MUC15 Inhibits Dimerization of EGFR and PI3K-AKT Signaling and Is Associated With Aggressive Hepatocellular Carcinomas in Patients
MUC15 Inhibits Dimerization of EGFR and PI3K-AKT Signaling and Is Associated With Aggressive Hepatocellular Carcinomas in Patients
复制标题
MUC15 抑制 EGFR 和 PI3K-AKT 信号转导的二聚化，并与患者的侵袭性肝细胞癌相关
DOI：
10.1053/j.gastro.2013.08.009
复制
发表时间：
2013-12-01
期刊：
影响因子：
29.4
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Wang, Ruo-Yu;Chen, Lei;Wang, Hong-Yang
背景与目标
MUC 15的异常表达与结直肠腺癌的发生发展相关，并且已有报道MUC 15可以防止人胎盘滋养层细胞的侵袭。然而，关于MUC 15在肝细胞癌（HCC）发病机制中的作用知之甚少。
方法
我们分析了从2006年1月至2009年9月在中国上海接受肝切除术的313例患者的HCC样本和匹配的非肿瘤肝组织（对照）。信使RNA和蛋白质的水平通过免疫组织化学、定量逆转录聚合酶链反应和免疫印迹分析来确定。使用统计分析将MUC 15水平与肿瘤特征和患者结果相关联。
结果
MUC 15信使RNA和蛋白质的水平在HCC样品中比对照组织中降低的百分比更大。MUC 15水平降低的肿瘤比MUC 15水平低的肿瘤更可能具有侵袭性特征（例如，高水平的甲胎蛋白、血管浸润、缺乏包膜和分化差）。肿瘤MUC 15水平降低的患者的总生存时间较短（24个月vs高MUC 15水平肿瘤患者的46个月）和疾病复发时间。MUC 15在HCC细胞系（SMMC-7721和HCC-LM 3）中的稳定表达降低了它们在体外的增殖和侵袭特征，以及在小鼠中形成转移性肿瘤的能力。MUC 15减少基质金属蛋白酶2和7的转录，增加金属蛋白酶-2的组织抑制剂的表达，这需要磷酸肌醇3-激酶-v-akt鼠胸腺瘤病毒癌基因同源物信号传导。MUC 15和表皮生长因子受体之间的物理相互作用导致其在早期内体中的重新定位和降解，并且是磷酸肌醇3-激酶-v-akt小鼠胸腺瘤病毒癌基因同源物信号转导失活所需的。
结论
HCC中MUC 15水平降低与患者生存时间缩短和疾病复发时间缩短相关。MUC 15在HCC细胞中的表达通过诱导表皮生长因子受体二聚化和通过v-akt小鼠胸腺瘤病毒癌基因同源物减少磷酸肌醇3-激酶信号传导来降低其体外和小鼠中的攻击行为。
BACKGROUND & AIMS
Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC).
METHODS
We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes.
RESULTS
Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling.
CONCLUSIONS
Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.