Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Sci. 2011 Jun;102(6):1144-50. doi: 10.1111/j.1349-7006.2011.01912.x. Epub 2011 Mar 15.
The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.
刺猬 (Hh) 信号通路在包括胰腺导管腺癌在内的各种类型的癌症中被激活。已经表明，肿瘤组织中存在极低的氧张力（低于 1% O2），包括胰腺导管腺癌细胞（PDAC），并增加 PDAC 的侵袭性。为了研究 Hh 通路对低氧诱导的侵袭性的贡献，我们研究了低氧如何影响 Hh 通路的激活和 PDAC 的侵袭性。在本研究中，三种人胰腺导管腺癌系在常氧（20% O2）或低氧（1% O2）条件下培养。低氧上调 Sonic hedgehog (Shh)、Smoothened (Smo)、Gli1 和基质金属蛋白酶 9 (MMP9) 的转录，并增加 PDAC 的侵袭性。重要的是，添加重组 Shh (rhShh) 或 Shh 的沉默都不会影响这些基因的转录和 PDAC 的侵袭性。另一方面，Smo 的沉默降低了 Gli1 和 MMP9 的转录和 PDAC 的侵袭性。Gli1 或 MMP9 的沉默降低了 PDAC 的侵袭性。这些结果表明，低氧通过增加 Smo 的转录以非配体依赖的方式激活 PDAC 的 Hh 通路，并增加 PDAC 的侵袭性。
