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Published in: Journal of Neuro-Oncology 1/2015

01-10-2015 | Laboratory Investigation

Hugl-1 inhibits glioma cell growth in intracranial model

Authors: Xuejiao Liu, Dong Lu, Peng Ma, Huaqiang Liu, Yuewen Cao, Ben Sang, Xianlong Zhu, Qiong Shi, Jinxia Hu, Rutong Yu, Xiuping Zhou

Published in: Journal of Neuro-Oncology | Issue 1/2015

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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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Literature
1.
go back to reference Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY (2012) Primary brain tumours in adults. Lancet 379(9830):1984–1996CrossRefPubMed Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY (2012) Primary brain tumours in adults. Lancet 379(9830):1984–1996CrossRefPubMed
2.
go back to reference 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):e78943PubMedCentralCrossRefPubMed 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):e78943PubMedCentralCrossRefPubMed
3.
go back to reference 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):1255–1262CrossRefPubMed 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):1255–1262CrossRefPubMed
5.
go back to reference 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):5960–5965CrossRefPubMed 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):5960–5965CrossRefPubMed
6.
go back to reference Ohshiro T, Yagami T, Zhang C, Matsuzaki F (2000) Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408(6812):593–596CrossRefPubMed Ohshiro T, Yagami T, Zhang C, Matsuzaki F (2000) Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408(6812):593–596CrossRefPubMed
7.
go back to reference 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):1361–1373CrossRefPubMed 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):1361–1373CrossRefPubMed
8.
go back to reference 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):1345–1360CrossRefPubMed 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):1345–1360CrossRefPubMed
9.
go back to reference 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):147–154PubMedCentralCrossRefPubMed 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):147–154PubMedCentralCrossRefPubMed
10.
go back to reference 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):573–581CrossRefPubMed 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):573–581CrossRefPubMed
11.
go back to reference 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):1089–1098PubMedCentralCrossRefPubMed 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):1089–1098PubMedCentralCrossRefPubMed
12.
go back to reference 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):1067–1073CrossRefPubMed 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):1067–1073CrossRefPubMed
13.
go back to reference 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):291–301PubMed 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):291–301PubMed
14.
go back to reference 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):8688–8694CrossRefPubMed 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):8688–8694CrossRefPubMed
15.
go back to reference 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):3100–3109CrossRefPubMed 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):3100–3109CrossRefPubMed
16.
go back to reference 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):103–110PubMed 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):103–110PubMed
17.
go back to reference 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):3287–3296CrossRefPubMed 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):3287–3296CrossRefPubMed
18.
go back to reference 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):3153–3159PubMed 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):3153–3159PubMed
19.
go back to reference 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):4127–4136PubMedCentralCrossRefPubMed 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):4127–4136PubMedCentralCrossRefPubMed
20.
go back to reference 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):431–444CrossRefPubMed 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):431–444CrossRefPubMed
21.
go back to reference 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):574–580CrossRefPubMed 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):574–580CrossRefPubMed
22.
go back to reference 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):45–56PubMedCentralCrossRefPubMed 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):45–56PubMedCentralCrossRefPubMed
23.
go back to reference 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):1311–1333CrossRefPubMed 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):1311–1333CrossRefPubMed
25.
go back to reference 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):431–435PubMed 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):431–435PubMed
26.
go back to reference 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):431–435PubMed 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):431–435PubMed
27.
go back to reference 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):103–110PubMed 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):103–110PubMed
29.
go back to reference Ware ML, Berger MS, Binder DK (2003) Molecular biology of glioma tumorigenesis. Histol Histopathol 18(1):207–216PubMed Ware ML, Berger MS, Binder DK (2003) Molecular biology of glioma tumorigenesis. Histol Histopathol 18(1):207–216PubMed
30.
go back to reference 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):2127–2141CrossRefPubMed 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):2127–2141CrossRefPubMed
31.
go back to reference 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):e82108PubMedCentralCrossRefPubMed 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):e82108PubMedCentralCrossRefPubMed
32.
go back to reference 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):2473–2480PubMedCentralCrossRefPubMed 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):2473–2480PubMedCentralCrossRefPubMed
33.
36.
go back to reference 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):928–939CrossRefPubMed 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):928–939CrossRefPubMed
37.
go back to reference 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):11730–11739PubMedCentralCrossRefPubMed 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):11730–11739PubMedCentralCrossRefPubMed
38.
go back to reference 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):2729–2741CrossRef 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):2729–2741CrossRef
Metadata
Title
Hugl-1 inhibits glioma cell growth in intracranial model
Authors
Xuejiao Liu
Dong Lu
Peng Ma
Huaqiang Liu
Yuewen Cao
Ben Sang
Xianlong Zhu
Qiong Shi
Jinxia Hu
Rutong Yu
Xiuping Zhou
Publication date
01-10-2015
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 1/2015
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-015-1901-3

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