Fuja Daniel G, Rainusso Nino C, Shuck Ryan L, Kurenbekova Lyazat, Donehower Lawrence A, Yustein Jason T
Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine Houston 77030, Texas, USA.
Integrative Molecular and Biological Sciences Program, Baylor College of Medicine Houston 77030, Texas, USA.
Am J Cancer Res. 2018 Sep 1;8(9):1752-1763. eCollection 2018.
Osteosarcoma (OS) is a highly aggressive mesenchymal malignancy and the most common primary bone tumor in the pediatric population. OS frequently presents with or develops distal metastases. Patients with metastatic disease have extremely poor survival rates, thus necessitating improved molecular insights into OS metastatic biology. Utilizing our previously characterized genetically engineered mouse model (GEMM) of metastatic OS, we identified enhanced differential expression of Transglutaminase-2 (TGM2) in metastatic OS. However, the role of TGM2 in sarcoma development and metastatic progression remains largely undefined. To further investigate the role of TGM2 in OS metastasis, we performed both gain- and loss-of-function studies for TGM2 in human and mouse OS cell lines. Our data provide evidence that enhanced expression of TGM2 in metastatic OS contributes to migratory and invasive phenotypes. Besides the effects on metastatic phenotypes, we also observed that TGM2 contributes to OS stem-like properties. In addition, treatment with transglutaminase inhibitors had analogous effects on proliferation and migration to TGM2 knockdown. Finally, xenograft studies demonstrated that TGM2 functionally alters metastatic potential and survival outcome. Together, these data highlight TGM2 as a pro-metastatic factor in OS and a potential avenue for future therapeutic intervention to inhibit metastatic disease.
骨肉瘤（OS）是一种具有高度侵袭性的间充质恶性肿瘤，是儿科人群中最常见的原发性骨肿瘤。骨肉瘤常伴有或发生远端转移。患有转移性疾病的患者生存率极低，因此有必要深入了解骨肉瘤转移生物学的分子机制。利用我们之前构建的转移性骨肉瘤基因工程小鼠模型（GEMM），我们发现转谷氨酰胺酶2（TGM2）在转移性骨肉瘤中差异表达增强。然而，TGM2在肉瘤发生和转移进展中的作用仍不清楚。为了进一步研究TGM2在骨肉瘤转移中的作用，我们在人和小鼠骨肉瘤细胞系中对TGM2进行了功能获得和功能缺失研究。我们的数据表明，转移性骨肉瘤中TGM2表达增强有助于迁移和侵袭表型。除了对转移表型的影响外，我们还观察到TGM2有助于骨肉瘤干细胞样特性。此外，用转谷氨酰胺酶抑制剂处理对增殖和迁移的影响与TGM2基因敲除类似。最后，异种移植研究表明，TGM2在功能上改变了转移潜能和生存结果。总之，这些数据突出了TGM2作为骨肉瘤中促转移因子的作用，以及未来抑制转移性疾病治疗干预的潜在途径。
