Long Feng, Cai Xinyan, Luo Wei, Chen Liang, Li Kanghua
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China.
Department of Neonatology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China.
Oncol Rep. 2014 Nov;32(5):2031-7. doi: 10.3892/or.2014.3473. Epub 2014 Sep 10.
Aldolase A (ALDOA) has been reported to be negative survival marker of osteosarcoma (OS) and may be implicated in OS development and progression. In the present study, we assessed for the first time the functional role of ALDOA in OS cell invasion and survival in vitro and in vivo, using human OS cell lines and an orthotopic xenograft nude mouse model. Overexpression and knockdown of ALDOA were respectively performed in MG-63 and U-2 OS cells, which showed relatively low and high constitutive ALDOA expression levels, respectively. Overexpression of ALDOA in MG-63 cells significantly increased in vitro cell invasion, matrix metalloproteinase (MMP)-2 expression, and cell survival against cisplatin-induced apoptosis. On the other hand, knockdown of ALDOA in U-2 cells markedly decreased in vitro cell invasion, MMP-2 expression, and cell survival against cisplatin-induced apoptosis. In an orthotopic xenograft nude mouse model, intra-tibial injection of MG-63 cells overexpressing ALDOA led to significantly increased primary tumor volume and pulmonary metastasis as well as decreased cell apoptosis in the primary tumors, compared with the controls. In contrast, intra-tibial injection of U-2 cells with knockdown of ALDOA led to markedly decreased primary tumor volume and pulmonary metastasis as well as increased cell apoptosis in the primary tumors, compared with the controls. In conclusion, our in vitro data indicate that ALDOA promotes OS cell invasion and survival, and our in vivo data demonstrate an important role of ALDOA in promoting OS tumor growth and metastasis. The present study provides the first in vitro and in vivo evidence supporting a critical functional role of ALDOA in OS progression and metastasis, suggesting that ALDOA could serve as a novel therapeutic target in OS. Additionally, our results suggest that ALDOA is involved in the development of OS chemoresistance.
据报道，醛缩酶A（ALDOA）是骨肉瘤（OS）的负性生存标志物，可能与OS的发生发展有关。在本研究中，我们首次使用人OS细胞系和原位异种移植裸鼠模型，评估了ALDOA在OS细胞体外和体内侵袭及生存中的功能作用。分别在MG-63和U-2 OS细胞中进行ALDOA的过表达和敲低，这两种细胞分别显示出相对较低和较高的组成性ALDOA表达水平。MG-63细胞中ALDOA的过表达显著增加了体外细胞侵袭、基质金属蛋白酶（MMP）-2表达以及对顺铂诱导凋亡的细胞存活能力。另一方面，U-2细胞中ALDOA的敲低显著降低了体外细胞侵袭、MMP-2表达以及对顺铂诱导凋亡的细胞存活能力。在原位异种移植裸鼠模型中，与对照组相比，胫骨内注射过表达ALDOA的MG-63细胞导致原发性肿瘤体积和肺转移显著增加，以及原发性肿瘤中的细胞凋亡减少。相反，与对照组相比，胫骨内注射敲低ALDOA的U-2细胞导致原发性肿瘤体积和肺转移显著减少，以及原发性肿瘤中的细胞凋亡增加。总之，我们的体外数据表明ALDOA促进OS细胞侵袭和存活，我们的体内数据证明ALDOA在促进OS肿瘤生长和转移中起重要作用。本研究提供了首个体外和体内证据，支持ALDOA在OS进展和转移中的关键功能作用，表明ALDOA可作为OS的新型治疗靶点。此外，我们的结果表明ALDOA参与了OS化疗耐药性的发展。
