EXPRESSION OF ErbB3 AND Flotillin-2 AND CLINICAL PATHOLOGICAL SIGNIFICANCE IN OSTEOSARCOMA_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIUYuwei ¹ , CHENGLiang ¹ , ZHUJianxi ¹ , YANGCheng ² , XIAOKai ¹ , LUOWei ¹ , GAOShuguang ¹ ,  LIKanghua ¹

1. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha Hunan, 410008, P. R. China;
2. Department of Orthopedics, Affiliated Haikou Hospital. Xiangya School of Medicine, Central South University;

Corresponding author：

LIKanghua, Email: lkh8738@sina.com

Keywords：

ErbB3; Flotillin-2; Osteosarcoma; Immunohistochemistry

DOI：

10.7507/1002-1892.20150128

Video：

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Objective To investigate the expression of ErbB3 and Flotillin-2 in osteosarcoma biopsies and possible clinical pathology significance. Methods The tissue biopsies were harvested from 38 osteosarcoma patients and 13 osteochondroma patients between September 2009 and March 2014 for immunohistochemical staining. The ErbB3 and Flotillin-2 expressions were observed in osteosarcoma and osteochondroma biopsies, and the correlation and the relationship to the clinical and pathological features were analyzed. Results The expression levels of ErbB3 and Flotillin-2 in osteosarcoma were significantly higher than those in osteochondroma (P<0.05). The high expressions of ErbB3 and Flotillin-2 had good consistency in osteosarcoma (Kappa=0.434, P=0.000). The high expression of ErbB3 was positively correlated to the clinical stages and lung metastasis (P<0.05), but it was not associated with gender, age, tumor location, and size (P>0.05). The high expression of Flotillin-2 had no correlation with clinical and pathological features (P>0.05). The influence factors of patients' overall survival included clinical stages, lung metastasis, high expression of ErbB3, and tumor size (P<0.05). Only lung metastasis and high expression of ErbB3 were independent factor affecting overall survival (P<0.05). Conclusion The ErbB3 and Flotillin-2 express highly in osteosarcoma and the high expression has good consisitency. Besides, the high expression of ErbB3 is associated with the clinical stages and lung metastasis, indicating a poor prognosis for osteosarcoma.

Citation： LIUYuwei, CHENGLiang, ZHUJianxi, YANGCheng, XIAOKai, LUOWei, GAOShuguang, LIKanghua. EXPRESSION OF ErbB3 AND Flotillin-2 AND CLINICAL PATHOLOGICAL SIGNIFICANCE IN OSTEOSARCOMA. Chinese Journal of Reparative and Reconstructive Surgery, 2015, 29(5): 590-594. doi: 10.7507/1002-1892.20150128 Copy

1.	Baselga J, Swain SM. Novel anticancer targets:revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer, 2009, 9(7):463-475.
2.	Holbro T, Beerli RR, Maurer F, et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit:ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A, 2003, 100(15):8933-8938.
3.	Pust S, Klokk TI, Musa N, et al. Flotillins as regulators of ErbB2 levels in breast cancer. Oncogene, 2013, 32(29):3443-3451.
4.	Neumann-Giesen C, Falkenbach B, Beicht P, et al. Membrane and raft association of reggie-1/flotillin-2:role of myristoylation, palmitoylation and oligomerization and induction of filopodia by overexpression. Biochem J, 2004, 378(Pt 2):509-518.
5.	Kato N, Nakanishi M, Hirashima N. Flotillin-1 regulates IgE receptor-mediated signaling in rat basophilic leukemia (RBL-2H3) cells. J Immunol, 2006, 177(1):147-154.
6.	Berger T, Ueda T, Arpaia E, et al. Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene, 2013, 32(41):4989-4994.
7.	Asp N, Pust S, Sandvig K. Flotillin depletion affects ErbB protein levels in different human breast cancer cells. Biochim Biophys Acta, 2014, 1843(9):1987-1996.
8.	Jullien N, Dieudonné FX, Habel N, et al. ErbB3 silencing reduces osteosarcoma cell proliferation and tumor growth in vivo. Gene, 2013, 521(1):55-61.
9.	Cao CM, Yang FX, Wang PL, et al. Clinicopathologic significance of S100A4 expression in osteosarcoma. Eur Rev Med Pharmacol Sci, 2014, 18(6):833-839.
10.	Tanner B, Hasenclever D, Stern K, et al. ErbB-3 predicts survival in ovarian cancer. J Clin Oncol, 2006, 24(26):4317-4323.
11.	Tang N, Song WX, Luo J, et al. Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res, 2008, 466(9):2114-2130.
12.	Himelstein BP. Osteosarcoma and other bone cancers. Curr Opin Oncol, 1998, 10(4):326-333.
13.	Jaffe N. Osteosarcoma:review of the past, impact on the future. The American experience. Cancer Treat Res, 2009, 152:239-262.
14.	Sithanandam G, Fornwald LW, Fields J, et al. Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549. Oncogene, 2005, 24(11):1847-1859.
15.	Soler M, Mancini F, Meca-Cortes O, et al. HER3 is required for the maintenance of neuregulin-dependent and -independent attributes of malignant progression in prostate cancer cells. Int J Cancer, 2009, 125(11):2565-2575.
16.	Chen N, Ye XC, Chu K, et al. A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res, 2007, 67(14):6544-6548.
17.	Vakar-Lopez F, Cheng CJ, Kim J, et al. Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol, 2004, 203(2):688-695.
18.	Citri A, Yarden Y. EGF-ERBB signaling:towards the systems level. Nat Rev Mol Cell Biol, 2006, 7(7):505-516.
19.	Cook RS, Garrett JT, Sanchez V, et al. ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res, 2011, 71(11):3941-3951.
20.	Amaddii M, Meister M, Banning A, et al. Flotillin-1/reggie-2 protein plays dual role in activation of receptor-tyrosine kinase/mitogen-activated protein kinase signaling. J Biol Chem, 2012, 287(10):7265-7278.
21.	Solis GP, Schrock Y, Hülsbusch N, et al. Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking. Mol Biol Cell, 2012, 23(10):1812-1825.
22.	Zhu Z, Wang J, Sun Z, et al. Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. PLoS One, 2013, 8(5):e62365.
23.	Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2001, 2(2):127-137.
24.	Yarden Y, Pines G. The ERBB network:at last, cancer therapy meets systems biology. Nat Rev Cancer, 2012, 12(8):553-563.

