Recently, a large number of long non-coding RNAs (lncRNAs) have been reported in mammalian genomes and are evolutionarily conserved and presumably function in many biological events, especially in the pathogenesis of diverse human cancers. A lncRNA, named HOST2 (human ovarian cancer-specific transcript 2), was once reported to specifically be expressed at high level in human ovarian cancer. However, how HOST2 acts to regulate gene functions in ovarian carcinogenesis has remained enigmatic. Here we report, for the first time, that HOST2 promotes tumor cell migration, invasion and proliferation in epithelial ovarian cancer by working in key aspects of biological behaviors. In the present study, bioinformatics analysis indicated that HOST2 binds with microRNA let-7b, a potent tumor suppressor, which was then verified to target HOST2. Our results showed that HOST2 harbors a let-7b binding site and modulates let-7b availability by acting as a molecular sponge. HOST2 inhibits let-7b functions, which post-transcriptionally suppress the expression of targets, including some oncogenes that regulate cell growth and motility. Additionally, understanding HOST2/let-7b-dependent regulation may lead to alternative approaches for the diagnosis and cure of this deadly disease.