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Hugl-1 inhibits glioma cell growth in intracranial model

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Abstract

Drosophila lethal (2) giant larvae (lgl) has been reported as a tumor suppressor and could regulate the Drosophila hippo signaling. Human giant larvae-1(Hugl-1), one human homologue of Drosophila lgl, also has been reported to be involved in the development of some human cancers. However, whether Hugl-1 is associated with the pathogenesis of malignant gliomas remains poorly understood. In the present work, we examined the effect of Hugl-1 on glioma cell growth both in vitro and in vivo. Firstly, we found that Hugl-1 protein levels decreased in the human glioma tissues, suggesting that Hugl-1 is involved in glioma progression. Unfortunately, either stably or transiently over-expressing Hugl-1 did not affect glioma cell proliferation in vitro. In addition, Hugl-1 over-expression did not regulate hippo signaling pathway. Interestingly, over-expression of Hugl-1 not only inhibited gliomagenesis but also markedly inhibited cell proliferation and promoted the apoptosis of U251 cells in an orthotopic model of nude mice. Taken together, this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy.

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References

  1. Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY (2012) Primary brain tumours in adults. Lancet 379(9830):1984–1996

    Article  PubMed  Google Scholar 

  2. Oike T, Suzuki Y, Sugawara K, Shirai K, Noda SE, Tamaki T, Nagaishi M, Yokoo H, Nakazato Y, Nakano T (2013) Radiotherapy plus concomitant adjuvant temozolomide for glioblastoma: Japanese mono-institutional results. PLoS ONE 8(11):e78943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Schmidt NO, Ziu M, Carrabba G, Giussani C, Bello L, Sun Y, Schmidt K, Albert M, Black PM, Carroll RS (2004) Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model. Clin Cancer Res 10(4):1255–1262

    Article  CAS  PubMed  Google Scholar 

  4. Vasioukhin V (2006) Lethal giant puzzle of Lgl. Dev Neurosci 28(1–2):13–24

    Article  CAS  PubMed  Google Scholar 

  5. Grifoni D, Garoia F, Bellosta P, Parisi F, De Biase D, Collina G, Strand D, Cavicchi S, Pession A (2007) aPKCζ cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia. Oncogene 26(40):5960–5965

    Article  CAS  PubMed  Google Scholar 

  6. Ohshiro T, Yagami T, Zhang C, Matsuzaki F (2000) Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408(6812):593–596

    Article  CAS  PubMed  Google Scholar 

  7. Strand D, Jakobs R, Merdes G, Neumann B, Kalmes A, Heid HW, Husmann I, Mechler BM (1994) The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain. J Cell Biol 127(5):1361–1373

    Article  CAS  PubMed  Google Scholar 

  8. Strand D, Raska I, Mechler BM (1994) The Drosophila lethal(2)giant larvae tumor suppressor protein is a component of the cytoskeleton. J Cell Biol 127(5):1345–1360

    Article  CAS  PubMed  Google Scholar 

  9. Froldi F, Ziosi M, Tomba G, Parisi F, Garoia F, Pession A, Grifoni D (2008) Drosophila lethal giant larvae neoplastic mutant as a genetic tool for cancer modeling. Curr Genomics 9(3):147–154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE (2010) Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20(7):573–581

    Article  CAS  PubMed  Google Scholar 

  11. Rolls MM, Albertson R, Shih HP, Lee CY, Doe CQ (2003) Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia. J Cell Biol 163(5):1089–1098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Zimmermann T, Kashyap A, Hartmann U, Otto G, Galle PR, Strand S, Strand D (2008) Cloning and characterization of the promoter of Hugl-2, the human homologue of Drosophila lethal giant larvae (lgl) polarity gene. Biochem Biophys Res Commun 366(4):1067–1073

    Article  CAS  PubMed  Google Scholar 

  13. Strand D, Unger S, Corvi R, Hartenstein K, Schenkel H, Kalmes A, Merdes G, Neumann B, Krieg-Schneider F, Coy JF et al (1995) A human homologue of the Drosophila tumour suppressor gene l(2)gl maps to 17p11.2-12 and codes for a cytoskeletal protein that associates with nonmuscle myosin II heavy chain. Oncogene 11(2):291–301

    CAS  PubMed  Google Scholar 

  14. Grifoni D, Garoia F, Schimanski CC, Schmitz G, Laurenti E, Galle PR, Pession A, Cavicchi S, Strand D (2004) The human protein Hugl-1 substitutes for Drosophila lethal giant larvae tumour suppressor function in vivo. Oncogene 23(53):8688–8694

    Article  CAS  PubMed  Google Scholar 

  15. Schimanski CC, Schmitz G, Kashyap A, Bosserhoff AK, Bataille F, Schafer SC, Lehr HA, Berger MR, Galle PR, Strand S, Strand D (2005) Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene 24(19):3100–3109

    Article  CAS  PubMed  Google Scholar 

  16. Kuphal S, Wallner S, Schimanski CC, Bataille F, Hofer P, Strand S, Strand D, Bosserhoff AK (2006) Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene 25(1):103–110

    CAS  PubMed  Google Scholar 

  17. Lu XF, Feng XJ, Man XB, Yang G, Tang L, Du D, Zhang F, Yuan HX, Huang Q, Zhang Z, Liu YK, Strand D, Chen ZJ (2009) Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression. Clin Cancer Res 15(10):3287–3296

    Article  CAS  PubMed  Google Scholar 

  18. Biesterfeld S, Kauhausen A, Kost C, Gockel I, Schimanski CC, Galle PR (2012) Preservation of HUGL-1 expression as a favourable prognostic factor in pancreatic carcinoma. Anticancer Res 32(8):3153–3159

