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LncRNA DLGAP1-AS2 overexpression associates with gastric tumorigenesis: a promising diagnostic and therapeutic target

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Abstract

Background

Aberrant expression of long noncoding RNAs (lncRNAs) is associated with the progression of human cancers, including gastric cancer (GC). The function of lncRNA DLGAP1-AS2, as a promising oncogene, has been identified in several human cancers. Therefore, this study was aimed to explore the association of DLGAP1-AS2 with gastric tumorigenesis, as well.

Methods and results

The expression level of DLGAP1-AS2 was initially pre-evaluated in GC datasets from Gene Expression Omnibus (GEO). Moreover, qRT-PCR experiment was performed on 25 GC and 25 adjacent normal tissue samples. The Cancer Genome Atlas (TCGA) data were also analyzed for further validation. Consistent with data obtained from GEO datasets, qRT-PCR results revealed that DLGAP1-AS2 was significantly (p < 0.0032) upregulated in GC specimens compared to normal samples, which was additionally confirmed using TCGA analysis (p < 0.0001). DLGAP1-AS2 expression level was also correlated with age (p = 0.0008), lymphatic and vascular invasion (p = 0.0415) in internal samples as well as poor survival of GC patients (p = 0.00074) in GEO datasets. Also, Gene Ontology analysis illustrated that DLGAP1-AS2 may be involved in the cellular process, including hippo signaling, regulated by YAP1, as its valid downstream target, in GC samples. Moreover, ROC curve analysis showed the high accuracy of the DLGAP1-AS2 expression pattern as a diagnostic biomarker for GC.

Conclusion

Our findings indicated that DLGAP1-AS2 might display oncogenic properties through gastric tumorigenesis and could be suggested as a therapeutic, diagnostic, and prognostic target.

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Data availability

All data generated in this study are available in the manuscript. This manuscript is published as a preprint with https://doi.org/10.21203/rs.3.rs-529611/v1

Code availability

Not applicable.

References

  1. Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, Chivu-Economescu M (2019) Recent advances in gastric cancer early diagnosis. World J Gastroenterol 25(17):2029–2044. https://doi.org/10.3748/wjg.v25.i17.2029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Thrift AP, El-Serag HB (2020) Burden of gastric cancer. Clin Gastroenterol Hepatol 18(3):534–542. https://doi.org/10.1016/j.cgh.2019.07.045

    Article  PubMed  Google Scholar 

  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 68(6):394–424

    Google Scholar 

  5. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP (2018) Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 10:239–248. https://doi.org/10.2147/cmar.s149619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cuzzuol BR, Vieira ES, Araújo GRL, Apolonio JS, de Carvalho LS, da Silva Junior RT, de Melo FF (2020) Gastric cancer: a brief review, from risk factors to treatment. Arch Gastroenterol Res 1(2):34–39

    Google Scholar 

  7. Marin J, Al-Abdulla R, Lozano E, Briz O, Bujanda L, Banales M, Macias R (2016) Mechanisms of resistance to chemotherapy in gastric cancer. ACAMC 16(3):318–334

    Article  CAS  Google Scholar 

  8. Shi WJ, Gao JB (2016) Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 8(9):673–681. https://doi.org/10.4251/wjgo.v8.i9.673

    Article  PubMed  PubMed Central  Google Scholar 

  9. Amini M, Ghorban K, Mokhtarzadeh A, Dadmanesh M, Baradaran B (2020) CD40 DNA hypermethylation in primary gastric tumors; as a novel diagnostic biomarker. Life Sci 254:117774. https://doi.org/10.1016/j.lfs.2020.117774

    Article  CAS  PubMed  Google Scholar 

  10. Padmanabhan N, Ushijima T, Tan P (2017) How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol 14(8):467

    Article  Google Scholar 

  11. Nasrollahzadeh-Khakiani M, Emadi-Baygi M, Schulz WA, Nikpour P (2016) Long noncoding RNAs in gastric cancer carcinogenesis and metastasis. Brief Funct Genom 16(3):129–145. https://doi.org/10.1093/bfgp/elw011

