y, Huang X, Jiang X. Long non-coding RNA OIP5-AS1 inhibition upregulates microRNA-129-5p to repress resistance to temozolomide in glioblastoma cells via downregulating IGF2BP2. Cell Biol Toxicol. 2022;38:963–77. https://doi.org/10.1007/s10565-021-09614-z.CrossRefPubMed

17.

Ghafouri-Fard S, Dashti S, Farsi M, Hussen BM, Taheri M. A review on the role of oncogenic lncRNA OIP5-AS1 in human malignancies. Biomed Pharmacother. 2021;137: 111366. https://doi.org/10.1016/j.biopha.2021.111366.CrossRefPubMed

18.

Huang J, Hou S, Xu J, Wu J, Yin J. Long non-coding RNA OIP5-AS1 promotes cell proliferation and aerobic glycolysis in gastric cancer through sponging miR-186. Arch Med Sci. 2021;17:1742–51. https://doi.org/10.5114/aoms.2019.87213.CrossRefPubMed

19.

Xie R, Liu L, Lu X, Hu Y. LncRNA OIP5-AS1 facilitates gastric cancer cell growth by targeting the miR-422a/ANO1 axis. Acta Biochim Biophys Sin (Shanghai). 2020;52:430–8. https://doi.org/10.1093/abbs/gmaa012.CrossRefPubMed

20.

Tan L, Tang Y, Li H, et al. N6-methyladenosine modification of LncRNA DUXAP9 promotes renal cancer cells proliferation and motility by activating the PI3K/AKT signaling pathway. Front Oncol. 2021;11: 641833. https://doi.org/10.3389/fonc.2021.641833.CrossRefPubMedPubMedCentral

21.

Zhong GY, Tan JN, Huang J, et al. LncRNA LINC01537 Promotes Gastric Cancer Metastasis and Tumorigenesis by Stabilizing RIPK4 to Activate NF-kappaB Signaling. Cancers (Basel). 2022. https://doi.org/10.3390/cancers14215237.CrossRefPubMedPubMedCentral

22.

Guo T, Bai YH, Cheng XJ, et al. Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4. Cancer Commun (Lond). 2021;41:258–72. https://doi.org/10.1002/cac2.12141.CrossRefPubMed

23.

Mo Y, Wang Y, Zhang S, et al. Circular RNA circRNF13 inhibits proliferation and metastasis of nasopharyngeal carcinoma via SUMO2. Mol Cancer. 2021;20:112. https://doi.org/10.1186/s12943-021-01409-4.CrossRefPubMedPubMedCentral

24.

Ping M, Wang S, Guo Y, Jia J. TRIM21 improves apatinib treatment in gastric cancer through suppressing EZH1 stability. Biochem Biophys Res Commun. 2022;586:177–84. https://doi.org/10.1016/j.bbrc.2021.07.040.CrossRefPubMed

25.

Zhang J, Zhao T, Tian L, Li Y. LncRNA OIP5-AS1 promotes the proliferation of hemangioma vascular endothelial cells via regulating miR-195-5p/NOB1 axis. Front Pharmacol. 2019;10:449. https://doi.org/10.3389/fphar.2019.00449.CrossRefPubMedPubMedCentral

26.

Shi C, Yang Q, Pan S, et al. LncRNA OIP5-AS1 promotes cell proliferation and migration and induces angiogenesis via regulating miR-3163/VEGFA in hepatocellular carcinoma. Cancer Biol Ther. 2020;21:604–14. https://doi.org/10.1080/15384047.2020.1738908.CrossRefPubMedPubMedCentral

27.

Wang Y, Shi F, Xia Y, Zhao H. LncRNA OIP5-AS1 predicts poor prognosis and regulates cell proliferation and apoptosis in bladder cancer. J Cell Biochem. 2018. https://doi.org/10.1002/jcb.28024.CrossRefPubMedPubMedCentral

28.

