Friese Klaus, Kost Bernd, Vattai Aurelia, Marmé Frederik, Kuhn Christina, Mahner Sven, Dannecker Christian, Jeschke Udo, Heublein Sabine
Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Klinik Bad Trissl GmbH, Oberaudorf, Germany.
J Cancer Res Clin Oncol. 2018 Jan;144(1):13-19. doi: 10.1007/s00432-017-2510-7. Epub 2017 Sep 18.
Estrogen signalling is transmitted via various receptors and multiple intracellular signalling pathways. Estrogen receptor alpha (ERα)-mediated transcription of target genes has been demonstrated to be closely linked to human papilloma virus (HPV)-induced carcinogenesis in case of cervical cancer. So far, the role of non-genomic estrogen signals in cervical cancer, e.g. transmitted by the G protein-coupled estrogen receptor (GPER) remains to be rather elusive. Today's knowledge on the role of GPER in cervical cancer is sparse and-to the best of our knowledge-GPER has not been investigated in context with clinicopathological parameters or prognosis of cervical cancer. Therefore, the current study investigated whether GPER is expressed in cervical cancer tissue. Further, GPER was correlated to clinicopathological parameters, tissue markers of cervical carcinogenesis and to patient overall and recurrence-free survival.
Cervical cancer tissue was collected from 156 patients during surgery between 1993 and 2002. GPER immunostaining was performed on all the cases and correlated to clinicopathological data. More than half of all patients were diagnosed at advanced stage (FIGO II-IV 93/156; 59.6%) of disease. The large majority of patients presented with tumours of intermediate or high grade (G2-3 140/152, 92.1%). 22 cervical cancer-related deaths (22/156, 14.1%) were documented during the follow-up period.
GPER was detected in various subcellular staining patterns. In 129/156 (82.7%) cases GPER was expressed in the tumour cell cytoplasm (GPER). GPER immunopositivity at the cell membrane (GPER) was found in 114/156 (73.1%) cases. While co-occurrence of both membrane and cytoplasmic staining (GPER + GPER) was detected in the majority of tissue samples (101/156; 64.7%), only few cases (14/156, 9.0%) were classified as not expressing GPER at all. GPER was positively correlated with tumour grade. Statistical associations of GPER and both p16 and p53 were detected. Finally, immunopositivity of GPER was predictive for favourable overall as well as recurrence-free survival in cervical cancer of early stage (FIGO I).
This retrospective study reports GPER to be associated with improved overall and recurrence-free survival in early-stage cervical cancer. Further investigations are needed thus to determine whether this observation may be of clinical impact. Interestingly, Raloxifene-a GPER-activating selective estrogen receptor modulator-has recently been demonstrated to be preventive for cervical cancer relapse in mice. Whether this effect is only reliant on raloxifene blocking ERα or may also be related to activation of GPER remains to be determined.
雌激素信号通过多种受体和多条细胞内信号通路进行传递。在宫颈癌中，雌激素受体α（ERα）介导的靶基因转录已被证明与人类乳头瘤病毒（HPV）诱导的致癌作用密切相关。到目前为止，非基因组雌激素信号在宫颈癌中的作用，例如由G蛋白偶联雌激素受体（GPER）传递的信号，仍然相当难以捉摸。目前关于GPER在宫颈癌中作用的知识很少，据我们所知，尚未结合宫颈癌的临床病理参数或预后对GPER进行研究。因此，本研究调查了GPER在宫颈癌组织中是否表达。此外，还将GPER与临床病理参数、宫颈癌发生的组织标志物以及患者的总生存期和无复发生存期进行了关联分析。
收集了1993年至2002年期间156例患者手术时的宫颈癌组织。对所有病例进行了GPER免疫染色，并与临床病理数据进行关联分析。超过一半的患者在疾病晚期（国际妇产科联盟II-IV期93/156；59.6%）被诊断出来。绝大多数患者表现为中或高级别肿瘤（G2-3 140/152，92.1%）。在随访期间记录到22例宫颈癌相关死亡（22/156，14.1%）。
检测到GPER有多种亚细胞染色模式。在129/156（82.7%）例中，GPER在肿瘤细胞质中表达（GPER）。在114/156（73.1%）例中发现细胞膜上有GPER免疫阳性（GPER）。虽然在大多数组织样本中检测到膜和细胞质染色同时出现（GPER + GPER）（101/156；64.7%），但只有少数病例（14/156，9.0%）被归类为完全不表达GPER。GPER与肿瘤分级呈正相关。检测到GPER与p16和p均有统计学关联。最后，GPER免疫阳性可预测早期（国际妇产科联盟I期）宫颈癌患者良好的总生存期和无复发生存期。
这项回顾性研究报告称，GPER与早期宫颈癌患者总生存期和无复发生存期的改善相关。因此，需要进一步研究以确定这一观察结果是否具有临床意义。有趣的是，雷洛昔芬——一种激活GPER的选择性雌激素受体调节剂——最近已被证明可预防小鼠宫颈癌复发。这种作用是否仅依赖于雷洛昔芬阻断ERα，还是也可能与GPER的激活有关，仍有待确定。
