TGF-β induces HLA-G expression through inhibiting miR-152 in gastric cancer cells

Journal of Biomedical Science

Hui Qu¹  Kexin Wang¹  Dong Sun¹  Fengjun Liu¹  Bingtan Song³  Zhongzheng Guan² 

[1] Department of General Surgery, Qilu Hospital, Shandong University, No.107, West Wenhua Road, Jinan 250012, Shandong Province, China;Department of General Surgery, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong, China;Department of General Surgery, Liaocheng Third People’s Hospital, Liaocheng 252000, Shandong, China

关键词: HLA-G;    TGF-β;    miR-152;    Gastric cancer;   

Others  :  1235083
DOI  :  10.1186/s12929-015-0177-4

 received in 2015-04-25, accepted in 2015-08-05,  发布年份 2015

【 摘 要 】

Background

Mounting evidences have showed the important role of transforming growth factor-β (TGF-β) in immunological surveillance of tumors. Some studies have also indicated human leukocyte antigen (HLA)-G-associated immune escape involving TGF-β management in gastric cancer (GC). However, the mechanism underlying it is unclear. This study aims to verify the correlations between HLA-G and TGF-β, involving the potential targeting of miR-152 on HLA-G.

Results

TGF-β and HLA-G levels were analyzed in blood samples from twenty GC patients with ELISA assays, while TGF-β showed directly proportional to HLA-G levels in GC patients, and TGF-β induced HLA-G up-regulation was also confirmed in GC cell lines. Furthermore, miR-152 expression could be inhibited by TGF-β, and the negative post-transcriptionally regulation of miR-152 on HLA-G was also demonstrated through gain- and loss-of-function studies. Besides, miR-152 overexpression repressed HLA-G up-regulation induced by TGF-β. And, miR-152 expression levels showed inversely proportional to both HLA-G and also TGF-β levels in GC patients.

Conclusion

TGF-β could induce HLA-G expression in GC by inhibiting miR-152, involving its negative regulation on HLA-G. Since TGF-β induced HLA-G up-regulation plays important role in immune escape, a potential application of miR-152 was suggested in GC treatment, or miR-152 might be one potential biomarker for GC.

