López-Bermejo A, Buckway C K, Devi G R, Hwa V, Plymate S R, Oh Y, Rosenfeld R G
Department of Pediatrics, Oregon Health Sciences University, Portland 97201, USA.
Endocrinology. 2000 Nov;141(11):4072-80. doi: 10.1210/endo.141.11.7783.
Insulin-like growth factor (IGF)-binding protein (IGFBP)-related proteins (IGFBP-rPs) are newly described cysteine-rich proteins that share significant aminoterminal structural similarity with the conventional IGFBPs and are involved in a diversity of biological functions, including growth regulation. IGFBP-rP1 (MAC25/Angiomodulin/prostacyclin-stimulating factor) is a potential tumor-suppressor gene that is differentially expressed in meningiomas, mammary and prostatic cancers, compared with their malignant counterparts. We have previously shown that IGFBP-rP1 is preferentially produced by primary cultures of human prostate epithelial cells (HPECs) and by poorly tumorigenic P69SV40T cells, compared with the cancerous prostatic LNCaP, DU145, PC-3, and M12 cells. We now show that IGFBP-rP1 increases during senescence of HPEC. IGFBP-rP2 (also known as connective tissue growth factor), a downstream effector of transforming growth factor (TGF)-beta and modulator of growth for both fibroblasts and endothelial cells, was detected in most of the normal and malignant prostatic epithelial cells tested, with a marked up-regulation of IGFBP-rP2 during senescence of HPEC. Moreover, IGFBP-rP2 noticeably increased in response to TGF-beta1 and all-trans retinoic acid (atRA) in HPEC and PC-3 cells, and it decreased in response to IGF-I in HPEC. IGFBP-rP3 [nephroblastoma overexpressed (NOV)], the protein product of the NOV protooncogene, was not detected in HPEC but was expressed in the tumorigenic DU145 and PC-3 cells. It was also synthesized by the SV40-T antigen-transformed P69 and malignant M12 cells, where it was down-regulated by atRA. These observations suggest biological roles of IGFBP-rPs in the human prostate. IGFBP-rP1 and IGFBP-rP2 are likely to negatively regulate growth, because they seem to increase during senescence of the prostate epithelium and in response to growth inhibitors (TGF-beta1 and atRA). Although the data collected on IGFBP-rP3 in prostate are modest, its role as a growth stimulator and/or protooncogene is supported by its preferential expression in cancerous cells and its down-regulation by atRA.
胰岛素样生长因子（IGF）结合蛋白（IGFBP）相关蛋白（IGFBP-rP）是新发现的富含半胱氨酸的蛋白，其氨基末端结构与传统IGFBP具有显著相似性，并参与多种生物学功能，包括生长调节。IGFBP-rP1（MAC25/血管调节蛋白/前列环素刺激因子）是一种潜在的肿瘤抑制基因，与脑膜瘤、乳腺癌和前列腺癌的恶性对应物相比，在这些肿瘤中差异表达。我们之前已经表明，与癌性前列腺LNCaP、DU145、PC-3和M12细胞相比，人前列腺上皮细胞（HPEC）原代培养物以及致瘤性较差的P69SV40T细胞优先产生IGFBP-rP1。我们现在表明，IGFBP-rP1在HPEC衰老过程中增加。IGFBP-rP2（也称为结缔组织生长因子）是转化生长因子（TGF）-β的下游效应物，也是成纤维细胞和内皮细胞生长的调节剂，在大多数测试的正常和恶性前列腺上皮细胞中均有检测到，在HPEC衰老过程中IGFBP-rP2显著上调。此外，在HPEC和PC-3细胞中，IGFBP-rP2对TGF-β1和全反式维甲酸（atRA）有明显反应而增加，而在HPEC中对IGF-I有反应而减少。IGFBP-rP3[肾母细胞瘤过度表达（NOV）]是NOV原癌基因的蛋白产物，在HPEC中未检测到，但在致瘤性DU145和PC-3细胞中表达。它也由SV40-T抗原转化的P69和恶性M12细胞合成，在这些细胞中它被atRA下调。这些观察结果提示IGFBP-rP在人前列腺中的生物学作用。IGFBP-rP1和IGFBP-rP2可能对生长起负调节作用，因为它们似乎在前列腺上皮衰老过程中以及对生长抑制剂（TGF-β1和atRA）反应时增加。虽然关于前列腺中IGFBP-rP3的数据有限，但其在癌细胞中的优先表达以及被atRA下调支持了它作为生长刺激因子和/或原癌基因的作用。
