MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response

  • Authors:
    • Min Zhao
    • Qian Liu
    • Wenxiang Liu
    • He Zhou
    • Xuan Zang
    • Jiangyang Lu
  • View Affiliations

  • Published online on: July 8, 2019     https://doi.org/10.3892/mmr.2019.10475
  • Pages: 2484-2492
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Immune checkpoint blockade is a promising therapeutic strategy against various human malignancies. MicroRNAs (miRNAs/miRs) regulate gene expression, by repressing mRNA translation or promoting its degradation. The aim of the current study was to investigate the role and molecular mechanisms of miR‑140 in Helicobacter pylori (Hp)‑associated gastric cancer, and to examine its relationship with immune function in gastric cancer. Gastritis tissue samples from gastritis patients, and gastric cancer tissue samples from gastric cancer patients were collected for miR‑140 expression detection. miR‑140 expression was detected using reverse transcription‑quantitative polymerase chain reaction, and protein expression was measured by western blotting. TargetScan and dual luciferase reporter assays were used to reveal the association between miR‑140 and programmed cell death‑ligand 1 (PD‑L1). BGC823 cell proliferation was detected by MTT assays. Ex vivo immune analysis by flow cytometry and ELISA were used to analyze immune function. It was demonstrated that miR‑140 expression was significantly reduced in Hp‑positive gastric cancer. PD‑L1 was confirmed as a direct target of miR‑140 in gastric cancer cells. In addition, PD‑L1 expression was significantly increased in Hp‑positive gastric cancer. Overexpression of miR‑140 significantly suppressed gastric cancer cell proliferation through regulating PD‑L1 expression. In vivo experiments also revealed that miR‑140 markedly repressed tumor growth in the C57BL/6 mice. Furthermore, it was determined that the tumor‑suppressive role of miR‑140 in gastric cancer was associated with increased cytotoxic CD8+ T cell and reduced myeloid‑derived suppressive and regulatory T cell infiltration. miR‑140 significantly prevented mammalian target of rapamycin signaling in gastric cancer cells. Notably, these miR‑140 overexpression‑induced alterations were inhibited by PD‑L1 plasmid. These findings indicated that miR‑140 exerted an anti‑gastric cancer effect by targeting immune checkpoint molecule PD‑L1. Thus, miR‑140 may be a promising and novel immunotherapeutic target for gastric cancer treatment.

References

1 

Muhammad JS, Sugiyama T and Zaidi SF: Gastric pathophysiological ins and outs of helicobacter pylori: A review. J Pak Med Assoc. 63:1528–1533. 2013.PubMed/NCBI

2 

Ali Z, Deng Y and Ma C: Progress of research in gastric cancer. J Nanosci Nanotechnol. 12:8241–8248. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Lordick F, Allum W, Carneiro F, Mitry E, Tabernero J, Tan P, Van Cutsem E, van de Velde C and Cervantes A: Unmet needs and challenges in gastric cancer: The way forward. Cancer Treat Rev. 40:692–700. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Graham DY: History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol. 20:5191–5204. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Falt P, Hanousek M, Kundrátová E and Urban O: Precancerous conditions and lesions of the stomach. Klin Onkol. 26 (Suppl):S22–S28. 2013.(In Czech). View Article : Google Scholar : PubMed/NCBI

6 

Xiao D, Zhang H, He L, Peng X, Wang Y, Xue G, Su P and Zhang J: High natural variability bacteria identification and typing: Helicobacter pylori analysis based on peptide mass fingerprinting. J Proteomics. 98:112–122. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Katada T, Ishiguro H, Kuwabara Y, Kimura M, Mitui A, Mori Y, Ogawa R, Harata K and Fujii Y: MicroRNA expression profile in undifferentiated gastric cancer. Int J Oncol. 34:537–542. 2009.PubMed/NCBI

8 

Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C, Grønbæk K, Federspiel B, Lund AH and Friis-Hansen L: miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Mol Cancer. 10:292011. View Article : Google Scholar : PubMed/NCBI

