Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.
Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.
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DOI：
10.1371/journal.pone.0058935
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Merchant JL
中科院分区：
文献类型：
--
作者：
El-Zaatari M;Kao JY;Tessier A;Bai L;Hayes MM;Fontaine C;Eaton KA;Merchant JL
胃中的慢性炎症诱导化生，即在炎症驱动的肿瘤转化之前的癌前病变。虽然Hedgehog信号传导有助于一些癌症的发生，但其在胃转化中的作用仍然不清楚。我们发现，螺杆菌感染的C57 BL/6小鼠在感染后6个月出现广泛的粘液细胞化生，但在感染后2个月则没有。胃上皮化生与CD 45 +MHCII+ CD 11b + CD 11 c+髓样细胞的出现相一致，这些细胞在2个月时通常不存在于慢性胃炎中。骨髓调节基因Schlafen-4在比较感染的WT与Gli 1缺失小鼠的微阵列分析中被鉴定，并且在CD 11b + CD 11 c+骨髓群体中表达。此外，该相同群体表达IL-1β和TNFα促炎细胞因子。6个月时，粘液颈细胞化生（SPEM）表达IL-6，磷酸化STAT 3和增殖标记Ki 67。在Gli 1突变小鼠中未观察到表达，这与Gli 1诱导这种肿瘤前表型的要求一致。单独的异位Shh配体表达不足以诱导SPEM，但与螺杆菌感染协同增加炎症的组织学严重程度。因此，Hedgehog信号传导是必需的，但不足以在慢性胃炎期间产生肿瘤前变化。Gli 1依赖的髓样细胞分化在髓样细胞亚型的出现中起着关键作用，表面上是SPEM发育所需的。此外，它表明，能够靶向这种表型转换的疗法可能会阻止化生的进展，化生是在异型增生和胃癌之前发生的癌前变化，这也发生在由慢性炎症引发的其他上皮源性瘤形成中。
Chronic inflammation in the stomach induces metaplasia, the pre-cancerous lesion that precedes inflammation-driven neoplastic transformation. While Hedgehog signaling contributes to the initiation of some cancers, its role in gastric transformation remains poorly defined. We found that Helicobacter-infected C57BL/6 mice develop extensive mucous cell metaplasia at 6 month but not at 2 months post-infection. Gastric metaplasia coincided with the appearance of CD45+MHCII+CD11b+CD11c+ myeloid cells that were normally not present in the chronic gastritis at 2 months. The myeloid regulatory gene Schlafen-4 was identified in a microarray analysis comparing infected WT versus Gli1 null mice and was expressed in the CD11b+CD11c+ myeloid population. Moreover this same population expressed IL-1β and TNFα pro-inflammatory cytokines. By 6 months, the mucous neck cell metaplasia (SPEM) expressed IL-6, phosphorylated STAT3 and the proliferative marker Ki67. Expression was not observed in Gli1 mutant mice consistent with the requirement of Gli1 to induce this pre-neoplastic phenotype. Ectopic Shh ligand expression alone was not sufficient to induce SPEM, but with Helicobacter infection synergistically increased the histologic severity observed with the inflammation. Therefore Hedgehog signaling is required, but is not sufficient to generate pre-neoplastic changes during chronic gastritis. Gli1-dependent myeloid cell differentiation plays a pivotal role in the appearance of myeloid cell subtypes ostensibly required for SPEM development. Moreover, it suggests that therapies capable of targeting this phenotypic switch might prevent progression to metaplasia, the pre-neoplastic change that develops prior to dysplasia and gastric cancer, which also occurs in other epithelial-derived neoplasias initiated by chronic inflammation.
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影响因子：
29.4
作者：
El-Zaatari M;Zavros Y;Tessier A;Waghray M;Lentz S;Gumucio D;Todisco A;Merchant JL
通讯作者：
Merchant JL
影响因子：
50.3
作者：
Quante M;Bhagat G;Abrams JA;Marache F;Good P;Lee MD;Lee Y;Friedman R;Asfaha S;Dubeykovskaya Z;Mahmood U;Figueiredo JL;Kitajewski J;Shawber C;Lightdale CJ;Rustgi AK;Wang TC
通讯作者：
Wang TC
影响因子：
7.6
作者：
Shiotani, A.;Iishi, H.;Merchant, J. L.
通讯作者：
Merchant, J. L.
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel