LIM kinases modulate multiple aspects of cancer development, including cell proliferation and survival. As the mechanisms of LIMK‐associated tumorigenesis are still unclear, we analyzed the tumorigenic functions of LIM kinase 2 (LIMK2) in human bladder cancer (BC) and explored whether the newly identified LIMK2 3´‐UTR SNP rs2073859 (G‐to‐A allele) is correlated with clinical features. Expression levels of LIMK2 in 38 human BC tissues and eight cell lines were examined using quantitative real‐time PCR and immunohistochemistry. LIMK2 was overexpressed in most BC tissues (27/38, 71%) and BC‐derived cell lines (6/8), and was more frequently overexpessed in high‐grade than low‐grade BC (80% vs. 47%). The effects of LIMK2 on BC cell proliferation, survival and migration, were studied by overexpression and RNA interference approaches in vitro and in vivo. LIMK2 overexpression promoted proliferation, migration and invasion of BC cells, while LIMK2 depletion inhibited cell invasion and viability and induced growth arrest in vitro and in vivo. PCR‐Restriction Fragment Length Polymorphism (RFLP) was used to genotype LIMK2 SNP rs2073859 and multivariate logistic regression applied to assess the relationship between allele frequency and clinical features in 139 BC patients. Functional analyses localized SNP rs2073859 within the microRNA‐135a seed‐binding region and revealed significantly lower LIMK2 G allele expression. The frequency of A genotypes (AG + AA) was higher in the BC group than normal controls and correlated with risks of high‐grade and high‐stage BC. In conclusion, LIMK2 may function as an oncogene in human BC, while allele‐specific regulation by microRNA‐135a may influence disease risk.
What's new? Genetic variations in microRNA (miRNA)‐binding regions are suspected to influence tumorigenesis. In this study, in tissues from bladder cancer (BC) patients, the single nucleotide polymorphism rs2073859 (G‐to‐A allele) in the 3’‐UTR miRNA‐135a‐binding site of the oncogene LIM kinase 2 (LIMK2) was associated with gene overexpression and higher clinical grade. A high frequency of rs2073859 A genotypes was detected in BC tissues. In BC cells and mice, LIMK2 overexpression promoted cell proliferation, migration, and invasion and accelerated BC tumor growth. The findings suggest that LIMK2 normally is downregulated by miRNA‐135a and becomes tumorigenic following miRNA‐135a disruption by rs2073859 variant A.