Valve E M, Nevalainen M T, Nurmi M J, Laato M K, Martikainen P M, Härkönen P L
Department of Anatomy and MediCity Research Laboratory, Tampere University Hospital, Tampere, Finland.
Lab Invest. 2001 Jun;81(6):815-26. doi: 10.1038/labinvest.3780291.
Fibroblast growth factor 8 (FGF-8) is implicated in growth of prostate cancer. Alternative splicing of the human FGF-8 gene potentially allows coding for four protein isoforms (a, b, e, and f). These isoforms differ in their binding to FGF receptors (FGFR) and in their mitogenic and transforming capacity in transfection assays. Here, we used RT-PCR and immunohistochemistry to study the expression of FGF-8 and FGFR isoforms in human prostate cancer (n = 31). Nonmalignant prostate specimens from cystoprostatectomies (n = 24) were examined as controls. Most prostate cancer samples and some control prostates also contained prostatic intraepithelial neoplasia (PIN) lesions. FGF-8a and e were expressed at significantly higher frequencies in prostate cancer (FGF-8a, 55%; FGF-8e, 45%) than in control samples (FGF-8a, 17%, p = 0.0052; FGF-8e, 8%, p = 0.0031). On the contrary, FGF-8b was found at an equal frequency in prostate cancer (55%) and in control prostates (50%). Furthermore, a combination of two or three FGF-8 isoforms (a, b, and/or e) was also expressed at a higher frequency in prostate cancer than in control samples (45% and 8%, respectively, p = 0.0031). Immunohistochemistry with an antibody recognizing all FGF-8 isoforms was more strongly immunoreactive in prostate cancer cells and PIN lesions than in normal-type epithelium. The receptor splicing variants FGFR1IIIc and FGFR2IIIc, which are activated by FGF-8, were found both in prostate cancer and control samples. Interestingly, immunoreactivity for FGFR1 and FGFR2 was much stronger in prostate cancer cells and PIN than in normal epithelium. These results demonstrate, for the first time, that FGF-8 isoforms and their receptors FGFR1IIIc and FGFR2IIIc are expressed at an increased level not only in prostate cancer but also in premalignant PIN lesions. These data suggest that FGF-8 may have an important autocrine role in the development of human prostate cancer. In addition to FGF-8b, the FGF-8 isoforms a and e may be involved in this process.
成纤维细胞生长因子8（FGF-8）与前列腺癌的生长有关。人类FGF-8基因的可变剪接可能编码四种蛋白质异构体（a、b、e和f）。这些异构体在与FGF受体（FGFR）的结合以及转染试验中的促有丝分裂和转化能力方面存在差异。在此，我们使用逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法研究了FGF-8和FGFR异构体在人类前列腺癌（n = 31）中的表达。将膀胱前列腺切除术获得的非恶性前列腺标本（n = 24）作为对照。大多数前列腺癌样本以及一些对照前列腺中也存在前列腺上皮内瘤变（PIN）病变。FGF-8a和e在前列腺癌中的表达频率（FGF-8a为55%；FGF-8e为45%）显著高于对照样本（FGF-8a为17%，p = 0.0052；FGF-8e为8%，p = 0.0031）。相反，FGF-8b在前列腺癌（55%）和对照前列腺（50%）中的出现频率相同。此外，两种或三种FGF-8异构体（a、b和/或e）的组合在前列腺癌中的表达频率也高于对照样本（分别为45%和8%，p = 0.0031）。使用识别所有FGF-8异构体的抗体进行免疫组织化学检测发现，前列腺癌细胞和PIN病变中的免疫反应性比正常类型上皮更强。被FGF-8激活的受体剪接变体FGFR1IIIc和FGFR2IIIc在前列腺癌和对照样本中均有发现。有趣的是，FGFR1和FGFR2在前列腺癌细胞和PIN中的免疫反应性比正常上皮强得多。这些结果首次证明，FGF-8异构体及其受体FGFR1IIIc和FGFR2IIIc不仅在前列腺癌中，而且在癌前PIN病变中表达水平均升高。这些数据表明，FGF-8可能在人类前列腺癌的发生发展中具有重要的自分泌作用。除了FGF-8b外，FGF-8异构体a和e可能也参与了这一过程。