    Article  CAS  Google Scholar 

  12. Li H, Yu B, Li J, Su L, Yan M, Zhu Z, Liu B (2014) Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 5(8):2318

    Article  Google Scholar 

  13. Li T, Mo X, Fu L, Xiao B, Guo J (2016) Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget 7(8):8601–8612. https://doi.org/10.18632/oncotarget.6926

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tan H, Zhang S, Zhang J, Zhu L, Chen Y, Yang H, Liu B (2020) Long non-coding RNAs in gastric cancer: New emerging biological functions and therapeutic implications. Theranostics 10(19):8880

    Article  CAS  Google Scholar 

  15. Xiao N, Hu Y, Juan L (2020) Comprehensive analysis of differentially expressed lncRNAs in gastric cancer. Front Cell Dev Biol 8:557

    Article  Google Scholar 

  16. Foroughi K, Amini M, Atashi A, Mahmoodzadeh H, Hamann U, Manoochehri M (2018) Tissue-specific down-regulation of the long non-coding RNAs PCAT18 and LINC01133 in gastric cancer development. Int J Mol Sci 19(12):3881. https://doi.org/10.3390/ijms19123881

    Article  CAS  PubMed Central  Google Scholar 

  17. Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J, Fang G (2012) Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. Febs j 279(17):3159–3165. https://doi.org/10.1111/j.1742-4658.2012.08694.x

    Article  CAS  PubMed  Google Scholar 

  18. Yang F, Xue X, Bi J, Zheng L, Zhi K, Gu Y, Fang G (2013) Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol 139(3):437–445. https://doi.org/10.1007/s00432-012-1324-x

    Article  CAS  PubMed  Google Scholar 

  19. Yang F, Xue X, Zheng L, Bi J, Zhou Y, Zhi K, Fang G (2014) Long non-coding RNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-Myc mRNA stability. FEBS J 281(3):802–813. https://doi.org/10.1111/febs.12625

    Article  CAS  PubMed  Google Scholar 

  20. Zhang EB, Han L, Yin DD, Kong R, De W, Chen J (2014) c-Myc-induced, long, noncoding H19 affects cell proliferation and predicts a poor prognosis in patients with gastric cancer. Med Oncol 31(5):914. https://doi.org/10.1007/s12032-014-0914-7

    Article  CAS  PubMed  Google Scholar 

  21. Zhuang M, Gao W, Xu J, Wang P, Shu Y (2014) The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. Biochem Biophys Res Commun 448(3):315–322. https://doi.org/10.1016/j.bbrc.2013.12.126

    Article  CAS  PubMed  Google Scholar 

  22. Li J, Xu Q, Wang W, Sun S (2019) MIR100HG: a credible prognostic biomarker and an oncogenic lncRNA in gastric cancer. Biosci Reps. https://doi.org/10.1042/BSR20190171

  23. Liu H, Wu N, Zhang Z, Zhong X, Zhang H, Guo H, Liu Y (2019) Long non-coding RNA LINC00941 as a potential biomarker promotes the proliferation and metastasis of gastric cancer. Front Genet 10:5

    Article  Google Scholar 

  24. Yang Z, Guo X, Li G, Shi Y, Li L (2016) Long noncoding RNAs as potential biomarkers in gastric cancer: opportunities and challenges. Cancer Lett 371(1):62–70. https://doi.org/10.1016/j.canlet.2015.11.011

    Article  CAS  PubMed  Google Scholar 

  25. Chen K, Zhang Z, Yu A, Li J, Liu J, Zhang X (2020) lncRNA DLGAP1-AS2 knockdown inhibits hepatocellular carcinoma cell migration and invasion by regulating miR-154-5p methylation. BioMed Res Int 200:1–6

