Abstract
Bone is one of the most frequent targets of small cell lung cancer (SCLC) metastasis, but the molecular mechanism remains unclear. β3-integrin plays an important role in invasion of various kinds of tumors. Yet, its role in bone-metastasis of SCLC is still unknown. In this study, we first examined the expression of β3-integrin in SBC-5 and SBC-3 cells by real-time PCR, western blot and immunofluorescence. We found that, compared to none bone-metastatic SBC-3 cells, β3-integrin was highly expressed in SBC-5 cells, a specific bone-metastatic SCLC cells line characterized in our previous study. We next constructed β3-integrin siRNA and transfected SBC-5 cell line, and found that β3-integrin siRNA significantly down-regulated the β3-integrin mRNA level and protein expression in SBC-5 cell line. We further found that inhibition of β3-integrin significantly reduced tumor cell proliferation and induced apoptosis. In addition, the β3-integrin down-regulated cells presented significant decrease in cell adhesion, migration and invasion activity. Our results suggest the β3-integrin has an essential effect on tumor cell proliferation and progression, and may be a potential therapeutic target for the prevention of skeletal metastases of lung cancer.
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References
Jemal A, Siegel R, Ward E et al (2008) Cancer statistics. CA Cancer J Clin 58:71–96
Sone S, Yano S (2007) Molecular pathogenesis and its therapeutic modalities of lung cancer metastasis to bone. Cancer Metastasis Rev 26(3–4):685–689
van der Flier A, Sonnenberg A (2001) Function and interactions of integrins. Cell Tissue Res 305(3):285–298
Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687
Hall CL, Dai J, van Golen KL, Keller ET, Long MW (2006) Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res 66(17):8648–8654
Takahashi M, Furihata M, Akimitsu N, Watanabe M, Kaul S, Yumoto N, Okada T (2008) A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1. Clin Exp Metastasis 25:517–529
McCabe NP, De S, Vasanji A, Brainard J, Byzova TV (2007) Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene 26(42):6238–6243
Clezardin P (2009) Integrins in bone metastasis formation and potential therapeutic implications. Curr Cancer Drug Targets 9(7):801–806
Zhao Y, Bachelier R, Treilleux I et al (2007) Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67(12):5821–5830
Harms JF, Welch DR, Samant RS et al (2004) A small molecule antagonist of the αvβ3-integrin suppresses MDA-MB-435 skeletal metastasis. Clin Exp Metastasis 21:119–128
Khalili P, Arakelian A, Chen G et al (2006) A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther 5(9):2271–2280
Miki T, Yano S, Hanibuchi M, Sone S (2000) Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. Oncol Res 12(5):209–217
Zhang H, Yano S, Miki T et al (2003) A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice. Clin Exp Metastasis 20(2):153–159
Brakebusch C, Bouvard D, Stanchi F, Sakai T, Fassler R (2002) Integrins in invasive growth. J Clin Invest 109(8):999–1006
Fu BH, Wu ZZ, Qin J (2010) Effects of integrins on laminin chemotaxis by hepatocellular carcinoma cells. Mol Biol Rep 37(3):1665–1670
Fu BH, Wu ZZ, Qin J (2011) Effects of integrin alpha6beta1 on migration of hepatocellular carcinoma cells. Mol Biol Rep 38(5):3271–3276
Li SG, Ye ZY, Zhao Z, Tao HQ, Wang YY, Niu CY (2008) Correlation of integrin beta3 mRNA and vascular endothelial growth factor protein expression profiles with the clinicopathological features and prognosis of gastric carcinoma. World J Gastroenterol 14(3):421–427
Hsu MY, Shih DT, Meier FE et al (1998) Adenoviral gene transfer of beta3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma. Am J Pathol 153(5):1435–1442
Albelda SM, Mette SA, Elder DE et al (1990) Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res 50(20):6757–6764
Kanamori M, Vanden Berg SR, Bergers G, Berger MS, Pieper RO (2004) Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme. Cancer Res 64(8):2751–2758
Sato T, Miwa A (2002) Ets-1 and integrin beta3 for lung metastasis from colorectal cancer. APMIS 10(4):347–353
Kaur S, Kenny HA, Jagadeeswaran S et al (2009) {beta}3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. Am J Pathol 175(5):2184–2196
Pecheur I, Peyruchaud O, Serre CM et al (2002) Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone. FASEB J 16(10):1266–1268
Sloan EK, Pouliot N, Stanley KL et al (2006) Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res 8(2):R20
Miki T, Yano S, Hanibuchi M, Kanematsu T, Muguruma H, Sone S (2004) Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice. Int J Cancer 108(4):511–515
Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369(9574):1742–1757
Schneider JG, Amend SR, Weilbaecher KN (2011) Integrins and bone metastasis: Integrating tumor cell and stromal cell interactions. Bone 48(1):54–65
Ginsberg MH, O’Toole TE, Loftus JC, Plow EF (1992) Ligand binding to integrins: dynamic regulation and common mechanisms. Cold Spring Harb Symp Quant Biol 57:221–231
Plow EF, Haas TA, Zhang L, Loftus J, Smith JW (2000) Ligand binding to integrins. J Biol Chem 275(29):21785–21788
Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2(2):91–100
Desgrosellier JS, Barnes LA, Shields DJ et al (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15(10):1163–1169
Acknowledgments
We thank Professor Sone (Third Department of Internal Medicine, University of Tokushima, Japan) for his generous gift of cell lines, and Jun-lei Zhang (Department of Microbiology, The Third Military Medical University, China) for his excellent technical assistance for the plasmid about Human β3-integrin-siRNA. This work was supported by grants from the National Natural Science Foundation of China (30873028) and from Foundation of Chinese Society of Clinical Oncology.
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Na Li and Jian-ping Zhang contributed equally to this work.
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Li, N., Zhang, Jp., Guo, S. et al. Down-regulation of β3-integrin inhibits bone metastasis of small cell lung cancer. Mol Biol Rep 39, 3029–3035 (2012). https://doi.org/10.1007/s11033-011-1065-y
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DOI: https://doi.org/10.1007/s11033-011-1065-y