Lung cancer is highly heterogenous and is composed of various subtypes that are in diverse differential stages. The newly identified integrin-interacting proteins Kindlin-1 and Kindlin-2 are the activators of transmembrane receptor integrins that play important roles in cancer progression. In this report we present the expression profiles of Kindlin-1 and Kindlin-2 in lung cancers using patient specimens and established their correlation with lung cancer progression. We found that Kindlin-1 was expressed in epithelia-derived non-small-cell lung cancer, especially in squamous cell lung cancer but expressed at low levels in poorly differentiated large cell lung cancer. However, Kindlin-2 was highly expressed in large cell lung cancer. Both Kindlin-1 and Kindlin-2 were found not expressed or expressed at very low levels in neuroendocrine-derived small cell lung cancer. Importantly, the Kindlin-1 expression level was positively correlated with the differentiation of squamous cell lung cancer. Surprisingly, we found that the very homologous Kindlin family proteins, Kindlin-1 and Kindlin-2, displayed counteracting functional roles in lung cancer cells. Ectopic expression of Kindlin-1 in non-small-cell lung cancer cells inhibited in vitro cell migration and in vivo tumor growth, while Kindlin-2 promoted these functions. Mechanistically, Kindlin-1 prohibited epithelail to mesenchymal transition in non-small-cell lung cancer cells, while Kindlin-2 enhanced epithelail to mesenchymal transition in these cells. Taken together, we demonstrated that Kindlin-1 and Kindlin-2 differentially regulate lung cancer cell progression. Further, the expression levels of Kindlin-1 might be potentially used as a marker for lung cancer differentiation and targeting Kindlin-2 might block the invasive growth of large cell lung cancer.
References
[1]
Travis WD, Travis LB, Devesa SS (1995) Lung cancer. Cancer 75: 191–202.
[2]
Travis WD (2002) Pathology of lung cancer. Clin Chest Med 23: 65–81, viii.
[3]
Larjava H, Plow EF, Wu C (2008) Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep 9: 1203–1208.
[4]
Kloeker S, Major MB, Calderwood DA, Ginsberg MH, Jones DA, et al. (2004) The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrin-mediated adhesion. J Biol Chem 279: 6824–6833.
[5]
Montanez E, Ussar S, Schifferer M, Bosl M, Zent R, et al. (2008) Kindlin-2 controls bidirectional signaling of integrins. Genes Dev 22: 1325–1330.
[6]
Kindler T (1954) Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Br J Dermatol 66: 104–111.
[7]
Jobard F, Bouadjar B, Caux F, Hadj-Rabia S, Has C, et al. (2003) Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum Mol Genet 12: 925–935.
[8]
Siegel DH, Ashton GH, Penagos HG, Lee JV, Feiler HS, et al. (2003) Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet 73: 174–187.
[9]
Weinstein EJ, Bourner M, Head R, Zakeri H, Bauer C, et al. (2003) URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochim Biophys Acta 1637: 207–216.
[10]
An Z, Dobra K, Lock JG, Stromblad S, Hjerpe A, et al. (2010) Kindlin-2 is expressed in malignant mesothelioma and is required for tumor cell adhesion and migration. Int J Cancer 127: 1999–2008.
[11]
Gong X, An Z, Wang Y, Guan L, Fang W, et al. (2010) Kindlin-2 controls sensitivity of prostate cancer cells to cisplatin-induced cell death. Cancer Lett 299: 54–62.
[12]
Shen Z, Ye Y, Dong L, Vainionpaa S, Mustonen H, et al. (2012) Kindlin-2: a novel adhesion protein related to tumor invasion, lymph node metastasis, and patient outcome in gastric cancer. Am J Surg 203: 222–229.
[13]
Sin S, Bonin F, Petit V, Meseure D, Lallemand F, et al. (2011) Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis. J Natl Cancer Inst 103: 1323–1337.
[14]
Talaat S, Somji S, Toni C, Garrett SH, Zhou XD, et al. (2011) Kindlin-2 expression in arsenite- and cadmium-transformed bladder cancer cell lines and in archival specimens of human bladder cancer. Urology 77: 1507 e1501–1507.
[15]
Kruger M, Moser M, Ussar S, Thievessen I, Luber CA, et al. (2008) SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell 134: 353–364.
[16]
Moser M, Nieswandt B, Ussar S, Pozgajova M, Fassler R (2008) Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 14: 325–330.
[17]
Wu WB, Zhang Q, Li Y, Shan SL, Li XY, et al. (2012) [Expression of kindlins and angiopoietins in acute myeloid leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 20: 7–11.
[18]
Harris ES, Smith TL, Springett GM, Weyrich AS, Zimmerman GA (2012) Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family. Am J Hematol 87: 311–313.
[19]
van de Vijver E, Maddalena A, Sanal O, Holland SM, Uzel G, et al. (2012) Hematologically important mutations: leukocyte adhesion deficiency (first update). Blood Cells Mol Dis 48: 53–61.
[20]
Malinin NL, Plow EF, Byzova TV (2010) Kindlins in FERM adhesion. Blood 115: 4011–4017.
[21]
Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, et al. (2008) Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res 102: 423–431.
[22]
Shin MS, Jackson LK, Shelton RW Jr, Greene RE (1986) Giant cell carcinoma of the lung. Clinical and roentgenographic manifestations. Chest 89: 366–369.
[23]
Vaporciyan AA, Nesbitt JC, Lee JS, et al. (2000) Cancer Medicine. B C Decker 1227–1292 ISBN 1-55009-113-1.
