Yi Feng-Tao, Lu Qi-Ping
Department of Radiotherapy, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, Hubei 430070, P.R. China.
Department of General Surgery, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, Hubei 430070, P.R. China.
Oncol Lett. 2017 Dec;14(6):7571-7576. doi: 10.3892/ol.2017.7119. Epub 2017 Oct 3.
Mucin 1 (MUC1) is aberrantly overexpressed in numerous human cancer types, including hepatocellular carcinoma (HCC) and contributes to chemoresistance of tumor cells. The aim of the present study was to evaluate the possible implication of MUC1 in radioresistance of HCC cells and the underlying mechanisms. It was demonstrated that MUC1 was significantly upregulated in HCC cells following irradiation exposure, which was coupled with increased phosphorylation of signal transducer and activator of transcription 3 (STAT3). Enforced expression of MUC1 significantly (P<0.05) promoted the clonogenic survival of HCC cells following irradiation compared with empty vector-transfected cells. MUC1 overexpression resulted in >60% reduction in apoptosis induced by irradiation, as determined by Annexin-V/propidium iodide double staining and flow cytometry analysis. Furthermore, overexpression of MUC1 significantly (P<0.05) attenuated the activation of caspase-3 and poly (ADP-ribose) polymerase in response to irradiation exposure. Mechanistically, MUC1 inhibited irradiation-induced apoptosis through activation of janus kinase 2 (JAK2) and STAT3, and induction of anti-apoptotic proteins induced myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and BCL2 like 1 (Bcl-xL). Small hairpin RNA-mediated knockdown of STAT3 or MUC1 resensitized MUC1-overexpressing cells to irradiation-induced apoptosis, which was accompanied by reduced expression of Bcl-xL and Mcl-1. Collectively, MUC1 contributes to radioresistance of HCC cells likely through activation of the JAK2/STAT3 signaling pathway and thus represents a potential target for improving radiotherapy against HCC.
粘蛋白1（MUC1）在包括肝细胞癌（HCC）在内的多种人类癌症类型中异常过表达，并导致肿瘤细胞的化疗耐药性。本研究的目的是评估MUC1在HCC细胞放射抗性中的可能作用及其潜在机制。结果表明，照射后HCC细胞中MUC1显著上调，同时信号转导和转录激活因子3（STAT3）的磷酸化增加。与空载体转染细胞相比，MUC1的强制表达显著（P<0.05）促进了照射后HCC细胞的克隆存活。通过膜联蛋白V/碘化丙啶双染色和流式细胞术分析确定，MUC1过表达导致照射诱导的细胞凋亡减少>60%。此外，MUC1的过表达显著（P<0.05）减弱了照射后caspase-3和聚（ADP-核糖）聚合酶的激活。机制上，MUC1通过激活janus激酶2（JAK2）和STAT3以及诱导抗凋亡蛋白髓样白血病细胞分化蛋白Mcl-1（Mcl-1）和BCL2样1（Bcl-xL）来抑制照射诱导的细胞凋亡。小发夹RNA介导的STAT3或MUC1敲低使MUC1过表达细胞对照射诱导的细胞凋亡重新敏感，同时伴随着Bcl-xL和Mcl-1表达的降低。总之，MUC1可能通过激活JAK2/STAT3信号通路促进HCC细胞的放射抗性，因此代表了改善HCC放射治疗的潜在靶点。