9 

Chiang Y, Zhou X, Wang Z, Song Y, Liu Z, Zhao F, Zhu J and Xu H: Expression levels of microRNA-192 and −215 in gastric carcinoma. Pathol Oncol Res. 18:585–591. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Zhang H, Cheng Y, Jia C, Yu S, Xiao Y and Chen J: MicroRNA-29s could target AKT2 to inhibit gastric cancer cells invasion ability. Med Oncol. 32:3422015. View Article : Google Scholar : PubMed/NCBI

11 

Zhang R, Li F, Wang W, Wang X, Li S and Liu J: The effect of antisense inhibitor of miRNA 106b~25 on the proliferation, invasion, migration, and apoptosis of gastric cancer cell. Tumour Biol. 37:10507–10515. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Xiang XJ, Deng J, Liu YW, Wan LY, Feng M, Chen J and Xiong JP: MiR-1271 Inhibits Cell Proliferation, Invasion and EMT in Gastric Cancer by Targeting FOXQ1. Cell Physiol Biochem. 36:1382–1394. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Zhou X, Xia Y, Li L and Zhang G: MiR-101 inhibits cell growth and tumorigenesis of Helicobacter pylori related gastric cancer by repression of SOCS2. Cancer Biol Ther. 16:160–169. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Zhou X, Xu G, Yin C, Jin W and Zhang G: Down-regulation of miR-203 induced by Helicobacter pylori infection promotes the proliferation and invasion of gastric cancer by targeting CASK. Oncotarget. 5:11631–11640. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Fassan M, Saraggi D, Balsamo L, Cascione L, Castoro C, Coati I, De Bernard M, Farinati F, Guzzardo V, Valeri N, et al: Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis. Oncotarget. 7:4915–4924. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Li Q, Wang N, Wei H, Li C, Wu J and Yang G: miR-24-3p Regulates Progression of Gastric Mucosal Lesions and Suppresses Proliferation and Invasiveness of N87 Via Peroxiredoxin 6. Dig Dis Sci. 61:3486–3497. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Yan X, Zhu Z, Xu S, Yang LN, Liao XH, Zheng M, Yang D, Wang J, Chen D, Wang L, et al: MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways. Sci Rep. 7:459152017. View Article : Google Scholar : PubMed/NCBI

18 

Yu L, Lu Y, Han X, Zhao W, Li J, Mao J, Wang B, Shen J, Fan S, Wang L, et al: microRNA −140-5p inhibits colorectal cancer invasion and metastasis by targeting ADAMTS5 and IGFBP5. Stem Cell Res Ther. 7:1802016. View Article : Google Scholar : PubMed/NCBI

19 

Su Y, Xiong J, Hu J, Wei X, Zhang X and Rao L: MicroRNA-140-5p targets insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress cervical cancer growth and metastasis. Oncotarget. 7:68397–68411. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Fang Z, Yin S, Sun R, Zhang S, Fu M, Wu Y, Zhang T, Khaliq J and Li Y: miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1. Mol Cancer. 16:1392017. View Article : Google Scholar : PubMed/NCBI

21 

Zou J and Xu Y: MicroRNA-140 Inhibits Cell Proliferation in Gastric Cancer Cell Line HGC-27 by Suppressing SOX4. Med Sci Monit. 22:2243–2252. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Song Z, Wu Y, Yang J, Yang D and Fang X: Progress in the treatment of advanced gastric cancer. Tumour Biol. 39:10104283177146262017. View Article : Google Scholar : PubMed/NCBI

23 

Zhang K, Peng Z, Huang X, Qiao Z, Wang X, Wang N, Xi H, Cui J, Gao Y, Huang X, et al: Phase II Trial of Adjuvant Immunotherapy with Autologous Tumor-derived Gp96 Vaccination in Patients with Gastric Cancer. J Cancer. 8:1826–1832. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Mimura K, Teh JL, Okayama H, Shiraishi K, Kua LF, Koh V, Smoot DT, Ashktorab H, Oike T, Suzuki Y, et al: PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 109:43–53. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Dos Santos Fernandes G, da Motta Girardi D, Dib Batista Bugiato Faria L, Giacomini Bernardes JP and de Almeida Coudry R: Impressive response to immunotherapy in a metastatic gastric cancer patient: Could somatic copy number alterations help patient selection? J Immunother Cancer. 5:842017. View Article : Google Scholar : PubMed/NCBI

