Department of Genetics, Medical College of Soochow University, Suzhou, China.
Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
J Exp Med. 2020 Mar 2;217(3). doi: 10.1084/jem.20190950.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60-aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.
三阴性乳腺癌（TNBC）是一种侵袭性最强、总体存活率最差的乳腺癌亚型。我们利用生物信息学工具，鉴定出 LINC00908 编码的 60 个氨基酸多肽，在 TNBC 组织中差异表达。我们将这种内源性表达的多肽命名为 ASRPS（STAT3 的一个小调节肽）。ASRPS 在 TNBC 中表达下调，与总体存活率差相关。我们表明，LINC00908 被 ERα 直接调控，这导致了 TNBC 中 LINC00908 的差异下调。ASRPS 通过卷曲螺旋结构域（CCD）直接与 STAT3 结合，下调 STAT3 磷酸化，从而导致 VEGF 表达减少。在人内皮细胞、小鼠异种移植乳腺癌模型和小鼠自发性乳腺癌模型中，ASRPS 表达减少了血管生成。在小鼠异种移植乳腺癌模型中，下调 ASRPS 促进了肿瘤生长，ASRPS 发挥了抗肿瘤肽的作用。我们提供了强有力的证据表明，LINC00908 编码的多肽 ASRPS 代表了一种 TNBC 特异性治疗靶点。
