Xu Xiuling, Chen Wenshu, Leng Shuguang, Padilla Mabel T, Saxton Bryanna, Hutt Julie, Tessema Mathewos, Kato Kosuke, Kim Kwang Chul, Belinsky Steven A, Lin Yong
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest DR. SE, Albuquerque, NM 87108, USA and.
Department of Otolaryngology, University of Arizona College of Medicine, Tucson, AZ 86715, USA.
Carcinogenesis. 2017 Jun 1;38(6):604-614. doi: 10.1093/carcin/bgx039.
Mucin 1 (MUC1) is a tumor antigen that is aberrantly overexpressed in various cancers, including lung cancer. Our previous in vitro studies showed that MUC1 facilitates carcinogen-induced EGFR activation and transformation in human lung bronchial epithelial cells (HBECs), which along with other reports suggests an oncogenic property for MUC1 in lung cancer. However, direct evidence for the role of MUC1 in lung carcinogenesis is lacking. In this study, we used the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J mouse lung tumor model to investigate the effect of whole-body Muc1 knockout (KO) on carcinogen-induced lung carcinogenesis. Surprisingly, lung tumor multiplicity was significantly increased in Muc1 KO compared to wild-type (WT) mice. The EGFR/AKT pathway was unexpectedly activated, and expression of the EGFR ligand epiregulin (EREG) was increased in the lung tissues of the Muc1 KO compared to the WT mice. EREG stimulated proliferation and protected against cigarette smoke extract (CSE)-induced cytotoxicity in in vitro cultured human bronchial epithelial cells. Additionally, we determined that MUC1 was expressed in human fibroblast cell lines where it suppressed CSE-induced EREG production. Further, suppression of MUC1 cellular activity with GO-201 enhanced EREG production in lung cancer cells, which in turn protected cancer cells from GO-201-induced cell death. Moreover, an inverse association between MUC1 and EREG was detected in human lung cancer, and EREG expression was inversely associated with patient survival. Together, these results support a promiscuous role of MUC1 in lung cancer development that may be related to cell-type specific functions of MUC1 in the tumor microenvironment, and MUC1 deficiency in fibroblasts and malignant cells results in increased EREG production that activates the EGFR pathway for lung carcinogenesis.
粘蛋白1（MUC1）是一种肿瘤抗原，在包括肺癌在内的多种癌症中异常过度表达。我们之前的体外研究表明，MUC1促进致癌物诱导的人肺支气管上皮细胞（HBECs）中的表皮生长因子受体（EGFR）激活和转化，这与其他报告一起表明MUC1在肺癌中具有致癌特性。然而，缺乏MUC1在肺癌发生中作用的直接证据。在本研究中，我们使用4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J小鼠肺癌模型来研究全身Muc1基因敲除（KO）对致癌物诱导的肺癌发生的影响。令人惊讶的是，与野生型（WT）小鼠相比，Muc1基因敲除小鼠的肺肿瘤多发性显著增加。EGFR/AKT通路意外激活，与WT小鼠相比，Muc1基因敲除小鼠肺组织中EGFR配体表皮调节素（EREG）的表达增加。EREG刺激体外培养的人支气管上皮细胞增殖并保护其免受香烟烟雾提取物（CSE）诱导的细胞毒性。此外，我们确定MUC1在人成纤维细胞系中表达，在其中它抑制CSE诱导的EREG产生。此外，用GO-201抑制MUC1细胞活性可增强肺癌细胞中EREG的产生，这反过来又保护癌细胞免受GO-201诱导的细胞死亡。此外，在人肺癌中检测到MUC1与EREG之间呈负相关，并且EREG表达与患者生存率呈负相关。总之，这些结果支持MUC1在肺癌发展中具有混杂作用，这可能与MUC1在肿瘤微环境中的细胞类型特异性功能有关，并且成纤维细胞和恶性细胞中的MUC1缺乏导致EREG产生增加，从而激活EGFR通路促进肺癌发生。
