The Clinical Significance and Potential Therapeutic Role of GPx3 in Tumor Recurrence after Liver Transplantation.
The Clinical Significance and Potential Therapeutic Role of GPx3 in Tumor Recurrence after Liver Transplantation.
复制标题
GPx3在肝移植术后肿瘤复发中的临床意义和潜在治疗作用
作者：
Qi X;Ng KT;Shao Y;Li CX;Geng W;Ling CC;Ma YY;Liu XB;Liu H;Liu J;Yeung WH;Lo CM;Man K
背景和目的：我们先前的研究表明，小体积的肝移植可能为肿瘤的生长提供有利的微环境。在我们最近的研究中，抗氧化剂GPx3不仅可以减轻氧化应激，还可以抑制肝肿瘤的生长。在此，我们旨在探讨GPx3在肝移植后肝细胞癌复发中的作用及其临床意义。方法：建立大鼠原位肝移植肿瘤模型，探讨GPx3表达与肝细胞癌侵袭性的关系。为了探讨GPx3的临床相关性，我们收集了105例接受肝移植的肝细胞癌患者。通过伤口愈合、Matrigel侵袭实验和肺转移模型研究GPx3对肝癌细胞的抑制作用。实时活体成像系统被应用于直接可视化肿瘤细胞在活体动物中的侵袭。对其内在机制进行了进一步探讨。结果：在大鼠小体积肝移植模型中，GPx3被确定为下调蛋白，并与肿瘤生长的侵袭性表型显著相关。小体积移植组大鼠移植后血浆GPx3水平显著降低(d1：33vs1147；d3：3209vs4459；d7：303vs2506；mU/mL，P<；0.05)。临床上，肝细胞癌术后复发的受者血浆GPX3水平显著低于移植后第1天：4.16vs8.99µg/mL，P<；0.001；第7天：3.86vs9.99µg/mL，P<；0.001。此外，较低的血浆GPx3被确认为移植后总体存活率较低的独立预测因素(HR=4.528，P=0.046)。过表达的GPx3显著抑制了肝癌细胞的迁移、侵袭和转移。实时活体成像显示，GPx3显著抑制了肝癌在活体动物中的侵袭性。GPx3通过抑制JNK-cJun-MMP2通路抑制肿瘤侵袭力。结论：GPx3可能对肝移植后肝细胞癌患者的预后和治疗有一定的预测价值。
Background and Aims: Our previous study showed that small-for-size liver graft may provide favorable micro-environment for tumor growth. GPx3, an anti-oxidant, not only attenuates oxidative stress, but also suppresses liver tumor growth in our recent study. Here, we aimed to characterize the clinical significance and explore the functional role of GPx3 in HCC recurrence after liver transplantation. Methods: To explore the association between GPx3 expression and HCC invasiveness, a rat orthotopic liver transplantation model with tumor development was established. To investigate the clinical relevance of GPx3, 105 HCC patients who underwent liver transplantation were recruited. The suppressive role of GPx3 in HCC cells was studied using wound healing, Matrigel invasion assay and lung metastasis model. The real-time intravital imaging system was applied to directly visualize the tumor cells invasion in a living animal. The underlying mechanism was further explored. Results: GPx3 was identified as a down-regulated protein in small-for-size liver graft and significantly associated with invasive phenotype of tumor growth in a rat model. Plasma GPx3 was significantly lower in small-for-size graft group post-transplantation (day1: 33 vs 1147; day3: 3209 vs 4459; day7: 303 vs 2506; mU/mL, P<0.05) in rat model. Clinically, the plasma GPx3 was significantly lower in the recipients with HCC recurrence post-transplantation (day1: 4.16 vs 8.99 µg/mL, P<0.001; day7: 3.86 vs 9.99 µg/mL, P<0.001). Furthermore, lower plasma GPx3 was identified as an independent predictor (HR=4.528, P=0.046) for poor overall survival post-transplantation. Over-expression of GPx3 significantly suppressed migration, invasiveness and metastasis of HCC cells. Real-time intravital imaging showed that GPx3 significantly suppressed HCC invasiveness in a live animal. GPx3 suppressed the tumor invasiveness through inhibition of JNK-cJun-MMP2 pathway. Conclusion: GPx3 may possess prognostic and therapeutic value for HCC patients after liver transplantation.