microRNA(miR) may function endogenous siRNA and regulate a diversity of cellular function through translational repression. Dysregulations of miR expression are involved in carcinogenesis and progression in various cancers. By combining the miR microarray and genomic DNA-methylation array, we identified an intronic miR, miR-135b, which is up-regulated in high invasive lung cancer cell CL1-5. The promoter region of miR-135b is highly de-methylated in high invasive cells and its expression in the less invasive lung cancer cells can be induced by demethylating agent 5’-aza-CdR treatment. Ectopically expression of miR-135b enhanced cell invasive and migratory ability in vitro as well as the orthotopic tumor growth and lung metastasis activity in vivo, whereas specific inhibition of miR-135b decreased tumor growth and metastatic activities. Using the bioinformatic prediction tools, we identified and confirmed that miR-135b could directly repress the expression of Lzts1 through 3’UTR seed-binding. Ectopically-expressed Lzts1 inhibited cell invasion and migration activity, implicating that miR-135b may promote lung cancer cell metastasis by down-regulating Lzts1. Moreover, high level of miR-135b and low level of Lzts1 expressions were associated with poor overall survival in lung cancer patients. We also showed that the miR-135b expression was regulated by NF-κB signaling-cascade and synergistically induced by co-treatment of 5’-aza-CdR and TNF-α, implying that the abnormal expression of miR-135b in cancers may result from inflammatory stimulation and epigenetic modulation. Our results support that miR-135b is an oncogenic miR that may contribute to lung cancer progression and metastasis. The miR-135b/Lzts1 pathway is a promising therapeutic target of lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2011-3976