DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1

Journal of Experimental & Clinical Cancer Research

Guosheng Tan²  Heping Li²  Shiqiu Xiong⁴  Bing Zhang²  Xiaonong Wang³  Junming Ye¹  Weihao Lin⁵  Binhui Xie³ 

[1] Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China;Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China;Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK;Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China

关键词: EMT;    SNAIL1;    ERK;    HCC;    DDR2;   

Others  :  1226255
DOI  :  10.1186/s13046-015-0218-6

 received in 2015-06-23, accepted in 2015-09-04,  发布年份 2015

【 摘 要 】

Background

Several studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression. However, the role of DDR2 in hepatocellular carcinoma (HCC) progression and its downstream signaling pathways remain unclear.

Methods

DDR2 expression was assessed in several cell lines and 112 pairs of HCC and matched adjacent noncancerous liver tissues. Clinical significance of DDR2 in HCC was analyzed. Phosphorylated DDR2 (p-DDR2) expression was detected by immunoblotting to evaluate its correlation with DDR2. The effect of DDR2 on HCC cell migration and invasion were examined. Cycloheximide chase experiments were performed to detect the half-life of SNAIL1. Moreover, DDR2 expression was detected by immunohistochemistry to evaluate its correlation with SNAIL1. The regulatory effect of DDR2 on ERK signaling, SNAIL1, EMT, MT1-MMP and MMP2 was confirmed by immunoblotting. The effect of type I collagen on DDR2/ERK2/SNAIL1 signaling was assessed.

Results

DDR2 was more highly expressed in HCC than in non-HCC tissues. DDR2 overexpression was correlated with clinicopathological features of poor prognosis. Clinical analysis revealed that DDR2 is an independent prognostic marker for predicting overall survival and disease free survival of HCC patients. Overexpression of DDR2 is associated with p-DDR2 amplification. In vitro studies showed that DDR2 facilitates HCC cell invasion, migration and EMT via activating ERK2 and stabilizing SNAIL1. DDR2 can up-regulate MT1-MMP and MMP2 expression through ERK2/SNAIL1 signaling in HCC. Additionally, collagen I can induce DDR2/ERK2/SNAIL1 signaling activation in HCC cells.

Conclusions

Our findings suggest that DDR2 plays an important role in promoting HCC cell invasion and migration, and may serve as a novel therapeutic target in HCC.

【 授权许可】

   
2015 Xie 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 Cancer J Clin 2011, 61(2):69-90.
• [2]Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 2015, 24(1):1-17.
• [3]Liu Q, Yang P, Tu K, Zhang H, Zheng X, Yao Y, et al.: TPX2 knockdown suppressed hepatocellular carcinoma cell invasion via inactivating AKT signaling and inhibiting MMP2 and MMP9 expression. Chin J Cancer Res 2014, 26(4):410-417.
• [4]Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009, 27(9):1485-1491.
• [5]Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C: Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004. Hepatology 2008, 48(1):137-145.
• [6]He F, Li J, Xu J, Zhang S, Xu Y, Zhao W, et al.: Decreased expression of ARID1A associates with poor prognosis and promotes metastases of hepatocellular carcinoma. J Exp Clin Cancer Res 2015, 34:47. BioMed Central Full Text
• [7]Bosetti C, Turati F, La Vecchia C: Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 2014, 28(5):753-770.
• [8]Liao R, Sun J, Wu H, Yi Y, Wang JX, He HW, et al.: High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res 2013, 32:3. BioMed Central Full Text
• [9]Vogel W, Gish GD, Alves F, Pawson T: The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997, 1(1):13-23.
• [10]Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, et al.: An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell 1997, 1(1):25-34.
• [11]Leitinger B: Transmembrane collagen receptors. Annu Rev Cell Dev Biol 2011, 27:265-290.
• [12]Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al.: DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 2001, 108(9):1369-1378.
• [13]Olaso E, Labrador JP, Wang L, Ikeda K, Eng FJ, Klein R, et al.: Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J Biol Chem 2002, 277(5):3606-3613.
• [14]Chua HH, Yeh TH, Wang YP, Huang YT, Sheen TS, Lo YC, et al.: Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma. Head Neck 2008, 30(4):427-436.
• [15]Yan Z, Jin S, Wei Z, Huilian H, Zhanhai Y, Yue T, et al.: Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein. Biochim Biophys Acta 2014, 1842(9):1350-1363.
• [16]Xu J, Lu W, Zhang S, Zhu C, Ren T, Zhu T, et al.: Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma. Cancer Biol Ther 2014, 15(5):612-622.
• [17]Kim D, Ko P, You E, Rhee S: The intracellular juxtamembrane domain of discoidin domain receptor 2 (DDR2) is essential for receptor activation and DDR2-mediated cancer progression. Int J Cancer 2014, 135(11):2547-2557.
• [18]Ren T, Zhang J, Zhang J, Liu X, Yao L: Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients. Med Oncol 2013, 30(1):397.
• [19]Tran DD, Corsa CA, Biswas H, Aft RL, Longmore GD: Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence. Mol Cancer Res 2011, 9(12):1644-1657.
• [20]Kaufhold S, Bonavida B: Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res 2014, 33:62. BioMed Central Full Text
• [21]Liu Z, Tu K, Liu Q: Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. FEBS Lett 2014, 588(17):3089-3097.
• [22]Drasin DJ, Robin TP, Ford HL: Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res 2011, 13(6):226. BioMed Central Full Text
• [23]Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, et al.: The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 2013, 15(6):677-687.
• [24]Whittaker S, Marais R, Zhu AX: The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 2010, 29(36):4989-5005.
• [25]Muntane J, De la Rosa AJ, Docobo F, Garcia-Carbonero R, Padillo FJ: Targeting tyrosine kinase receptors in hepatocellular carcinoma. Curr Cancer Drug Targets 2013, 13(3):300-312.
• [26]van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, et al.: Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 2009, 5(8):1169-1179.
• [27]Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, et al.: Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma. BMC Cancer 2013, 13:108. BioMed Central Full Text
• [28]Liu Q, Tu K, Zhang H, Zheng X, Yao Y, Liu Q. TPX2 as a novel prognostic biomarker for hepatocellular carcinoma. Hepatol Res. 2014. doi:10.1111/hepr.12428.
• [29]Wang ZL, Fan ZQ, Jiang HD, Qu JM: Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling. Carcinogenesis 2013, 34(3):638-646.
• [30]Xu L, Peng H, Wu D, Hu K, Goldring MB, Olsen BR, et al.: Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 2005, 280(1):548-555.
• [31]Kan H, Guo W, Huang Y, Liu D: MicroRNA-520 g induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by targeting SMAD7. FEBS Lett 2015, 589(1):102-109.
• [32]Du R, Wu S, Lv X, Fang H, Wu S, Kang J: Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Exp Clin Cancer Res 2014, 33:105. BioMed Central Full Text
• [33]Zheng F, Wu J, Zhao S, Luo Q, Tang Q, Yang L, et al.: Baicalein increases the expression and reciprocal interplay of RUNX3 and FOXO3a through crosstalk of AMPKalpha and MEK/ERK1/2 signaling pathways in human non-small cell lung cancer cells. J Exp Clin Cancer Res 2015, 34:41. BioMed Central Full Text
• [34]Ip YC, Cheung ST, Leung KL, Fan ST: Mechanism of metastasis by membrane type 1-matrix metalloproteinase in hepatocellular carcinoma. World J Gastroenterol 2005, 11(40):6269-6276.