    PubMed  Google Scholar 

  19. Song J, Peng XL, Ji MY, Ai MH, Zhang JX, Dong WG (2013) Hugl-1 induces apoptosis in esophageal carcinoma cells both in vitro and in vivo. World J Gastroenterol 19(26):4127–4136

    Article  PubMed Central  PubMed  Google Scholar 

  20. Wang T, Liu Y, Xu XH, Deng CY, Wu KY, Zhu J, Fu XQ, He M, Luo ZG (2011) Lgl1 activation of rab10 promotes axonal membrane trafficking underlying neuronal polarization. Dev Cell 21(3):431–444

    Article  CAS  PubMed  Google Scholar 

  21. Zhou X, Meng Q, Xu X, Zhi T, Shi Q, Wang Y, Yu R (2012) Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway. Biochem Biophys Res Commun 427(3):574–580

    Article  CAS  PubMed  Google Scholar 

  22. Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15(1):45–56

    Article  PubMed Central  PubMed  Google Scholar 

  23. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15(11):1311–1333

    Article  CAS  PubMed  Google Scholar 

  24. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507

    Article  CAS  PubMed  Google Scholar 

  25. Tsuruga T, Nakagawa S, Watanabe M, Takizawa S, Matsumoto Y, Nagasaka K, Sone K, Hiraike H, Miyamoto Y, Hiraike O, Minaguchi T, Oda K, Yasugi T, Yano T, Taketani Y (2007) Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer. Oncol Res 16(9):431–435

    CAS  PubMed  Google Scholar 

  26. Tsuruga T, Nakagawa S, Watanabe M, Takizawa S, Matsumoto Y, Nagasaka K, Sone K, Hiraike H, Miyamoto Y, Hiraike O, Minaguchi T, Oda K, Yasugi T, Yano T, Taketani Y (2007) Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer. Oncol Res 16(9):431–435

    CAS  PubMed  Google Scholar 

  27. Kuphal S, Wallner S, Schimanski CC, Bataille F, Hofer P, Strand S, Strand D, Bosserhoff AK (2006) Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene 25(1):103–110

    CAS  PubMed  Google Scholar 

  28. Alderton GK (2011) Tumorigenesis: the origins of glioma. Nat Rev Cancer 11(9):627

    Article  CAS  PubMed  Google Scholar 

  29. Ware ML, Berger MS, Binder DK (2003) Molecular biology of glioma tumorigenesis. Histol Histopathol 18(1):207–216

    CAS  PubMed  Google Scholar 

  30. Auvergne RM, Sim FJ, Wang S, Chandler-Militello D, Burch J, Al Fanek Y, Davis D, Benraiss A, Walter K, Achanta P, Johnson M, Quinones-Hinojosa A, Natesan S, Ford HL, Goldman SA (2013) Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes. Cell Rep 3(6):2127–2141

    Article  CAS  PubMed  Google Scholar 

  31. Milinkovic V, Bankovic J, Rakic M, Stankovic T, Skender-Gazibara M, Ruzdijic S, Tanic N (2013) Identification of novel genetic alterations in samples of malignant glioma patients. PLoS ONE 8(12):e82108

    Article  PubMed Central  PubMed  Google Scholar 

  32. Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, Coussens LM, DeClerck YA (2012) Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 72(10):2473–2480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kim Y, Stolarska MA, Othmer HG (2011) The role of the microenvironment in tumor growth and invasion. Prog Biophys Mol Biol 106(2):353–379

    Article  PubMed Central  PubMed  Google Scholar 

  34. Pan D (2010) The hippo signaling pathway in development and cancer. Dev Cell 19(4):491–505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Halder G, Johnson RL (2011) Hippo signaling: growth control and beyond. Development 138(1):9–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Chan SW, Lim CJ, Chen L, Chong YF, Huang C, Song H, Hong W (2011) The Hippo pathway in biological control and cancer development. J Cell Physiol 226(4):928–939

    Article  CAS  PubMed  Google Scholar 

  37. Konsavage WM, Kyler SL, Rennoll SA, Jin G, Yochum GS (2012) Wnt/beta-catenin signaling regulates yes-associated protein (YAP) gene expression in colorectal carcinoma cells. J Biol Chem 287(15):11730–11739

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Fernandez A, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM (2009) YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23(23):2729–2741

    Article  Google Scholar 

Download references

Acknowledgments

The research was supported by National Natural Science Foundation of China (No. 81272777; No. 81372699; No. 81472345; No. 81402074); Natural Science Foundation of Jiangsu province (No. BK20140224); Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 14KJB320022).

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    Authors and Affiliations

    1. Institute of Nervous System Diseases, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002, Jiangsu, People’s Republic of China

      Xuejiao Liu, Dong Lu, Qiong Shi, Jinxia Hu, Rutong Yu & Xiuping Zhou

    2. Brain Hospital, Affiliated Hospital of Xuzhou Medical College, 99 West Huai-hai Road, Xuzhou, 221002, Jiangsu, People’s Republic of China

      Xuejiao Liu, Dong Lu, Qiong Shi, Jinxia Hu, Rutong Yu & Xiuping Zhou

    3. The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, People’s Republic of China

      Peng Ma, Huaqiang Liu, Yuewen Cao, Ben Sang & Xianlong Zhu

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    1. Xuejiao Liu
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    Xuejiao Liu, Dong Lu and Peng Ma contributed equally to this work.

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    Liu, X., Lu, D., Ma, P. et al. Hugl-1 inhibits glioma cell growth in intracranial model. J Neurooncol 125, 113–121 (2015). https://doi.org/10.1007/s11060-015-1901-3

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