Recent studies have demonstrated that various long non‐coding RNAs (lncRNAs) participate in the gastric cancer (GC) development and metastasis. Some lncRNAs exert their regulatory function by interacting with microRNAs. Here we identified a novel lncRNA RP11‐81H3.2 that was highly expressed in the GC tissue and cell lines. RP11‐81H3.2 knockdown significantly inhibited the proliferation, migration, and invasion of GC cells. Mechanistically, we demonstrated that RP11‐81H3.2 directly interacted with miR‐339 while miR‐339 regulated the HNRNPA1 expression by targeting HRRNPA1 3’‐UTR. RP11‐81H3.2‐miR‐339‐HNRNPA1 interaction network regulated the GC cell proliferation, migration, and invasion. Moreover, our results confirmed that RP11‐81H3.2 knockdown suppressed the tumor growth of GC in a xenograft model in vivo. In summary, the results suggest that RP11‐81H3.2 functions as an oncogene in GC and could be utilized as a promising diagnosis and therapeutic marker for GC treatment.
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