van der Ploeg Phyllis, Uittenboogaard Aniek, Bosch Steven L, van Diest Paul J, Wesseling-Rozendaal Yvonne J W, van de Stolpe Anja, Lambrechts Sandrina, Bekkers Ruud L M, Piek Jurgen M J
Department of Obstetrics and Gynecology, Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
Department of Obstetrics and Gynecology, Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands.
Gynecol Oncol. 2022 Apr;165(1):114-120. doi: 10.1016/j.ygyno.2022.01.027. Epub 2022 Feb 2.
To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE).
We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways.
There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression.
Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.
确定浆液性输卵管上皮内癌（STIC）和同期高级别浆液性癌（HGSC）中关键信号转导通路的活性，并将其与正常输卵管上皮（FTE）中的通路活性进行比较。
我们采用逆转录定量聚合酶链反应（RT-qPCR）评估了STIC、同期HGSC（n = 8）和正常FTE（n = 8）中通路特异性靶基因的mRNA表达水平。随后，使用信号转导通路分析来评估雄激素（AR）和雌激素受体（ER）、磷酸肌醇-3-激酶（PI3K）、刺猬因子（HH）、转化生长因子β（TGF-β）和经典无翅型MMTV整合位点（Wnt）通路的功能活性。
STIC和HGSC之间的通路活性无统计学显著差异，但与正常FTE相比，STIC和HGSC显示出ER活性显著降低，PI3K和HH通路活性更高，提示这些通路可能是早期驱动因素。此外，我们通过免疫组织化学测定了FOXO3a蛋白表达，发现与正常FTE相比，STIC和HGSC中FOXO3a蛋白表达缺失。这一观察结果证实，FOXO缺失导致的PI3K信号激活是浆液性癌发生的早期标志。此外，与FTE相比，HGSC显示出AR和Wnt通路活性显著丧失，提示这些通路参与疾病进展。
我们的观察结果，连同先前描述的p53信号与PI3K和HH通路活性之间的关联，提供了证据表明PI3K和HH通路活性增加以及ER通路活性丧失可能是导致FTE向STIC肿瘤转化的潜在事件。
