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http://dx.doi.org/10.14348/molcells.2019.2441

Up-regulation of Insulin-like Growth Factor Binding Protein-3 Is Associated with Brain Metastasis in Lung Adenocarcinoma  

Yang, Lishi (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Li, Junyang (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Fu, Shaozhi (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Ren, Peirong (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Tang, Juan (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Wang, Na (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Shi, Xiangxiang (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Wu, Jingbo (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Lin, Sheng (Department of Oncology, Affiliated Hospital of Southwest Medical University)
Publication Information
Molecules and Cells / v.42, no.4, 2019 , pp. 321-332 More about this Journal
Abstract
The brain is the most common metastatic site of lung adenocarcinoma; however, the mechanism of this selective metastasis remains unclear. We aimed to verify the hypothesis that exposure of tumor cells to the brain microenvironment leads to changes in their gene expression, which promotes their oriented transfer to the brain. A549 and H1299 lung adenocarcinoma cells were exposed to human astrocyte-conditioned medium to simulate the brain microenvironment. Microarray analysis was used to identify differentially expressed genes, which were confirmed by quantitative real-time PCR and western blotting. Knockdown experiments using microRNAs and the overexpression of genes by cell transfection were performed in addition to migration and invasion assays. In vitro findings were confirmed in clinical specimens using immunohistochemistry. We found and confirmed a significant increase in insulin-like growth factor binding protein-3 (IGFBP3) levels. Our results also showed that the up-regulation of IGFBP3 promoted A549 cell epithelial-mesenchymal transition, migration, and invasion, while the knockdown of IGFBP3 resulted in decreased cell motility. We also found that Transforming growth factor-${\beta}$ (TGF-${\beta}$)/Mothers against decapentaplegic homolog 4 (Smad4)-induced epithelial-mesenchymal transition was likely IGFBP3-dependent in A549 cells. Finally, expression of IGFBP3 was significantly elevated in pulmonary cancer tissues and intracranial metastatic tissues. Our data indicate that up-regulation of IGFBP3 might mediate brain metastasis in lung adenocarcinoma, which makes it a potential therapeutic target.
Keywords
brain metastasis; EMT; IGFBP3; lung adenocarcinoma;
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1 Balkwill, F., and Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet. 357, 539-545.   DOI
2 Bao, L., Liu, H., You, B., Gu, M., Shi, S., Shan, Y., Li, L., Chen, J., and You, Y. (2016). Overexpression of IGFBP3 is associated with poor prognosis and tumor metastasis in nasopharyngeal carcinoma. Tumour Biol. 37, 15043-15052.   DOI
3 Siegel, R.L., Miller, K.D., and Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J. Clin. 66, 7-30.   DOI
4 Sul, J., and Posner, J.B. (2007). Brain metastases: epidemiology and pathophysiology. Cancer Treat. Res. 136, 1-21.   DOI
5 Sun, Y., Ai, X., Shen, S., Gu, L., and Lu, S. (2015). Detection and correlation analysis of serum cytokines in non-small-cell lung cancer patients with bone and non-bone metastases. Patient Prefer Adherence 9, 1165-1169.   DOI
6 Takaoka, M., Harada, H., Andl, C.D., Oyama, K., Naomoto, Y., Dempsey, K.L., Klein-Szanto, A.J., El-Deiry, W.S., Grimberg, A., and Nakagawa, H. (2004). Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. Cancer Res. 64, 7711-7723.   DOI
7 Thiery, J.P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442-454.   DOI
8 Thiery, J.P., Acloque, H., Huang, R.Y., and Nieto, M.A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890.   DOI
9 Vestey, S.B., Perks, C.M., Sen, C., Calder, C.J., Holly, J.M., and Winters, Z.E. (2005). Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome. Breast Cancer Res. 7, R119-129.   DOI
10 Bardeesy, N., Cheng, K.H., Berger, J.H., Chu, G.C., Pahler, J., Olson, P., Hezel, A.F., Horner, J., Lauwers, G.Y., Hanahan, D., et al. (2006). Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130-3146.   DOI
11 Budczies, J., von Winterfeld, M., Klauschen, F., Bockmayr, M., Lennerz, J.K., Denkert, C., Wolf, T., Warth, A., Dietel, M., Anagnostopoulos, I., et al. (2015). The landscape of metastatic progression patterns across major human cancers. Oncotarget 6, 570-583.   DOI
12 Cheng, H., Fertig, E.J., Ozawa, H., Hatakeyama, H., Howard, J.D., Perez, J., Considine, M., Thakar, M., Ranaweera, R., Krigsfeld, G., et al. (2015). Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma. Cancer Biol. Ther. 16, 1252-1258.   DOI
13 David, C.J., Huang, Y.H., Chen, M., Su, J., Zou, Y., Bardeesy, N., Iacobuzio-Donahue, C.A., and Massague, J. (2016). TGF-beta tumor suppression through a lethal EMT. Cell 164, 1015-1030.   DOI
14 Deckers, M., van Dinther, M., Buijs, J., Que, I., Lowik, C., van der Pluijm, G., and ten Dijke, P. (2006). The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 66, 2202-2209.   DOI
15 Dragoj, M., Milosevic, Z., Bankovic, J., Tanic, N., Pesic, M., and Stankovic, T. (2017). Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma. Cell. Oncol. (Dordr.) 40, 47-62.