【 授权许可】

   
2015 Guan et al.

【 图 表 】

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer Journal for Clinicians. 2011; 61:69-90.
• [2]Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M et al.. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New Engl J Med. 2006; 355:11-20.
• [3]Otani K, Li X, Arakawa T, Chan FK, Yu J. Epigenetic-Mediated Tumor Suppressor Genes as Diagnostic or Prognostic Biomarkers in Gastric Cancer. 2013.
• [4]Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116:281-97.
• [5]Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014; 9:287.
• [6]Wang J, Song YX, Wang ZN. Non-coding RNAs in gastric cancer. Gene. 2015; 560:1-8.
• [7]Chen Y, Song Y, Wang Z, Yue Z, Xu H, Xing C et al.. Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010; 14:1170-9.
• [8]Zhai R, Kan X, Wang B, Du H, Long Y, Wu H et al.. miR-152 suppresses gastric cancer cell proliferation and motility by targeting CD151. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2014; 35:11367-73.
• [9]Maehara Y, Kakeji Y, Kabashima A, Emi Y, Watanabe A, Akazawa K et al.. Role of transforming growth factor-β1 in invasion and metastasis in gastric carcinoma. J Clin Oncol. 1999; 17:607.
• [10]Li X, Yue ZC, Zhang YY, Bai J, Xn M, Geng JS et al.. Elevated serum level and gene polymorphisms of TGF‐β1 in gastric cancer. J Clin Lab Anal. 2008; 22:164-71.
• [11]Zhang H-J, Qian W-Q, Chen R, Sun Z-Q, Song J-D, Sheng L. New Therapeutic Schedule for Prostatic Cancer-3 Cells with ET-1 RNAi and Endostar. Asian Pacific journal of cancer prevention: APJCP. 2014; 15:10079.
• [12]Cao M, Yie SM, Liu J, Ye S, Xia D, Gao E. Plasma soluble HLA‐G is a potential biomarker for diagnosis of colorectal, gastric, esophageal and lung cancer. Tissue Antigens. 2011; 78:120-8.
• [13]Du L, Xiao X, Wang C, Zhang X, Zheng N, Wang L et al.. Human leukocyte antigen‐G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells. Canc Sci. 2011; 102:1272-80.
• [14]Tuncel T, Karagoz B, Haholu A, Ozgun A, Emirzeoglu L, Bilgi O et al.. Immunoregulatory Function of HLA-G in Gastric Cancer. Asian Pacific Journal of Cancer Prevention. 2013; 14:7681-4.
• [15]Castelli EC, Moreau P, Oya e Chiromatzo A, Mendes-Junior CT, Veiga-Castelli LC, Yaghi L et al.. In silico analysis of microRNAS targeting the HLA-G 3' untranslated region alleles and haplotypes. Hum Immunol. 2009; 70:1020-5.
• [16]Zhu XM, Han T, Wang XH, Li YH, Yang HG, Luo YN et al.. Overexpression of miR-152 leads to reduced expression of human leukocyte antigen-G and increased natural killer cell mediated cytolysis in JEG-3 cells. Am J Obstet Gynecol. 2010; 202:592 e1-7.
• [17]Rudstein‐Svetlicky N, Loewenthal R, Horejsi V, Gazit E. HLA‐G levels in serum and plasma. Tissue Antigens. 2006; 67:111-6.
• [18]Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. J Pathol. 2011; 223:205-18.
• [19]Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W. A critical function for TGF-β signaling in the development of natural CD4+ CD25+ Foxp3+ regulatory T cells. Nat Immunol. 2008; 9:632-40.
• [20]Wang Y, Deng B, Tang W, Liu T, Shen X. TGF-β1 secreted by hepatocellular carcinoma induces the expression of the Foxp3 gene and suppresses antitumor immunity in the tumor microenvironment. Dig Dis Sci. 2013; 58:1644-52.
• [21]Li Z, Zhang LJ, Zhang HR, Tian GF, Tian J, Mao XL, Jia ZH, Meng ZY, Zhao LQ, Yin ZN, Wu ZZ. Tumor-Derived Transforming Growth Factor-β is Critical for Tumor Progression and Evasion from Immune Surveillance. Asian Pacific Journal of Cancer Prevention:apjcp. 2014; 15:5181-6.
• [22]Deng B, Zhu JM, Wang Y, Liu TT, Ding YB, Xiao WM et al.. Intratumor hypoxia promotes immune tolerance by inducing regulatory T cells via TGF-beta1 in gastric cancer. PloS one. 2013; 8: Article ID e63777
• [23]Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. The FASEB Journal. 2005; 19:681-93.
• [24]Yan W-H. Human leukocyte antigen-G in cancer: are they clinically relevant? Canc Lett. 2011; 311:123-30.
• [25]Zeng X-C, Zhang T, Huang D-H, Wang G-Y, Chen W, Li H et al.. RNA interfering targeting human leukocyte antigen-G enhanced immune surveillance mediated by the natural killer cells on hepatocellular carcinoma. Ann Clin Lab Sci. 2013; 43:135-44.
• [26]Huang J, Wang Y, Guo Y, Sun S. Down‐regulated microRNA‐152 induces aberrant DNA methylation in hepatitis B virus–related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010; 52:60-70.
• [27]Zhu C, Li J, Ding Q, Cheng G, Zhou H, Tao L et al.. miR‐152 controls migration and invasive potential by targeting TGFα in prostate cancer cell lines. The Prostate. 2013; 73:1082-9.
• [28]Xiang Y, Ma N, Wang D, Zhang Y, Zhou J, Wu G et al.. MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene. 2014; 33:378-86.