B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation.
B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation.
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DOI：
10.1158/1535-7163.mct-11-0072
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发表时间：
2011-06
影响因子：
5.7
通讯作者：
Tan M
中科院分区：
文献类型：
--
作者：
Liu H;Tekle C;Chen YW;Kristian A;Zhao Y;Zhou M;Liu Z;Ding Y;Wang B;Mælandsmo GM;Nesland JM;Fodstad O;Tan M
在许多类型的癌症中，免疫调节蛋白B7-H3的表达与预后不良有关。以前，我们观察到B7-H3与肿瘤细胞迁移和侵袭之间的联系，在目前的工作中，我们研究了B7-H3在乳腺癌化疗耐药中的作用。我们观察到，通过稳定的shRNA或瞬时的siRNA转染来沉默B7-H3，由于药物诱导的细胞凋亡增强，增加了多个人乳腺癌细胞系对紫杉醇的敏感性。B7-H3的过度表达使癌细胞对该药物产生更强的抗药性。接下来，我们研究了B7-H3介导紫杉醇耐药的机制，发现在B7-H3基因敲除的细胞中，STAT3 Tyr705的磷酸化水平降低，其直接下游靶标Mcl-1和Survivin的表达降低。STAT3上游分子JAK2的磷酸化水平也显著降低。相反，在B7-H3基因敲除和低B7-H3表达的细胞中重新表达B7-H3增加了JAK2和STAT3的磷酸化。体内动物实验表明，B7-H3击倒性移植瘤的生长速度慢于对照异种移植瘤。重要的是，紫杉醇治疗在B7-H3基因敲除肿瘤的小鼠中显示出很强的抗肿瘤活性，但在对照组中只有轻微的效果。综上所述，我们的数据表明，在乳腺癌细胞中，B7-H3至少部分地通过干扰JAK2/STAT3途径诱导紫杉醇耐药。这些结果为B7-H3的功能提供了新的见解，并鼓励设计和测试针对该蛋白质及其合作伙伴的方法。
In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present work we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable shRNA or transient siRNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3 mediated paclitaxel resistance, and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells, along with the expression of its direct downstream targets Mcl-1 and Survivin. The phosphorylation of Jak2, an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3- expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knock down tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong anti-tumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data demonstrate that in breast cancer cells B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners.