Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression
Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression
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DOI：
10.1073/pnas.0709307104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Yao, Qizhi
中科院分区：
文献类型：
--
作者：
Li, Min;Zhang, Yuqing;Yao, Qizhi
锌是一种必需的微量元素，也是多种金属酶和转录因子所使用的催化/结构成分。最近的研究表明锌含量可能与癌症风险相关；然而，锌和锌转运体在癌症进展中的确切作用尚不清楚。我们观察到，与周围正常组织相比，锌转运蛋白ZIP4 （SLC39A4）在17例临床胰腺腺癌标本中有16例（94%）明显过表达，并且ZIP4 mRNA在人胰腺癌细胞中的表达明显高于人胰腺导管上皮（HPDE）细胞。这表明ZIP4异常上调可能参与胰腺癌的发病和进展。我们研究了ZIP4过表达对胰腺癌细胞体外增殖和体内胰腺癌进展的影响。我们发现，与对照细胞相比，强迫表达ZIP4增加了细胞内锌水平，体外细胞增殖增加了2倍，肿瘤体积显著增加了13倍。在原位裸鼠模型中，ZIP4过表达不仅使原发肿瘤重量增加（7.2倍），而且增加了腹膜播散和腹水发生率。此外，在ZIP4过表达的肿瘤组织中，细胞增殖增加，锌含量升高。这些数据揭示了ZIP4异常表达在胰腺癌发病和进展中的重要作用。这可能提示了一种靶向ZIP4控制胰腺癌生长的治疗策略。
Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.