1. Baselga J, Swain SM. Novel anticancer targets:revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer, 2009, 9(7):463-475.
2. Holbro T, Beerli RR, Maurer F, et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit:ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A, 2003, 100(15):8933-8938.
3. Pust S, Klokk TI, Musa N, et al. Flotillins as regulators of ErbB2 levels in breast cancer. Oncogene, 2013, 32(29):3443-3451.
4. Neumann-Giesen C, Falkenbach B, Beicht P, et al. Membrane and raft association of reggie-1/flotillin-2:role of myristoylation, palmitoylation and oligomerization and induction of filopodia by overexpression. Biochem J, 2004, 378(Pt 2):509-518.
5. Kato N, Nakanishi M, Hirashima N. Flotillin-1 regulates IgE receptor-mediated signaling in rat basophilic leukemia (RBL-2H3) cells. J Immunol, 2006, 177(1):147-154.
6. Berger T, Ueda T, Arpaia E, et al. Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene, 2013, 32(41):4989-4994.
7. Asp N, Pust S, Sandvig K. Flotillin depletion affects ErbB protein levels in different human breast cancer cells. Biochim Biophys Acta, 2014, 1843(9):1987-1996.
8. Jullien N, Dieudonné FX, Habel N, et al. ErbB3 silencing reduces osteosarcoma cell proliferation and tumor growth in vivo. Gene, 2013, 521(1):55-61.
9. Cao CM, Yang FX, Wang PL, et al. Clinicopathologic significance of S100A4 expression in osteosarcoma. Eur Rev Med Pharmacol Sci, 2014, 18(6):833-839.
10. Tanner B, Hasenclever D, Stern K, et al. ErbB-3 predicts survival in ovarian cancer. J Clin Oncol, 2006, 24(26):4317-4323.
11. Tang N, Song WX, Luo J, et al. Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res, 2008, 466(9):2114-2130.
12. Himelstein BP. Osteosarcoma and other bone cancers. Curr Opin Oncol, 1998, 10(4):326-333.
13. Jaffe N. Osteosarcoma:review of the past, impact on the future. The American experience. Cancer Treat Res, 2009, 152:239-262.
14. Sithanandam G, Fornwald LW, Fields J, et al. Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549. Oncogene, 2005, 24(11):1847-1859.
15. Soler M, Mancini F, Meca-Cortes O, et al. HER3 is required for the maintenance of neuregulin-dependent and -independent attributes of malignant progression in prostate cancer cells. Int J Cancer, 2009, 125(11):2565-2575.
16. Chen N, Ye XC, Chu K, et al. A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res, 2007, 67(14):6544-6548.
17. Vakar-Lopez F, Cheng CJ, Kim J, et al. Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol, 2004, 203(2):688-695.
18. Citri A, Yarden Y. EGF-ERBB signaling:towards the systems level. Nat Rev Mol Cell Biol, 2006, 7(7):505-516.
19. Cook RS, Garrett JT, Sanchez V, et al. ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res, 2011, 71(11):3941-3951.
20. Amaddii M, Meister M, Banning A, et al. Flotillin-1/reggie-2 protein plays dual role in activation of receptor-tyrosine kinase/mitogen-activated protein kinase signaling. J Biol Chem, 2012, 287(10):7265-7278.
21. Solis GP, Schrock Y, Hülsbusch N, et al. Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking. Mol Biol Cell, 2012, 23(10):1812-1825.
22. Zhu Z, Wang J, Sun Z, et al. Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. PLoS One, 2013, 8(5):e62365.
23. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2001, 2(2):127-137.
24. Yarden Y, Pines G. The ERBB network:at last, cancer therapy meets systems biology. Nat Rev Cancer, 2012, 12(8):553-563.

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EXPRESSION OF ErbB3 AND Flotillin-2 AND CLINICAL PATHOLOGICAL SIGNIFICANCE IN OSTEOSARCOMA

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