Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer.
Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer.
复制标题
Sonic Hedgehog 通路对于维持人类胃癌中的癌症干细胞样细胞至关重要。
DOI：
10.1371/journal.pone.0017687
复制
发表时间：
2011-03-04
期刊：
影响因子：
3.7
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Song Z;Yue W;Wei B;Wang N;Li T;Guan L;Shi S;Zeng Q;Pei X;Chen L
Sonic hedgehog（SHH）通路的异常激活已在多种人类癌症和癌症干细胞（CSCs）中被描述，然而，SHH通路在胃CSCs中的作用尚未报道。在这项研究中，我们研究了SHH通路的异常激活维持胃CSC特征的可能性。首先，我们使用肿瘤球培养从人胃癌细胞系（HGC-27、MGC-803和MKN-45）中鉴定了癌症干细胞样细胞（CSLCs）。与贴壁细胞相比，漂浮瘤球细胞具有更强的自我更新能力和耐药性。表达肿瘤干细胞标志物（CD 44、CD 24和CD 133）的细胞在肿瘤球细胞中也显著多于贴壁细胞。更重要的是，体内异种移植研究表明，肿瘤可以用2×104个肿瘤球细胞产生，这比粘附细胞接种肿瘤所需的细胞少100倍。RT-PCR和Western blot结果显示，SHH通路靶基因Ptch和Gli 1在肿瘤球细胞中的表达水平明显高于贴壁细胞。实时荧光定量PCR检测结果与RT-PCR和Western blot结果相似。进一步分析表明，SHH通路被环巴胺或5E 1阻断后，HGC-27肿瘤球细胞的自我更新能力比贴壁细胞的自我更新能力降低更明显。我们还发现，SHH通路阻断强烈增强化疗药物在体外和体内HGC-27肿瘤球细胞中的疗效，但对贴壁细胞没有显着影响。最后，我们从胃癌标本中分离出肿瘤球，这些细胞也具有化疗耐药性和致瘤能力，SHH通路保持了原发性肿瘤标本中肿瘤球细胞的胃CSLCs特征。总之，我们的数据表明，SHH通路是必不可少的维持人类胃癌CSLCs。
Abnormal activation of the Sonic hedgehog (SHH) pathway has been described in a wide variety of human cancers and in cancer stem cells (CSCs), however, the role of SHH pathway in gastric CSCs has not been reported. In this study, we investigated the possibility that abnormal activation of the SHH pathway maintained the characteristics of gastric CSCs. First, we identified cancer stem-like cells (CSLCs) from human gastric cancer cell lines (HGC-27, MGC-803 and MKN-45) using tumorsphere culture. Compared with adherent cells, the floating tumorsphere cells had more self-renewing capacity and chemoresistance. The cells expressing CSCs markers (CD44, CD24 and CD133) were also significantly more in tumorsphere cells than in adherent cells. More importantly, in vivo xenograft studies showed that tumors could be generated with 2×104 tumorsphere cells, which was 100-fold less than those required for tumors seeding by adherent cells. Next, RT-PCR and Western blot showed that the expression levels of Ptch and Gli1 (SHH pathway target genes) were significantly higher in tumorsphere cells than in adherent cells. The results of quantitative real-time PCR were similar to those of RT-PCR and Western blot. Further analysis revealed that SHH pathway blocked by cyclopamine or 5E1 caused a higher reduction in self-renewing capacity of HGC-27 tumorsphere cells than that of adherent cells. We also found that SHH pathway blocking strongly enhanced the efficacy of chemotherapeutic drugs in HGC-27 tumorsphere cells in vitro and in vivo but had no significant effect in adherent cells. Finally, we isolated the tumorspheres from gastric cancer specimen, these cells also had chemoresistance and tumorigenic capacity, and SHH pathway maintained the gastric CSLCs characteristics of tumorsphere cells from primary tumor samples. In conclusion, our data suggested that SHH pathway was essential for maintenance of CSLCs in human gastric cancer.
登录
查看更多内容
影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
影响因子：
7.3
作者：
Suzuki, H;Minegishi, Y;Hibi, T
通讯作者：
Hibi, T
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
DOI：
10.1073/pnas.0307618100
发表时间：
2004-01-20
影响因子：
11.1
作者：
Kondo, T;Setoguchi, T;Taga, T
通讯作者：
Taga, T
影响因子：
4
作者：
Kang, Soo Kyung;Park, Jong Bae.;Cha, Seung Heun.
通讯作者：
Cha, Seung Heun.