Yuan Xuhui, Ma Cong, Li Jiayu, Li Junhong, Yu Ronghui, Cai Feng, Qu Gaoyang, Yu Bo, Liu Lang, Zeng Duo, Jiao QuanHui, Liao Qi, Lv Xiaobin
Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Central Laboratory, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China.
Department of Orthopedics, The First Hospital of Nanchang, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China.
J Bone Oncol. 2023 Feb 23;39:100472. doi: 10.1016/j.jbo.2023.100472. eCollection 2023 Apr.
Osteosarcoma is most prevalently found primary malignant bone tumors, with primary metastatic patients accounting for approximately 25% of all osteosarcoma patients, yet their 5-year OS remains below 30%. Bilirubin plays a key role in oxidative stress-associated events, including malignancies, making the regulation of its serum levels a potential anti-tumor strategy. Herein, we investigated the association of osteosarcoma prognosis with serum levels of TBIL, IBIL and DBIL, and further explored the mechanisms by which bilirubin affects tumor invasion and migration.
ROC curve was plotted to assess survival conditions based on the determined optimal cut-off values and the AUC. Then, Kaplan-Meier curves, along with Cox proportional hazards model, was applied for survival analysis. Inhibitory function of IBIL on the malignant properties of osteosarcoma cells was examined using the qRT-PCR, transwell assays, western blotting, and flow cytometry.
We found that, versus osteosarcoma patients with pre-operative higher IBIL (>8.9 μmol/L), those with low IBIL (≤8.9 μmol/L) had shorter OS and PFS. As indicated by the Cox proportional hazards model, pre-operative IBIL functioned as an independent prognostic factor for OS and PFS in total and gender-stratified osteosarcoma patients ( < 0.05 for all). In vitro experiments further confirmed that IBIL inhibits PI3K/AKT phosphorylation and downregulates MMP-2 expression reducing intracellular ROS, thereby decreasing the invasion of osteosarcoma cells.
IBIL may serve as an independent prognostic predictor for osteosarcoma patients. IBIL impairs invasion of osteosarcoma cells through repressing the PI3K/AKT/MMP-2 pathway by suppressing intracellular ROS, thus inhibiting its metastatic potential.
骨肉瘤是最常见的原发性恶性骨肿瘤，原发性转移患者约占所有骨肉瘤患者的25%，但其5年总生存率仍低于30%。胆红素在包括恶性肿瘤在内的氧化应激相关事件中起关键作用，因此调节其血清水平可能是一种潜在的抗肿瘤策略。在此，我们研究了骨肉瘤预后与总胆红素（TBIL）、间接胆红素（IBIL）和直接胆红素（DBIL）血清水平的关系，并进一步探讨了胆红素影响肿瘤侵袭和迁移的机制。
根据确定的最佳临界值和曲线下面积（AUC）绘制ROC曲线以评估生存状况。然后，应用Kaplan-Meier曲线和Cox比例风险模型进行生存分析。使用qRT-PCR、Transwell实验、蛋白质免疫印迹法和流式细胞术检测IBIL对骨肉瘤细胞恶性特性的抑制作用。
我们发现，与术前IBIL较高（>8.9 μmol/L）的骨肉瘤患者相比，IBIL较低（≤8.9 μmol/L）的患者总生存期（OS）和无进展生存期（PFS）较短。Cox比例风险模型表明，术前IBIL是总体及按性别分层的骨肉瘤患者OS和PFS的独立预后因素（所有P均<0.05）。体外实验进一步证实，IBIL抑制PI3K/AKT磷酸化并下调MMP-2表达，减少细胞内活性氧（ROS），从而降低骨肉瘤细胞的侵袭能力。
IBIL可能是骨肉瘤患者的独立预后预测指标。IBIL通过抑制细胞内ROS抑制PI3K/AKT/MMP-2通路，损害骨肉瘤细胞的侵袭能力，从而抑制其转移潜能。
