Yazdani Samaneh, Kasajima Atsuko, Ogata Hiroko, Felizola Saulo J A, Nakamura Yasuhiro, Onodera Yoshiaki, Watanabe Mika, Motoi Fuyuhiko, Unno Michiaki, Sasano Hironobu
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Neuroendocrinology. 2015;101(4):309-20. doi: 10.1159/000381455. Epub 2015 Mar 16.
Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients.
Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters.
CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035).
The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.
据报道，胰腺神经内分泌肿瘤（PNETs）表达孕激素受体（PR），其表达已被证明是这些患者的一个有利预后因素。我们研究了人PNET细胞系中PR亚型PRA和PRB的状态及其与肿瘤细胞增殖的关系，这与PNET患者的临床结局密切相关。
在用孕激素和RU-486（一种PR拮抗剂）处理后，对未转染和PRA转染的QGP-1神经内分泌肿瘤细胞系细胞进行定量逆转录聚合酶链反应（RT-PCR）和细胞增殖测定，该细胞系天然表达PRB。对87例PNET病例进行PRA、PRB和细胞周期蛋白D1（CCND1）的免疫定位，并将结果与临床病理参数进行比较。
与PRA转染细胞相比，在表达PRB的QGP-1细胞中，孕激素处理显著增加了CCND1、c-Fos和c-Jun的mRNA水平（分别为p = 0.02、p = 0.007和p = 0.001）。孕激素给药也显著刺激了表达PRB的QGP-1细胞的增殖活性（p = 0.008）。在高级别PNETs中，PRA免疫反应性显著降低（p = 0.04），而CCND1在高级别PNETs中显著升高（p = 0.035）。
本研究结果表明，PRA可能在PNETs的细胞增殖中发挥抑制作用，可能是通过在孕激素存在下抑制PRB介导的信号，从而导致CCND1表达降低。此外，肿瘤细胞中PRA的状态可能是PNETs的一个预后因素。
