Joko Ryoji, Yamada Daisuke, Nakamura Masahiro, Yoshida Aki, Takihira Shota, Takao Tomoka, Lu Ming, Sato Kohei, Ito Tatsuo, Kunisada Toshiyuki, Nakata Eiji, Ozaki Toshifumi, Takarada Takeshi
Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan; Department Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Transl Oncol. 2021 Jan;14(1):100960. doi: 10.1016/j.tranon.2020.100960. Epub 2020 Dec 9.
Paired related homeobox 1 (PRRX1) is a marker of limb bud mesenchymal cells, and deficiency of p53 or Rb in Prrx1-positive cells induces osteosarcoma in several mouse models. However, the regulatory roles of PRRX1 in human osteosarcoma have not been defined. In this study, we performed PRRX1 immunostaining on 35 human osteosarcoma specimens to assess the correlation between PRRX1 level and overall survival. In patients with osteosarcoma, the expression level of PRRX1 positively correlated with poor prognosis or the ratio of lung metastasis. Additionally, we found PRRX1 expression on in 143B cells, a human osteosarcoma line with a high metastatic capacity. Downregulation of PRRX1 not only suppressed proliferation and invasion but also increased the sensitivity to cisplatin and doxorubicin. When 143B cells were subcutaneously transplanted into nude mice, PRRX1 knockdown decreased tumor sizes and rates of lung metastasis. Interestingly, forskolin, a chemical compound identified by Connectivity Map analysis using RNA expression signatures during PRRX1 knockdown, decreased tumor proliferation and cell migration to the same degree as PRRX1 knockdown. These results demonstrate that PRRX1 promotes tumor malignancy in human osteosarcoma.
配对相关同源盒1（PRRX1）是肢芽间充质细胞的标志物，在几种小鼠模型中，Prrx1阳性细胞中p53或Rb的缺失会诱发骨肉瘤。然而，PRRX1在人类骨肉瘤中的调控作用尚未明确。在本研究中，我们对35例人类骨肉瘤标本进行了PRRX1免疫染色，以评估PRRX1水平与总生存期之间的相关性。在骨肉瘤患者中，PRRX1的表达水平与预后不良或肺转移率呈正相关。此外，我们在143B细胞（一种具有高转移能力的人类骨肉瘤细胞系）中发现了PRRX1的表达。PRRX1的下调不仅抑制了细胞增殖和侵袭，还增加了对顺铂和阿霉素的敏感性。当将143B细胞皮下移植到裸鼠体内时，PRRX1基因敲低可减小肿瘤大小并降低肺转移率。有趣的是，福司可林（一种在PRRX1基因敲低过程中通过使用RNA表达特征的连通性图谱分析鉴定出的化合物）与PRRX1基因敲低一样，可同等程度地降低肿瘤增殖和细胞迁移。这些结果表明，PRRX1促进人类骨肉瘤的肿瘤恶性进展。
