Siragusa Mauro, Zerilli Monica, Iovino Flora, Francipane Maria Giovanna, Lombardo Ylenia, Ricci-Vitiani Lucia, Di Gesù Giuseppe, Todaro Matilde, De Maria Ruggero, Stassi Giorgio
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Cancer Res. 2007 Jun 1;67(11):5522-30. doi: 10.1158/0008-5472.CAN-06-4197.
Overexpression of MUC1 oncoprotein is frequently observed in cancer and contributes to confer resistance to genotoxic agents. Papillary, follicular, and anaplastic thyroid carcinomas are the three forms of thyroid epithelial cancer. Anaplastic tumors are less differentiated and extremely aggressive, characterized by a poor prognosis. Little is known about the role of MUC1 in thyroid cancer. We recently showed that autocrine production of interleukin (IL)-4 and IL-10 controls thyroid cancer cell survival, growth, and resistance to chemotherapy through activation of Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) and phosphatidylinositide 3'-OH kinase (PI3K)/Akt pathways. In the present study, we showed that MUC1 COOH-terminal subunit (MUC1-C) is overexpressed in all the histologic variants of thyroid cancer cells and localizes to mitochondria where it interferes with the release of mitochondrial proapoptotic proteins. Moreover, IL-4 and IL-10 promote the increase of MUC1-C expression levels in normal thyroid cells, whereas blockage of both cytokines or neutralization of JAK/STAT and PI3K/Akt pathways through the exogenous expression of SOCS-1 and Akt(K179M) leads to a significant decrease of MUC1-C in primary thyroid cancer cells. Interestingly, down-regulation of MUC1 expression by direct targeting with RNA interference sensitizes anaplastic thyroid cancer cells to chemotherapy-induced apoptosis in vitro. Thus, MUC1 is a main component of the survival network acting in thyroid cancer and could be considered a key molecular target for sensitizing cancer cells to conventional or novel treatments.
黏蛋白1（MUC1）癌蛋白的过表达在癌症中经常被观察到，并且有助于赋予对基因毒性剂的抗性。乳头状、滤泡状和间变性甲状腺癌是甲状腺上皮癌的三种形式。间变性肿瘤分化程度较低且极具侵袭性，预后较差。关于MUC1在甲状腺癌中的作用知之甚少。我们最近表明，白细胞介素（IL）-4和IL-10的自分泌产生通过激活Janus激活激酶/信号转导和转录激活因子（JAK/STAT）以及磷脂酰肌醇3'-OH激酶（PI3K）/Akt途径来控制甲状腺癌细胞的存活、生长和对化疗的抗性。在本研究中，我们表明MUC1羧基末端亚基（MUC1-C）在甲状腺癌细胞的所有组织学变体中均过表达，并定位于线粒体，在那里它干扰线粒体促凋亡蛋白的释放。此外，IL-4和IL-10促进正常甲状腺细胞中MUC1-C表达水平的增加，而通过外源性表达细胞因子信号转导抑制因子1（SOCS-1）和Akt（K179M）阻断这两种细胞因子或中和JAK/STAT和PI3K/Akt途径会导致原发性甲状腺癌细胞中MUC1-C的显著降低。有趣的是，通过RNA干扰直接靶向下调MUC1表达可使间变性甲状腺癌细胞在体外对化疗诱导的凋亡敏感。因此，MUC1是甲状腺癌生存网络的主要组成部分，可被视为使癌细胞对传统或新型治疗敏感的关键分子靶点。
