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Over-expression of LRIG1 suppresses biological function of pituitary adenoma via attenuation of PI3K/AKT and Ras/Raf/ERK pathways in vivo and in vitro

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Summary

Pituitary adenomas (PAs) are well known as a common intracranial benign tumor, and a portion of PAs are refractory to current therapeutic methods. ErbB receptors family signaling pathway regulates the expression of PAs activation associated gene. Inhibition of epidermal growth factor receptor (EGFR) can inhibit proliferation of PAs. Leucine-rich repeats and immunoglobulin-like domains protein 1 ( LRIG1), a negative mediated gene of ErbB receptors family, plays a role in many tumors. However, there are seldom researches about the functional role of LRIG1 in PAs. The aim of this study is to explore the potential effect of LRIG1 and its regulating mechanism in PAs. First, we investigated the role of LRIG1 in cell migration, invasion of PAs with transfected LRIG1 or control. Then, we explored its impact on cell proliferation and apoptosis of PAs in vivo. To study the regulating mechanism of LRIG1, we examined the expression of molecular factor of PI3K/AKT and Ras/Raf/ERK pathway using Western blotting in vitro and RT-PCR in vitro and in vivo. It was found that LRIG1 over-expression inhibited cell migration, invasion and proliferation, and promoted apoptosis of PAs in vivo and in vitro. Furthermore, LRIG1 suppressed the expression of signaling of PI3K/AKT and Ras/Raf/ERK pathways in PAs. LRIG1, as a negative mediated gene of tumor, can inhibit biological function of PAs via inhibiting PI3K/AKT and Ras/Raf/ERK pathways, and it might be a new target for gene therapy of PAs.

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References

  1. Di Ieva A, Rotondo F, Syro L V, et al. Aggressive pituitary adenomas—diagnosis and emerging treatments. Nat Rev Endocrinol, 2014,10(7):423–435

    Article  PubMed  Google Scholar 

  2. Melmed S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Invest, 2003,112(11):1603–1618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gillam MP, Molitch ME, Lombardi G, et al. Advances in the treatment of prolactinomas. Endocr Rev, 2006,27(5):485–534

    Article  CAS  PubMed  Google Scholar 

  4. Newell-Price J, Bertagna X, Grossman A B, et al. Cushing's syndrome. Lancet, 2006,367(9522):1605–1617

    Article  CAS  PubMed  Google Scholar 

  5. Baker NE, Yu SY. The EGF receptor defines domains of cell cycle progression and survival to regulate cell number in the developing Drosophila eye. Cell, 2001,104(5):699–708

    Article  CAS  PubMed  Google Scholar 

  6. Andersson U, Guo D, Malmer B, et al. Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas. Acta Neuropathol, 2004,108(2):135–142

    Article  CAS  PubMed  Google Scholar 

  7. Fukuoka H, Cooper O, Ben-Shlomo A, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest, 2011,121(12):4712–4721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Onguru O, Scheithauer BW, Kovacs K, et al. Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas. Mod Pathol, 2004,17(7):772–780

    Article  CAS  PubMed  Google Scholar 

  9. Theodoropoulou M, Arzberger T, Gruebler Y, et al. Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J Endocrinol, 2004,183(2):385–394

    Article  CAS  PubMed  Google Scholar 

  10. Vlotides G, Siegel E, Donangelo I, et al. Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands. Cancer Res, 2008,68(15):6377–6386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fukuoka H, Cooper O, Mizutani J, et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy. Mol Endocrinol, 2011,25(1):92–103

    Article  CAS  PubMed  Google Scholar 

  12. Guo D, Holmlund C, Henriksson R, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics, 2004,84(1):157–165

    Article  CAS  PubMed  Google Scholar 

  13. Hedman H, Nilsson J, Guo D, et al. Is LRIG1 a tumour suppressor gene at chromosome 3p14.3? Acta Oncol, 2002,41(4):352–354

    Article  CAS  PubMed  Google Scholar 

  14. Guo D, Han L, Shu K, et al. Down-regulation of leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) in HP75 pituitary adenoma cell line. J Huazhong Univ Sci Technolog Med Sci, 2007,27(1):91–94

    Article  CAS  PubMed  Google Scholar 

  15. Ye F, Gao Q, Xu T, et al. Upregulation of LRIG1 suppresses malignant glioma cell growth by attenuating EGFR activity. J Neurooncol, 2009,94(2):183–194

    Article  CAS  PubMed  Google Scholar 

  16. Zhang H, Yan Q, Xu S, et al. Association of expression of Leucine-rich repeats and immunoglobulin-like domains 2 gene with invasiveness of pituitary adenoma. J Huazhong Univ Sci Technolog Med Sci, 2011,31(4):520–523

    Article  CAS  PubMed  Google Scholar 

  17. Laederich M B, Funes-Duran M, Yen L, et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem, 2004,279(45):47050–47056

