In vivo evidence that RBM5 is a tumour suppressor in the lung

• Published in: Scientific reports Vol. 7; no. 1; pp. 16323 - 8
• Main Authors: Jamsai, Duangporn, Watkins, D. Neil, O’Connor, Anne E., Merriner, D. Jo, Gursoy, Selen, Bird, Anthony D., Kumar, Beena, Miller, Alistair, Cole, Timothy J., Jenkins, Brendan J., O’Bryan, Moira K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-11-2017; Nature Publishing Group
• Subjects: 631/80/304; 692/4028/67/1612/1350; Adenocarcinoma; Animals; Carcinogens; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromosome 3; Cigarette smoking; Clonal deletion; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Genes, Tumor Suppressor - physiology; Humanities and Social Sciences; Humans; Lung - metabolism; Lung - pathology; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mice; multidisciplinary; Ribonucleic acid; Risk factors; RNA; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Tobacco; Tumor cell lines; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors
• ISSN: 2045-2322; 2045-2322
• 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.