Ni Nan, Fang Xin, Mullens Destiny A, Cai James J, Ivanov Ivan, Bartholin Laurent, Li Qinglei
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Cancers (Basel). 2022 Apr 27;14(9):2184. doi: 10.3390/cancers14092184.
Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors.
卵巢颗粒细胞瘤（GCTs）是一种罕见的性索间质肿瘤，约占卵巢肿瘤的5%。GCTs的病因仍不清楚。基因工程小鼠模型对于理解GCTs的发病机制具有潜在价值。携带组成型激活TGFβ信号（TGFBR1-CA）的小鼠会发生卵巢GCTs，其表现出与人类GCTs的几种激素和分子特征相似的表型。为了确定TGFβ信号激活后卵巢中的分子改变，我们使用1月龄TGFBR1-CA小鼠和年龄匹配的对照小鼠的卵巢，对与GCT发育相关的基因表达进行了转录组分析。RNA测序和生物信息学分析以及对选定靶基因的验证揭示了多个细胞事件和信号分子/信号通路的失调。差异表达基因不仅在已知的GCT相关信号通路和致瘤事件中富集，而且在TGFBR1-CA卵巢中可能由神经活性配体-受体相互作用、松弛素信号、胰岛素信号和补体介导的信号事件中也有富集。此外，将我们在小鼠中的数据与在人类GCTs或过表达突变型FOXL2（成人GCTs的遗传标志）的颗粒细胞中失调的基因进行比较分析，发现了在两种情况下都发生改变的一些共同基因。总之，本研究揭示了在具有TGFBR1组成型激活的小鼠模型中卵巢GCTs的分子特征。这些发现可能会被进一步利用来理解一类定义不明确的卵巢肿瘤的发病机制。