    Article  CAS  PubMed  Google Scholar 

  18. Gur G, Rubin C, Katz M, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J, 2004,23(16):3270–3281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stutz MA, Shattuck DL, Laederich MB, et al. LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene, 2008,27(43):5741–5752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yokdang N, Hatakeyama J, Wald J H, et al. LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene, 2016,35:1932–2947

    Article  Google Scholar 

  21. Sheu JJ, Lee CC, Hua CH, et al. LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene, 2014,33(11):1375–1384

    Article  CAS  PubMed  Google Scholar 

  22. Liu X, Kano M, Araki T, et al. ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology, 2015,156(1):71–79

    Article  PubMed  Google Scholar 

  23. Cooper O, Mamelak A, Bannykh S, et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine, 2014,46(2):318–327

    Article  CAS  PubMed  Google Scholar 

  24. Zhang X, Song Q, Wei C, et al. LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells. Cell Stress Chaperones, 2015,20(4):631–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kou C, Zhou T, Han X, et al. LRIG1, a 3p tumor suppressor, represses EGFR signaling and is a novel epigenetic silenced gene in colorectal cancer. Biochem Biophys Res Commun, 2015,464(2):519–525

    Article  CAS  PubMed  Google Scholar 

  26. Yang JA, Liu BH, Shao LM, et al. LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway. Int J Clin Exp Pathol, 2015,8(4):3580–3590

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov, 2006,5(8):671–688

    Article  CAS  PubMed  Google Scholar 

  28. Zhou J, Zhi X, Wang L, et al. Linc00152 promotes proliferation in gastric cancer through the EGFR-dependent pathway. J Exp Clin Cancer Res, 2015,34(1):135

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu JF, Tsao YT, Hou CH. Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma. Oncotarget, 2015,6(38):40880–40895

    PubMed  PubMed Central  Google Scholar 

  30. Yang Y, Sheng M, Huang F, et al. Downregulation of insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth. Pituitary, 2014,17(6):505–513

    Article  CAS  PubMed  Google Scholar 

  31. Bruhn MA, Pearson RB, Hannan RD, et al. Second AKT: the rise of SGK in cancer signaling. Growth Factors, 2010,28(6):394–408

    Article  CAS  PubMed  Google Scholar 

  32. Gao J, Liu X, Yang F, et al. By inhibiting Ras/Raf/ERK and MMP-9, knockdown of EpCAM inhibits breast cancer cell growth and metastasis. Oncotarget, 2015,6(29):27187–27198

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hu Y, Liu HX, He Y, et al. Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells. Biochem Pharmacol, 2013,85(7):1007–1017

    Article  CAS  PubMed  Google Scholar 

  34. Han T, Xiang DM, Sun W, et al. PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients. J Hepatol, 2015,63(3):651–660

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, the Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China

    Shi-qi Cheng  (程世奇), Heng-yi Fan  (范恒怡), Shi-gang Lv  (吕世刚), Min-hua Ye  (叶敏华), Miao-jing Wu  (吴淼经), Xiao-li Shen  (沈晓黎), Zu-jue Cheng  (程祖珏), Xin-gen Zhu  (祝新根) & Yan Zhang  (张 焱)

  2. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Xin Xu  (徐 新) & Wei-wei Gao  (高伟伟)

Authors
  1. Shi-qi Cheng  (程世奇)
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  2. Heng-yi Fan  (范恒怡)
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  3. Xin Xu  (徐 新)
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  4. Wei-wei Gao  (高伟伟)
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  5. Shi-gang Lv  (吕世刚)
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  6. Min-hua Ye  (叶敏华)
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  7. Miao-jing Wu  (吴淼经)
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  8. Xiao-li Shen  (沈晓黎)
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  9. Zu-jue Cheng  (程祖珏)
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  10. Xin-gen Zhu  (祝新根)
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  11. Yan Zhang  (张 焱)
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Corresponding authors

Correspondence to Xin-gen Zhu  (祝新根) or Yan Zhang  (张 焱).

Additional information

The authors contributed equally to this work.

This project was supported by grants from the National Natural Science Foundation of China (No. 81560412), Jiangxi Provincial Health Development Planning Commission Project (No. 20141065), and Jiangxi Provincial Natural Science Foundation of China (No. 20152BCB24009 and No. 20151BDH80009).

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Cheng, Sq., Fan, Hy., Xu, X. et al. Over-expression of LRIG1 suppresses biological function of pituitary adenoma via attenuation of PI3K/AKT and Ras/Raf/ERK pathways in vivo and in vitro . J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 558–563 (2016). https://doi.org/10.1007/s11596-016-1625-4

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  • DOI: https://doi.org/10.1007/s11596-016-1625-4

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