26 

Goodman A, Patel SP and Kurzrock R: PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol. 14:203–220. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A and Sahebkar A: PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. Feb 19–2019.(Epub ahead of print). View Article : Google Scholar

28 

Liu Y, Wu L, Tong R, Yang F, Yin L, Li M, You L, Xue J and Lu Y: PD-1/PD-L1 Inhibitors in Cervical Cancer. Front Pharmacol. 10:652019. View Article : Google Scholar : PubMed/NCBI

29 

Pawłowska A, Suszczyk D, Okła K, Barczyński B, Kotarski J and Wertel I: Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment. Clin Exp Immunol. 195:334–344. 2019. View Article : Google Scholar : PubMed/NCBI

30 

Ji X, Wang E and Tian F: MicroRNA-140 suppresses osteosarcoma tumor growth by enhancing anti-tumor immune response and blocking mTOR signaling. Biochem Biophys Res Commun. 495:1342–1348. 2018. View Article : Google Scholar : PubMed/NCBI

31 

McNicholl AG, Ducons J, Barrio J, Bujanda L, Forné-Bardera M, Aparcero R, Ponce J, Rivera R, Dedeu-Cuso JM, Garcia-Iglesias P, et al: Helicobacter pylori Study Group of the Asociación Española de Gastroenterología (AEG): Accuracy of the Ultra-Rapid Urease Test for diagnosis of Helicobacter pylori infection. Gastroenterol Hepatol. 40:651–657. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Bayne K: Revised Guide for the Care and Use of Laboratory Animals available. American Physiological Society. Physiologist. 39(199): 208–211. 1996.

34 

Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q, et al: Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell. 162:1242–1256. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Cortez MA, Anfossi S, Ramapriyan R, Menon H, Atalar SC, Aliru M, Welsh J and Calin GA: Role of miRNAs in immune responses and immunotherapy in cancer. Genes Chromosomes Cancer. 58:244–253. 2019. View Article : Google Scholar : PubMed/NCBI

36 

Wang Q, Lin W, Tang X, Li S, Guo L, Lin Y and Kwok HF: The Roles of microRNAs in Regulating the Expression of PD-1/PD-L1 Immune Checkpoint. Int J Mol Sci. 18:182017. View Article : Google Scholar

37 

Kapodistrias N, Bobori C and Theocharopoulou G: MiR-140-3p Downregulation in Association with PDL-1 Overexpression in Many Cancers: A Review from the Literature Using Predictive Bioinformatics Tools. Adv Exp Med Biol. 988:225–233. 2017.(In German). View Article : Google Scholar : PubMed/NCBI

38 

Kao SC, Cheng YY, Williams M, Kirschner MB, Madore J, Lum T, Sarun KH, Linton A, McCaughan B, Klebe S, et al: Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. J Thorac Oncol. 12:1421–1433. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Jia L, Xi Q, Wang H, Zhang Z, Liu H, Cheng Y, Guo X, Zhang J, Zhang Q, Zhang L, et al: miR-142-5p regulates tumor cell PD-L1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun. 488:425–431. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Cioffi M, Trabulo SM, Vallespinos M, Raj D, Kheir TB, Lin ML, Begum J, Baker AM, Amgheib A, Saif J, et al: The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget. 8:21609–21625. 2017. View Article : Google Scholar : PubMed/NCBI

41 

Xu S, Tao Z, Hai B, Liang H, Shi Y, Wang T, Song W, Chen Y, OuYang J, Chen J, et al: miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun. 7:114062016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhao, M., Liu, Q., Liu, W., Zhou, H., Zang, X., & Lu, J. (2019). MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response. Molecular Medicine Reports, 20, 2484-2492. https://doi.org/10.3892/mmr.2019.10475
MLA
Zhao, M., Liu, Q., Liu, W., Zhou, H., Zang, X., Lu, J."MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response". Molecular Medicine Reports 20.3 (2019): 2484-2492.
Chicago
Zhao, M., Liu, Q., Liu, W., Zhou, H., Zang, X., Lu, J."MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response". Molecular Medicine Reports 20, no. 3 (2019): 2484-2492. https://doi.org/10.3892/mmr.2019.10475