HMGB1在骨肉瘤侵袭转移中的作用及其机制的研究

Osteosarcoma is the most common primary malignant bone tumor. At present, its pathomechanism is still not clear. Osteosarcoma is still a tumor with a high mortality rate mainly ascribed to early pulmonary metastasis. So, it will be of great clinical significance to elucidate the possible invasion and metastasis mechanism in osteosarcoma. High-mobility group box 1 (HMGB1) is an evolutionarily conserved protein present in the nucleus of almost all eukaryotic cells, where it is involved in DNA replication, repair and transcription. It has been reported that HMGB1 was related to a varieties of malignant tumors. We have found in our previous study that HMGB1 was highly expressed in human osteosarcoma tissues, and the patients with higher HMGB1 expression in osteosarcoma tissues were more likely to have progression and metastasis of this disease. But the molecular mechanism is still not well-defined. So in this study, we explore the possible molecular mechanisms and the signaling regulation pathway by the following hypothesis: ① the effect and molecular mechanism of HMGB1 in the invasion and metastasis of osteosarcoma. ② whether the down regulation of HMGB1 by RNAi can inhibit the motion, invasion and metastasis of osteosarcoma. ③ To further validate the effect of HMGB1 on the motion, invasion and metastasis of osteosarcoma in orthotopic implantation pulmonary targeted metastasis model in nude mouse. Taken together, the resolution of these questions will provide new clinical insight and new way for the treatment of osteosarcoma.

骨肉瘤是最常见的原发性恶性骨肿瘤，其发病机制仍不明确。早期肺转移是导致病人死亡的主要原因，也是目前骨肉瘤治疗措施的主要研究方向，因此深入研究其侵袭转移机制进而防止早期肺部的转移，对骨肉瘤的治疗具有重要的临床意义。HMGB1是一组含量丰富进化保守的非组蛋白，已在多种恶性肿瘤中进行了研究，发现它的异常表达参与肿瘤的发生发展。我们前期的研究工作也证实，HMGB1高表达于骨肉瘤组织，与肿瘤临床分期及肺转移相关，但具体作用机理仍不明确，故设计了本课题探讨以下问题：① 阐明HMGB1作用于骨肉瘤细胞迁移、侵袭与转移的分子机制，可能的信号通路及调控机理。②通过干扰HMGB1的表达是否能抑制骨肉瘤细胞的迁移、侵袭和转移。③HMGB1对骨肉瘤细胞迁移、侵袭和转移的作用能否在裸鼠骨肉瘤原位移植肺转移模型中得到成功验证。以上问题的解决有助于进一步揭示骨肉瘤的病理发病机制, 为临床骨肉瘤的治疗开辟新思路和新途径