Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia
Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia
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DOI：
10.1111/cas.12236
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发表时间：
2013-10-01
期刊：
影响因子：
5.7
通讯作者：
Nagano, Osamu
中科院分区：
文献类型：
--
作者：
Wada, Takeyuki;Ishimoto, Takatsugu;Nagano, Osamu
癌症发生之前通常会出现癌前病变。在胃癌发生过程中，胃上皮的慢性炎症和组织病理学进展导致化生的发展并最终导致腺癌。细胞表面蛋白 CD44，尤其是其变体同工型 (CD44v)，与胃化生癌序列进展有关。我们最近发现CD44v与癌细胞中胱氨酸转运系统xc(-)的亚基xCT相互作用并稳定xCT，从而增加胱氨酸的摄取并赋予体内对各种类型细胞应激的抵抗力。然而，CD44v 和 xCT 在癌前病变发展中的功能相关性仍不清楚。我们现在已经研究了 CD44v-xCT 系统在胃癌小鼠模型中表达解痉多肽的化生 (SPEM) 发展中的作用。发现CD44v在SPEM中从头表达，并且与CD44v(-)细胞相比，CD44v(+)化生细胞表现出xCT表达上调。 CD44 的基因消融或柳氮磺吡啶（xCT 依赖性胱氨酸转运抑制剂）治疗可抑制 SPEM 的发展以及随后的胃肿瘤生长。因此，针对 CD44v-xCT 的治疗可有效预防或减弱 CD44v 依赖性的癌前病变和癌症的发展。
Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia-carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(-), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v(+) metaplastic cells manifested upregulation of xCT expression compared with CD44v(-) cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v-xCT could thus prove effective for prevention or attenuation of the CD44v-dependent development of preneoplastic lesions and cancer.