Li H, Wang D, Yi B, et al. SUMOylation of IGF2BP2 promotes vasculogenic mimicry of glioma via regulating OIP5-AS1/miR-495-3p axis. Int J Biol Sci. 2021;17:2912–30. https://doi.org/10.7150/ijbs.58035.CrossRefPubMedPubMedCentral

29.

Tao Y, Wan X, Fan Q, et al. Long non-coding RNA OIP5-AS1 promotes the growth of gastric cancer through the miR-367-3p/HMGA2 axis. Dig Liver Dis. 2020;52:773–9. https://doi.org/10.1016/j.dld.2019.11.017.CrossRefPubMed

30.

Li B, Zhao R, Qiu W, et al. The N(6)-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2. Theranostics. 2022;12:6363–79. https://doi.org/10.7150/thno.74600.CrossRefPubMedPubMedCentral

31.

Du M, Peng Y, Li Y, et al. MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma. Cell Death Discov. 2022;8:53. https://doi.org/10.1038/s41420-022-00844-6.CrossRefPubMedPubMedCentral

32.

Yang Z, Zhao F, Gu X, et al. Binding of RNA m6A by IGF2BP3 triggers chemoresistance of HCT8 cells via upregulation of ABCB1. Am J Cancer Res. 2021;11:1428–45.PubMedPubMedCentral

33.

Cui Y, Liu J, Liu L, et al. m(6)A-modified circFOXK2 targets GLUT1 to accelerate oral squamous cell carcinoma aerobic glycolysis. Cancer Gene Ther. 2022. https://doi.org/10.1038/s41417-022-00526-6.CrossRefPubMed

34.

Xu TP, Yu T, Xie MY, et al. LOC101929709 promotes gastric cancer progression by aiding LIN28B to stabilize c-MYC mRNA. Gastric Cancer. 2022. https://doi.org/10.1007/s10120-022-01348-z.CrossRefPubMedPubMedCentral

35.

Jian F, Che X, Zhang J, et al. The long-noncoding RNA SOCS2-AS1 suppresses endometrial cancer progression by regulating AURKA degradation. Cell Death Dis. 2021;12:351. https://doi.org/10.1038/s41419-021-03595-x.CrossRefPubMedPubMedCentral

36.

Pham TND, Stempel S, Shields MA, et al. Quercetin Enhances the Anti-Tumor Effects of BET Inhibitors by Suppressing hnRNPA1. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20174293.CrossRefPubMedPubMedCentral

37.

Liu X, Tian N, Huang Q, et al. hnRNPA1 enhances FOXP3 stability to promote the differentiation and functions of regulatory T cells. FEBS Lett. 2021;595:1962–74. https://doi.org/10.1002/1873-3468.14142.CrossRefPubMed

38.

Moller K, Wecker AL, Hoflmayer D, et al. Upregulation of the heterogeneous nuclear ribonucleoprotein hnRNPA1 is an independent predictor of early biochemical recurrence in TMPRSS2:ERG fusion-negative prostate cancers. Virchows Arch. 2020;477:625–36. https://doi.org/10.1007/s00428-020-02834-4.CrossRefPubMedPubMedCentral

39.

Zhao B, Lv X, Zhao X, et al. Tumor-promoting actions of HNRNP A1 in HCC are associated with cell cycle, mitochondrial dynamics, and necroptosis. Int J Mol Sci. 2022. https://doi.org/10.3390/ijms231810209.CrossRefPubMedPubMedCentral

40.

Chen FR, Sha SM, Wang SH, et al. RP11–81H3.2 promotes gastric cancer progression through miR-339-HNRNPA1 interaction network. Cancer Med. 2020;9:2524–34. https://doi.org/10.1002/cam4.2867.CrossRefPubMedPubMedCentral

41.

Erdem M, Ozgul I, Dioken DN, et al. Identification of an mRNA isoform switch for HNRNPA1 in breast cancers. Sci Rep. 2021;11:24444. https://doi.org/10.1038/s41598-021-04007-y.CrossRefPubMedPubMedCentral

42.

Liu X, Yin Z, Xu L, et al. Upregulation of LINC01426 promotes the progression and stemness in lung adenocarcinoma by enhancing the level of SHH protein to activate the hedgehog pathway. Cell Death Dis. 2021;12:173. https://doi.org/10.1038/s41419-021-03435-y.CrossRefPubMedPubMedCentral

43.

Long B, Yang X, Xu X, et al. Long noncoding RNA ASB16-AS1 inhibits adrenocortical carcinoma cell growth by promoting ubiquitination of RNA-binding protein HuR. Cell Death Dis. 2020;11:995. https://doi.org/10.1038/s41419-020-03205-2.CrossRefPubMedPubMedCentral

44.

Gilpin KM, Chang L, Monteiro MJ. ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1. Hum Mol Genet. 2015;24:2565–77. https://doi.org/10.1093/hmg/ddv020.CrossRefPubMed

45.

Zhang H, Deng T, Liu R, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19:43. https://doi.org/10.1186/s12943-020-01168-8.CrossRefPubMedPubMedCentral

46.

Wang LQ, Zheng YY, Zhou HJ, Zhang XX, Wu P, Zhu SM. LncRNA-Fendrr protects against the ubiquitination and degradation of NLRC4 protein through HERC2 to regulate the pyroptosis of microglia. Mol Med. 2021;27:39. https://doi.org/10.1186/s10020-021-00299-y.CrossRefPubMedPubMedCentral

47.

Wen Z, Lian L, Ding H, et al. LncRNA ANCR promotes hepatocellular carcinoma metastasis through upregulating HNRNPA1 expression. RNA Biol. 2020;17:381–94. https://doi.org/10.1080/15476286.2019.1708547.CrossRefPubMedPubMedCentral

48.

Taniguchi K, Uchiyama K, Akao Y. PTBP1-targeting microRNAs regulate cancer-specific energy metabolism through the modulation of PKM1/M2 splicing. Cancer Sci. 2021;112:41–50. https://doi.org/10.1111/cas.14694.CrossRefPubMed

49.

Yan Q, Zeng P, Zhou X, et al. RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing. Oncogene. 2021;40:2635–50. https://doi.org/10.1038/s41388-021-01666-z.CrossRefPubMedPubMedCentral

50.

Jia Y, Mao C, Ma Z, et al. PHB2 maintains the contractile phenotype of VSMCs by counteracting PKM2 splicing. Circ Res. 2022;131:807–24. https://doi.org/10.1161/CIRCRESAHA.122.321005.CrossRefPubMed

51.

Chen D, Wang Y, Lu R, et al. E3 ligase ZFP91 inhibits hepatocellular carcinoma metabolism reprogramming by regulating PKM splicing. Theranostics. 2020;10:8558–72. https://doi.org/10.7150/thno.44873.CrossRefPubMedPubMedCentral

52.

Lan Z, Yao X, Sun K, Li A, Liu S, Wang X. The interaction between lncRNA SNHG6 and hnRNPA1 contributes to the growth of colorectal cancer by enhancing aerobic glycolysis through the regulation of alternative splicing of PKM. Front Oncol. 2020;10:363. https://doi.org/10.3389/fonc.2020.00363.CrossRefPubMedPubMedCentral

Title: N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation
Authors: Rongjun Xie
Longfei Liu
Xianzhou Lu
Chengjian He
Hongyi Yao
Guoxin Li
Publication date: 28-10-2023
Publisher: Springer Nature Singapore
Keywords: Gastric Cancer
Gastric Cancer
Metastasis
Published in: Gastric Cancer / Issue 1/2024
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-023-01437-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

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

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

Helicobacter pylori testing prior to or at gastric cancer diagnosis and survival in a diverse US patient population

Automatic surgical phase recognition-based skill assessment in laparoscopic distal gastrectomy using multicenter videos

German, Austrian, and Swiss guidelines for gastric cancer

National guidelines for gastric cancer: redundant or needed?

5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer

Ethnic-specific associations between body mass index and gastric cancer: a Mendelian randomization study in European and Korean populations

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials