Zucchini Cinzia, Rocchi Anna, Manara Maria Cristina, De Sanctis Paola, Capanni Cristina, Bianchini Michele, Carinci Paolo, Scotlandi Katia, Valvassori Luisa
Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, 40126 Bologna, Italy.
Int J Oncol. 2008 Jan;32(1):17-31.
Metastasis is the most frequent cause of death among patients with osteosarcoma. We have previously demonstrated in independent experiments that the forced expression of L/B/K ALP and CD99 in U-2 OS osteosarcoma cell lines markedly reduces the metastatic ability of these cancer cells. This behavior makes these cell lines a useful model to assess the intersection of multiple and independent gene expression signatures concerning the biological problem of dissemination. With the aim to characterize a common transcriptional profile reflecting the essential features of metastatic behavior, we employed cDNA microarrays to compare the gene expression profiles of L/B/K ALP- and CD99-transfected osteosarcoma clones showing low metastatic ability with those of osteosarcoma cell lines showing contrasting behavior. Changes in gene expression were validated by real-time PCR and immunohistochemistry in independent samples. In our study we identified several differentially expressed genes (GADD45alpha, VCP, DHX9, survivin, alpha-catulin, ARPC1B) related to growth arrest and apoptosis. Most of these genes are functionally related with the nuclear factor (NF)-kappaB cell survival pathway that appeared to be inhibited in the less malignant osteosarcoma cells. Hence, we propose the inhibition of the NF-kappaB pathway as a rational strategy for effective management of human osteosarcoma.
转移是骨肉瘤患者最常见的死亡原因。我们之前在独立实验中证明，在U-2 OS骨肉瘤细胞系中强制表达L/B/K碱性磷酸酶（ALP）和CD99可显著降低这些癌细胞的转移能力。这种特性使这些细胞系成为一个有用的模型，可用于评估与肿瘤扩散这一生物学问题相关的多个独立基因表达特征的交集。为了描绘出反映转移行为基本特征的共同转录谱，我们使用cDNA微阵列比较了低转移能力的L/B/K ALP和CD99转染骨肉瘤克隆与具有相反行为的骨肉瘤细胞系的基因表达谱。通过实时PCR和免疫组织化学在独立样本中验证了基因表达的变化。在我们的研究中，我们鉴定了几个与生长停滞和凋亡相关的差异表达基因（GADD45α、VCP、DHX9、生存素、α-连环蛋白、肌动蛋白相关蛋白1B亚基）。这些基因中的大多数在功能上与核因子（NF）-κB细胞存活途径相关，而该途径在恶性程度较低的骨肉瘤细胞中似乎受到抑制。因此，我们提出抑制NF-κB途径是有效治疗人类骨肉瘤的合理策略。
