Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.
Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.
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DOI：
10.1111/cas.12348
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发表时间：
2014-03
期刊：
影响因子：
5.7
通讯作者：
Katano M
中科院分区：
文献类型：
--
作者：
Morifuji Y;Onishi H;Iwasaki H;Imaizumi A;Nakano K;Tanaka M;Katano M
胰腺导管腺癌(PDAC)是最致命的恶性肿瘤之一，因为它有很高的转移能力。PDAC被认为处于缺氧状态。因此，为了探讨转移过程的机制，我们在低氧条件下新产生了耐低氧的PDAC细胞3-6个月，并在体内模拟条件下进行了复氧实验。复氧可显著提高PDAC细胞的增殖、侵袭力和致瘤性。Hedgehog(HH)信号转导组分Gli1在复氧后显著增加。Gli1基因敲除可抑制复氧诱导的增殖和致瘤性增加，并通过抑制基质金属蛋白酶(MMP2)和MMP9来降低侵袭性。此外，抑制Sonic HH和Smoothed取消复氧可增加细胞的增殖和侵袭力。这些结果表明，PDAC的转移过程是通过激活HH信号通路来诱导的。因此，HH信号通路可能成为复氧诱导的难治性PDAC转移过程中的治疗靶点。
Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated under hypoxic condition for 3–6 months and reoxygenation experiments were performed using these chronic-hypoxia-resistant PDAC cells in in vivo-mimicking conditions. Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation. A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation. Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9. Moreover, inhibition of Sonic Hh and Smoothened abrogated reoxygenation induced increases in proliferation and invasiveness. These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway. Therefore, the Hh signaling pathway may be a therapeutic target for refractory PDAC in metastatic processes induced by reoxygenation.
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影响因子：
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