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Sci Rep
2017 Nov 24;71:16323. doi: 10.1038/s41598-017-15874-9.
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In vivo evidence that RBM5 is a tumour suppressor in the lung.
Jamsai D
,
Watkins DN
,
O'Connor AE
,
Merriner DJ
,
Gursoy S
,
Bird AD
,
Kumar B
,
Miller A
,
Cole TJ
,
Jenkins BJ
,
O'Bryan MK
.
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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.
Figure 1. Generation and characterisation of the Rbm5 gene trap mouse line. (a) The Rbm5 gene trap mouse line: The U3neoSVFS gene-trapped cassette was inserted into intron 1 of the Rbm5 gene (ENSMUSG00000032580). This produced a truncated Rbm5 mRNA containing exon 1 (ENSMUSE00000371436), resulting in the production of truncated Rbm5 mRNA and no protein production (null allele). SA: Splicing acceptor site; Neo: Neomycin resistance gene; Poly A: Polyadenylation signal. (b) Distribution of genotypes of progeny from heterozygous knockout breeding pairs at embryonic day 18.5 (E18.5), day of birth (Day 0) and at 3 weeks. WT: wild type; HET: heterozygous knockout; KO: homozygous knockout. (c) Verification of gene trapping efficient by RT-PCR on E18.5 lung using primers Ex1-Fw (5′-CTCCTGCTTTGTTCCCTCTG-3′) and Ex4-Rev (5′-CCATCTTCAGACCGGTCACT-3′). The WT allele expected PCR product is 298 bp and no products for the competed gene trap KO allele. -RT: negative control (no reverse transcriptase). (d,e) Quantitative PCR (qPCR) was performed to measure Rbm5 mRNA expression levels in adult lung (D) and adult testis (E) samples. n = 3 per genotype, 8 weeks old. Data is expressed as mean ± SD. Statistical significance for all analyses was determined using a two-tailed student t-test.
Figure 2. RBM5 localised to type II alveolar epithelial cells (AECs) and Clara cells. The localisation of RBM5 in the adult lung (8 weeks old) was determined by immunofluorescence using a RBM5 mouse monoclonal antibody as described previously17. (a,b) RBM5 localised to Clara cells as indicated by double staining for RBM5 (red) and CC10 (green). (c,d
) RBM5 localised to type II alveolar epithelial cells (AECs) as indicated by double staining of RBM5 (red) and Pro-surfactant protein C (SPC, in green). Insets = negative controls (no primary antibody). Scare bars = 20 μm.
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