BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood.MethodsUsing a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc.134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses.ResultsThe ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5′- and 3′-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408–1867 nt) binds to CUL4A (592–759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4A-mediated ubiquitination of LATS1 and increases YAPS127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAPS127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining.ConclusionsOur study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0449-4) contains supplementary material, which is available to authorized users.

Upregulation of matrix metalloproteinase MMP-14 (MT1-MMP) is associated with poor prognosis in cancer patients, but it is unclear how MMP-14 becomes elevated in tumors. Here we show that miR-181a-5p is downregulated in aggressive human breast and colon cancers where its levels correlate inversely with MMP-14 expression. In clinical specimens, enhanced expression of MMP-14 was observed in cancer cells located at the invasive front of tumors where miR-181a-5p was downregulated relative to adjacent normal cells. Bioinformatics analyses defined a potential miR-181a-5p response element within the 3' untranslated region (UTR) of MMP-14 that was validated in reporter gene experiments. Ectopic miR-181a-5p reduced MMP-14 expression, whereas miR-181a-5p attenuation elevated MMP-14 expression. In support of a critical relationship between these two genes, miR-181a-5p-mediated reduction of MMP-14 levels was sufficient to decrease cancer cell migration, invasion and activation of pro-MMP-2. Further, this reduction in MMP-14 levels was sufficient to reduce in vivo invasion and angiogenesis in chick chorioallantoic membrane assays. Taken together, our results establish the regulation of MMP-14 in cancers by miR-181a-5p through a post-transcriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis.

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