SCF/c-KIT Signaling Increased Mucin2 Production by Maintaining Atoh1 Expression in Mucinous Colorectal Adenocarcinoma.
SCF/c-KIT Signaling Increased Mucin2 Production by Maintaining Atoh1 Expression in Mucinous Colorectal Adenocarcinoma.
复制标题
SCF/c-KIT 信号通过维持粘液性结直肠腺癌中 Atoh1 的表达来增加 Mucin2 的产生
DOI：
10.3390/ijms19051541
复制
发表时间：
2018-05-22
影响因子：
5.6
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Shen P;Yang S;Sun H;Li G;Wu B;Ji F;Sun T;Zhou D
黏液性结直肠腺癌（MCA）患者往往表现出高的恶性潜能和较差的生存率。鉴于MCA的病理特征和肿瘤生物学特征与其丰富的细胞外黏液蛋白2 （MUC2）相关，我们有兴趣研究在高激活的干细胞因子(SCF)/c-KIT信号通路下促进MUC2产生的关键因素，我们认为这有助于MCA的形成。长期氮氧甲烷和葡聚糖硫酸钠治疗仅在野生型（WT）小鼠中成功诱导了37周和43周的MCA，而所有c-kit功能缺失突变小鼠（Wadsm/m）都发生了非MCA。值得注意的是，与非MCA小鼠相比，MCA小鼠MUC2及其关键转录因子Atoh1 （Atoh1）显著表达。Atoh1在体外受外源性SCF或过表达c-KIT刺激的结直肠癌（CRC）细胞中显著升高，而通过伊马替尼阻断SCF/c-KIT信号传导而降低。此外，Atoh1蛋白水平的维持是由于糖原合成酶激酶3β (p-GSK3β)的失活，由于活化的SCF/c- kit蛋白激酶B （AKT）信号传导。从ONCOMINE数据库和CRC患者中获得了类似的结果。总之，我们认为SCF/c-KIT信号通过维持Atoh1的表达来促进MUC2的产生和MCA的肿瘤发生。因此，靶向相关关键分子可能有利于MCA患者的治疗。
Mucinous colorectal adenocarcinoma (MCA) patients often a show high risk of malignant potential and a poorer survival rate. Given that the pathological feature and oncobiological characteristics of MCA are correlated with its abundant extracellular mucin2 (MUC2), we paid interest toward investigating the key factor that promotes MUC2 production exposure to highly-activated stem cell factor (SCF)/c-KIT signaling, which we believed to contribute to MCA formation. Long-term azoxymethane and dextran sodium sulfate treatment successfully induced MCA only in wild-type (WT) mice at week 37 and 43, while all c-kit loss-of-function mutant mice (Wadsm/m) developed non-MCA. Significantly, MUC2 and its key transcriptional factor Atonal homologue 1 (Atoh1) were remarkably expressed in MCA mice compared with non-MCA mice. Atoh1 was significantly elevated in colorectal cancer (CRC) cells stimulated by exogenous SCF or overexpressing c-KIT in vitro, while decreased by the blockage of SCF/c-KIT signaling with Imatinib. Furthermore, the maintained Atoh1 protein level was due to the inactive glycogen synthase kinase 3β (p-GSK3β) by virtue of the activated SCF/c-KIT-Protein Kinase B (AKT) signaling. Similar results were obtained from the ONCOMINE database and CRC patients. In conclusion, we suggested that SCF/c-KIT signaling promoted MUC2 production and MCA tumorigenesis by maintaining Atoh1 expression. Therefore, targeting the related key molecules might be beneficial for treating MCA patients.
登录
查看更多内容
影响因子：
5.2
作者：
Inamura K
通讯作者：
Inamura K
影响因子：
9
作者：
Nitsche U;Zimmermann A;Späth C;Müller T;Maak M;Schuster T;Slotta-Huspenina J;Käser SA;Michalski CW;Janssen KP;Friess H;Rosenberg R;Bader FG
通讯作者：
Bader FG
影响因子：
2.9
作者：
Mutoh, H;Sakamoto, H;Sugano, K
通讯作者：
Sugano, K
影响因子：
3.1
作者：
Hosseini S;Bananzadeh AM;Salek R;Zare-Bandamiri M;Kermani AT;Mohammadianpanah M
通讯作者：
Mohammadianpanah M
影响因子：
3.7
作者：
Inamura K;Yamauchi M;Nishihara R;Kim SA;Mima K;Sukawa Y;Li T;Yasunari M;Zhang X;Wu K;Meyerhardt JA;Fuchs CS;Harris CC;Qian ZR;Ogino S
通讯作者：
Ogino S