16 Xi, Y., Nakajima, G., Hamil, T., Fodstad, O., Riker, A., and Ju, J. (2006). Association of insulin-like growth factor binding protein-3 expression with melanoma progression. Mol. Cancer Ther. 5, 3078-3084.   DOI
17 Yen, Y.C., Hsiao, J.R., Jiang, S.S., Chang, J.S., Wang, S.H., Shen, Y.Y., Chen, C.H., Chang, I.S., Chang, J.Y., and Chen, Y.W. (2015). Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin ${\beta}1$. Oncotarget 6, 41837-41855.   DOI
18 Yousefi, M., Bahrami, T., Salmaninejad, A., Nosrati, R., Ghaffari, P., and Ghaffari, S.H. (2017). Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. Cell. Oncol. (Dordr.) 40, 419-441.
19 Yumoto, E., Nakatsukasa, H., Hanafusa, T., Yumoto, Y., Nouso, K., Matsumoto, E., Onishi, T., Takuma, Y., Tanaka, H., and Fujikawa, T. (2005). IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-B and/or Rb signaling pathways. Int. J. Oncol. 27, 1223-1230
20 Zhong, L.P., Yang, X., Zhang, L., Wei, K.J., Pan, H.Y., Zhou, X.J., Li, J., Chen, W.T., and Zhang, Z.Y. (2008). Overexpression of insulin-like growth factor binding protein 3 in oral squamous cell carcinoma. Oncol. Rep. 20, 1441-1447.
21 Fidler, I.J., Yano, S., Zhang, R.D., Fujimaki, T., and Bucana, C.D. (2002). The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol. 3, 53-57.   DOI
22 Fitzgerald, D.P., Palmieri, D., Hua, E., Hargrave, E., Herring, J.M., Qian, Y., Vega-Valle, E., Weil, R.J., Stark, A.M., Vortmeyer, A.O., et al. (2008). Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin. Exp. Metastasis 25, 799-810.   DOI
23 Gregory, P.A., Bracken, C.P., Smith, E., Bert, A.G., Wright, J.A., Roslan, S., Morris, M., Wyatt, L., Farshid, G., Lim, Y.Y., et al. (2011). An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol. Biol. Cell 22, 1686-1698.   DOI
24 Hansel, D.E., Rahman, A., House, M., Ashfaq, R., Berg, K., Yeo, C.J., and Maitra, A. (2004). Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin. Cancer Res. 10, 6152-6158.   DOI
25 Hesling, C., Fattet, L., Teyre, G., Jury, D., Gonzalo, P., Lopez, J., Vanbelle, C., Morel, A.P., Gillet, G., Mikaelian, I., et al. (2011). Antagonistic regulation of EMT by TIF1gamma and Smad4 in mammary epithelial cells. EMBO Rep. 12, 665-672.   DOI
26 Mujoomdar, A., Austin, J.H., Malhotra, R., Powell, C.A., Pearson, G.D., Shiau, M.C., and Raftopoulos, H. (2007). Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 242, 882-888.   DOI
27 Ioannou, M., Kouvaras, E., Papamichali, R., Samara, M., Chiotoglou, I., and Koukoulis, G. (2018). Smad4 and epithelial-mesenchymal transition proteins in colorectal carcinoma: an immunohistochemical study. J. Mol. Histol. 49, 235-244.   DOI
28 Kim, E.M., Jung, C.H., Song, J.Y., Park, J.K., and Um, H.D. (2018). Pro-apoptotic Bax promotes mesenchymal-epithelial transition by binding to respiratory complex-I and antagonizing the malignant actions of pro-survival Bcl-2 proteins. Cancer Lett. 424, 127-135.   DOI
29 Li, C., Harada, A., and Oh, Y. (2012). IGFBP-3 sensitizes antiestrogen-resistant breast cancer cells through interaction with GRP78. Cancer Lett. 325, 200-206.   DOI
30 Li, C., Wan, L., Liu, Z., Xu, G., Wang, S., Su, Z., Zhang, Y., Zhang, C., Liu, X., Lei, Z., et al. (2018). Long non-coding RNA XIST promotes TGF-beta-induced epithelial-mesenchymal transition by regulating miR-367/141-ZEB2 axis in non-small-cell lung cancer. Cancer Lett. 418, 185-195.   DOI
31 Natsuizaka, M., Ohashi, S., Wong, G.S., Ahmadi, A., Kalman, R.A., Budo, D., Klein-Szanto, A.J., Herlyn, M., Diehl, J.A., and Nakagawa, H. (2010). Insulin-like growth factor-binding protein-3 promotes transforming growth factor-{beta}1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells. Carcinogenesis 31, 1344-1353.   DOI
32 Seike, T., Fujita, K., Yamakawa, Y., Kido, M.A., Takiguchi, S., Teramoto, N., Iguchi, H., and Noda, M. (2011). Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin. Exp. Metastasis 28, 13-25.   DOI
33 Noda, M., Yamakawa, Y., Matsunaga, N., Naoe, S., Jodoi, T., Yamafuji, M., Akimoto, N., Teramoto, N., Fujita, K., Ohdo, S., et al. (2012). IL-6 receptor is a possible target against growth of metastasized lung tumor cells in the brain. Int. J. Mol. Sci. 14, 515-526.   DOI
34 Jogie-Brahim, S., Feldman, D., and Oh, Y. (2009). Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr. Rev. 30, 417-437.   DOI
35 Pardali, K., and Moustakas, A. (2007). Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim. Biophys. Acta 1775, 21-62.