Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor
Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor
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DOI：
10.1038/sj.onc.1204106
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发表时间：
2001-01-25
期刊：
影响因子：
8
通讯作者：
Carraway, KL
中科院分区：
文献类型：
--
作者：
Komatsu, M;Jepson, S;Carraway, KL
在人类和大鼠的乳腺肿瘤恶性进展过程中都观察到膜黏蛋白MUC4/唾液酸黏蛋白复合物（SMC）的过度表达，这表明MUC4/SMC表达的失调可能促进这些恶性肿瘤的发展。如先前报道，SMC的过度表达导致肿瘤细胞的细胞黏附和免疫杀伤均受到抑制。SMC还作为ErbB2/Neu的配体，在有和没有调蛋白的情况下调节受体酪氨酸激酶的磷酸化。本研究利用四环素诱导的SMC表达系统在异种移植肿瘤模型中研究了Muc4/SMC上调对原发性肿瘤生长的影响。SMC上调促使转染的A375黑色素瘤在裸鼠中快速生长。然而，SMC的上调并没有显著增加A375细胞在体外的增殖。相反，在SMC过度表达的肿瘤中观察到原位细胞凋亡受到强烈抑制。这些数据表明，Muc4/SMC表达至少部分通过抑制肿瘤细胞凋亡促进体内肿瘤生长。重要的是，在体外也观察到凋亡减少，这表明SMC的抗凋亡作用与肿瘤 - 宿主相互作用无关。这些发现有力地表明，SMC上调改变细胞内信号传导以促进细胞存活，首次为MUC家族基因对程序性细胞死亡的调控提供了证据。
Overexpression of the membrane mucin MUC4/Sialo-mucin complex (SMC) has been observed during malignant progression of mammary tumors in both humans and rats, suggesting that deregulation of MUC4/SMC expression might facilitate development of these malignancies, As previously reported, overexpression of SMC results in suppression of both cell adhesion and immune killing of tumor cells, SMC also acts as a ligand for ErbB2/Neu, modulating phosphorylation of the receptor tyrosine kinase in the presence and absence of heregulin. The present studies investigated the effect of Muc4/SMC up-regulation on primary tumor growth using a tetracycline-inducible SMC expression system in a xenotransplanted tumor model. SMC upregulation provoked rapid growth of transfected A375 melanoma in nude mice. Up-regulation of SMC, however, did not significantly increase proliferation of A375 cells in vitro, Instead, a strong suppression of apoptosis was observed in situ in SMC-overexpressing tumors, These data suggest that Muc4/SMC expression promotes tumor growth in vivo at least in part via suppression of tumor cell apoptosis, Importantly, reduction of apoptosis was also observed in vitro, indicating that anti-apoptotic effect of SMC is independent of tumor-host interactions, These findings strongly suggest that SMC up-regulation alters intracellular signaling to favor cell survival, providing for the first time evidence for the regulation of programmed cell death by a gene of the MUC family.