Lin S-H, Cheng C-J, Lee Y-C, Ye X, Tsai W-W, Kim J, Pasqualini R, Arap W, Navone N M, Tu S-M, Hu M, Yu-Lee L-Y, Logothetis C J
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2008 Sep 4;27(39):5195-203. doi: 10.1038/onc.2008.156. Epub 2008 May 19.
ErbB3 is a transmembrane growth factor receptor that has been implicated in the pathogenesis of human cancer. After finding that a truncated form of ErbB3 was present and upregulated in metastatic prostate cancer cells in lymph nodes and bone, we explored the pathophysiological functions of this unusual form of ErbB3 in the context of mouse calvaria as well as osteoblasts in vitro and the femur microenvironment in vivo. Here we demonstrate that prostate cancer cells expressed an alternatively spliced transcript that encodes a 45-kDa glycosylated protein (p45-sErbB3). The recombinant p45-sErbB3 purified from conditioned medium stimulated calvarial bone formation and induced osteoblast differentiation. Overexpression of p45-sErbB3 in the osteolytic prostate cancer cell line PC-3 converted its phenotype from bone lysing to bone forming upon injection into the femurs of immunodeficient mice. Further, we detected sErbB3 in plasma samples from patients with castration-resistant prostate cancer with bone metastasis. These observations establish that p45-sErbB3 is a structurally and functionally unique gene product of ErbB3 and suggest that p45-sErbB3 is likely one of the factors involved in the osteoblastic bone metastases of prostate cancer.
ErbB3是一种跨膜生长因子受体，与人类癌症的发病机制有关。在发现截短形式的ErbB3存在于淋巴结和骨骼中的转移性前列腺癌细胞中且表达上调后，我们在小鼠颅骨以及体外成骨细胞和体内股骨微环境的背景下，探究了这种异常形式的ErbB3的病理生理功能。在此我们证明，前列腺癌细胞表达了一种选择性剪接的转录本，该转录本编码一种45 kDa的糖基化蛋白（p45-sErbB3）。从条件培养基中纯化的重组p45-sErbB3刺激了颅骨骨形成并诱导了成骨细胞分化。在溶骨性前列腺癌细胞系PC-3中过表达p45-sErbB3，将其注射到免疫缺陷小鼠的股骨中后，其表型从溶骨转变为成骨。此外，我们在去势抵抗性前列腺癌伴骨转移患者的血浆样本中检测到了sErbB3。这些观察结果表明，p45-sErbB3是ErbB3在结构和功能上独特的基因产物，并提示p45-sErbB3可能是参与前列腺癌成骨性骨转移的因素之一。
