Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
Biomolecules. 2024 Aug 31;14(9):1093. doi: 10.3390/biom14091093.
(1) Background: Periostin (Pn) is a secreted protein found in the extracellular matrix, and it plays a variety of roles in the human body. Physiologically, Pn has a variety of functions, including bone formation and wound healing. However, it has been implicated in the pathogenesis of various malignant tumors and chronic inflammatory diseases. Pn has alternative splicing variants (ASVs), and our previous research revealed that aberrant ASVs contribute to the pathogenesis of breast cancer and heart failure. However, the difference in expression pattern between physiologically expressed Pn-ASVs and those expressed during pathogenesis is not clear. (2) Methods and results: We examined normal and breast cancer tissues, focusing on the Pn-ASVs expression pattern to assess the significance of pathologically expressed Pn-ASVs as potential diagnostic and therapeutic targets. We found that most physiologically expressed Pn isoforms lacked exon 17 and 21. Next, we used human breast cancer and normal adjacent tissue (NAT) to investigate the expression pattern of Pn-ASVs under pathological conditions. Pn-ASVs with exon 21 were significantly increased in tumor tissues compared with NAT. In situ hybridization identified the synthesis of Pn-ASVs with exon 21 in peri-tumoral stromal cells. Additionally, the in vivo bio-distribution of Zr-labeled Pn antibody against exon 21 (Pn-21Ab) in mice bearing breast cancer demonstrated selective and specific accumulation in tumors, while Pn-21Ab significantly suppressed tumor growth in the mouse breast cancer model. (3) Conclusions: Together, these data indicate that Pn-ASVs might have potential for use as diagnostic and therapeutic targets for breast cancer.
（1）背景：骨膜蛋白（Pn）是一种存在于细胞外基质中的分泌蛋白，在人体中发挥着多种作用。生理上，Pn 具有多种功能，包括骨形成和伤口愈合。然而，它与各种恶性肿瘤和慢性炎症性疾病的发病机制有关。Pn 有选择性剪接变异体（ASVs），我们之前的研究表明，异常的 ASVs 导致乳腺癌和心力衰竭的发病机制。然而，生理表达的 Pn-ASVs 与发病机制表达的 Pn-ASVs 之间表达模式的差异尚不清楚。（2）方法和结果：我们检查了正常和乳腺癌组织，重点研究了 Pn-ASVs 的表达模式，以评估病理性表达的 Pn-ASVs 作为潜在的诊断和治疗靶点的意义。我们发现大多数生理表达的 Pn 异构体缺乏外显子 17 和 21。接下来，我们使用人乳腺癌和正常相邻组织（NAT）来研究病理性条件下 Pn-ASVs 的表达模式。与 NAT 相比，肿瘤组织中带有外显子 21 的 Pn-ASVs 显著增加。原位杂交鉴定了带有外显子 21 的 Pn-ASVs 在肿瘤周围基质细胞中的合成。此外，在携带乳腺癌的小鼠中，Zr 标记的针对外显子 21 的 Pn 抗体（Pn-21Ab）的体内生物分布显示在肿瘤中具有选择性和特异性积累，而 Pn-21Ab 显著抑制了小鼠乳腺癌模型中的肿瘤生长。（3）结论：综上所述，这些数据表明 Pn-ASVs 可能有潜力作为乳腺癌的诊断和治疗靶点。