    Google Scholar 

  26. Liu Z, Pan L, Yan X, Duan X (2020) The long noncoding RNA DLGAP1-AS2 facilitates cholangiocarcinoma progression via miR-505 and GALNT10. FEBS Open Bio. https://doi.org/10.1002/2211-5463.13061

    Article  PubMed  PubMed Central  Google Scholar 

  27. Miao W, Li N, Gu B, Yi G, Su Z, Cheng H (2020) LncRNA DLGAP1-AS2 modulates glioma development by up-regulating YAP1 expression. J Biochem 167(4):411–418

    Article  CAS  Google Scholar 

  28. Matsuoka T, Yashiro M (2018) Biomarkers of gastric cancer: current topics and future perspective. World J Gastroenterol 24(26):2818–2832. https://doi.org/10.3748/wjg.v24.i26.2818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fang XY, Pan HF, Leng RX, Ye DQ (2015) Long noncoding RNAs: novel insights into gastric cancer. Cancer Lett 356(2):357–366. https://doi.org/10.1016/j.canlet.2014.11.005

    Article  CAS  PubMed  Google Scholar 

  30. Ma Z, Liu X, Paul ME, Chen M, Zheng P, Chen H (2021) Comparative investigation of early-onset gastric cancer. Oncol Lett 21(5):1–6

    Article  Google Scholar 

  31. Hu X, Xin Y, Xiao Y, Zhao J (2014) Overexpression of YAP1 is correlated with progression, metastasis and poor prognosis in patients with gastric carcinoma. Pathol Oncol Res 20(4):805–811. https://doi.org/10.1007/s12253-014-9757-y

    Article  CAS  PubMed  Google Scholar 

  32. Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, To KF (2011) Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res 17(8):2130–2139. https://doi.org/10.1158/1078-0432.ccr-10-2467

    Article  CAS  PubMed  Google Scholar 

  33. Liu J, Zhao X, Wang K, Zhang X, Yu Y, Lv Y, Li J (2019) A novel YAP1/SLC35B4 regulatory axis contributes to proliferation and progression of gastric carcinoma. Cell Death Dis 10(6):452. https://doi.org/10.1038/s41419-019-1674-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun D, Li X, He Y, Li W, Wang Y, Wang H, Xin Y (2016) YAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo. Oncotarget 7(49):81062–81076. https://doi.org/10.18632/oncotarget.13188

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yu L, Gao C, Feng B, Wang L, Tian X, Wang H, Ma D (2017) Distinct prognostic values of YAP1 in gastric cancer. Tumour Biol. https://doi.org/10.1177/1010428317695926

    Article  PubMed  Google Scholar 

  36. Kang W, Cheng AS, Yu J, To KF (2016) Emerging role of Hippo pathway in gastric and other gastrointestinal cancers. World J Gastroenterol 22(3):1279

    Article  CAS  Google Scholar 

Download references

Funding

The authors are grateful for supports from the Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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Authors and Affiliations

Authors

Contributions

R.S and M.Am performed the majority of experiments and data analysis. S.A contributed to carrying out the experiments and interpreted the results; M.AM and H.B helped with project design; M.M.M and N.B wrote the manuscript. B.B and A.J contributed to designing the project; M.As helped with sample preparation. A.M revised the manuscript, designed and conducted the project.

Corresponding author

Correspondence to Ahad Mokhtarzadeh.

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The authors declare no conflict of interest.

Ethical approval

The study was approved by the ethical committee of Tabriz University of Medical Sciences, Tabriz, Iran.

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All of the patients who participated in the study had given written informed consent.

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Patients signed informed consent regarding publishing their data.

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Soltani, R., Amini, M., Mazaheri Moghaddam, M. et al. LncRNA DLGAP1-AS2 overexpression associates with gastric tumorigenesis: a promising diagnostic and therapeutic target. Mol Biol Rep 49, 6817–6826 (2022). https://doi.org/10.1007/s11033-021-07038-w

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  • DOI: https://doi.org/10.1007/s11033-021-07038-w

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