The School of Biological Sciences, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia.
The Development and Stem Cells Program of Monash Biomedicine Discovery Institute, 19 Innovation Walk, Clayton, Victoria, 3800, Australia.
Sci Rep. 2017 Nov 24;7(1):16323. doi: 10.1038/s41598-017-15874-9.
Cigarette smoking is undoubtedly a risk factor for lung cancer. Moreover, smokers with genetic mutations on chromosome 3p21.3, a region frequently deleted in cancer and notably in lung cancer, have a dramatically higher risk of aggressive lung cancer. The RNA binding motif 5 (RBM5) is one of the component genes in the 3p21.3 tumour suppressor region. Studies using human cancer specimens and cell lines suggest a role for RBM5 as a tumour suppressor. Here we demonstrate, for the first time, an in vivo role for RBM5 as a tumour suppressor in the mouse lung. We generated Rbm5 loss-of-function mice and exposed them to a tobacco carcinogen NNK. Upon exposure to NNK, Rbm5 loss-of-function mice developed lung cancer at similar rates to wild type mice. As tumourigenesis progressed, however, reduced Rbm5 expression lead to significantly more aggressive lung cancer i.e. increased adenocarcinoma nodule numbers and tumour size. Our data provide in vivo evidence that reduced RBM5 function, as occurs in a large number of patients, coupled with exposure to tobacco carcinogens is a risk factor for an aggressive lung cancer phenotype. These data suggest that RBM5 loss-of-function likely underpins at least part of the pro-tumourigenic consequences of 3p21.3 deletion in humans.
吸烟无疑是肺癌的一个危险因素。此外，染色体 3p21.3 上有基因突变的吸烟者，该区域在癌症中经常缺失，尤其是在肺癌中，患有侵袭性肺癌的风险显著增加。RNA 结合基序 5（RBM5）是 3p21.3 肿瘤抑制区域的组成基因之一。使用人类癌症标本和细胞系的研究表明，RBM5 作为肿瘤抑制因子发挥作用。在这里，我们首次在小鼠肺部证明了 RBM5 作为肿瘤抑制因子的体内作用。我们生成了 Rbm5 功能丧失型小鼠，并将其暴露于烟草致癌剂 NNK 中。在接触 NNK 后，Rbm5 功能丧失型小鼠的肺癌发病率与野生型小鼠相似。然而，随着肿瘤发生的进展，Rbm5 表达的减少导致更具侵袭性的肺癌，即增加腺癌结节数量和肿瘤大小。我们的数据提供了体内证据，表明大量患者中发生的 RBM5 功能降低，加上接触烟草致癌剂，是侵袭性肺癌表型的一个危险因素。这些数据表明，RBM5 功能丧失很可能至少部分解释了人类 3p21.3 缺失的促肿瘤发生后果。
