Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis
Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis
复制标题
DOI：
10.1073/pnas.1222079110
复制
发表时间：
2013-05-14
影响因子：
11.1
通讯作者：
Taramelli, Roberto
中科院分区：
文献类型：
--
作者：
Acquati, Francesco;Lualdi, Marta;Taramelli, Roberto
近年来，为了充分了解癌症的发生和进展，基质微环境所发挥的作用受到越来越多的关注。由于癌症是一种基于组织的疾病，因此组织结构的完整性是癌症生长的主要限制因素。事实上，对癌症的天然抵抗力的很大一部分源于基质微环境成分，其失调会促进癌症的发生。例如，最近的实验证据强调了基质细胞参与卵巢癌发生，通过小鼠 Dicer 和 Pten 基因双重敲除获得的卵巢异种移植物就是例证。同样，我们报道了一种古老的细胞外 RNase，称为核糖核酸酶 T2 (RNASET2)，在卵巢基质微环境中的作用。事实上，RNASET2 的超表达能够通过在肿瘤部位募集巨噬细胞（主要是抗癌 M1 亚型）来控制肿瘤发生。我们展示了在肿瘤遗传性差且 RNASET2 高表达的人 OVCAR3 细胞系中通过 RNASET2 沉默获得的生物学数据。在裸鼠体内显微注射 OVCAR3 细胞后，RNASET2 敲除可在早期刺激体内肿瘤生长。此外，我们通过分子分析研究了人和小鼠细胞异种移植物的体内表达特征，并揭示了与先天免疫反应的激活和 ECM 成分的调节相关的途径的激活。最后，我们提供了 RNASET2 在触发巨噬细胞体外趋化反应中的作用的证据。这些结果进一步强调了微环境在RNASET2介导的卵巢肿瘤抑制中发挥的关键作用，这最终可能有助于更好地阐明这种疾病的发病机制。
In recent years, the role played by the stromal microenvironment has been given growing attention in order to achieve a full understanding of cancer initiation and progression. Because cancer is a tissue-based disease, the integrity of tissue architecture is a major constraint toward cancer growth. Indeed, a large contribution of the natural resistance to cancer stems from stromal microenvironment components, the dysregulation of which can facilitate cancer occurrence. For instance, recent experimental evidence has highlighted the involvement of stromal cells in ovarian carcinogenesis, as epitomized by ovarian xenografts obtained by a double KO of the murine Dicer and Pten genes. Likewise, we reported the role of an ancient extracellular RNase, called Ribonuclease T2 (RNASET2), within the ovarian stromal microenvironment. Indeed, hyperexpression of RNASET2 is able to control tumorigenesis by recruiting macrophages (mostly of the anticancer M1 subtype) at the tumor sites. We present biological data obtained by RNASET2 silencing in the poorly tumorigenetic and highly RNASET2-expressing human OVCAR3 cell line. RNASET2 knockdown was shown to stimulate in vivo tumor growth early after microinjection of OVCAR3 cells in nude mice. Moreover, we have investigated by molecular profiling the in vivo expression signature of human and mouse cell xenografts and disclosed the activation of pathways related to activation of the innate immune response and modulation of ECM components. Finally, we provide evidence for a role of RNASET2 in triggering an in vitro chemotactic response in macrophages. These results further highlight the critical role played by the microenvironment in RNASET2-mediated ovarian tumor suppression, which could eventually contribute to better clarify the pathogenesis of this disease.