BackgroundLong noncoding RNAs (lncRNAs) have emerged as critical regulators in a variety of human cancers, including gastric cancer (GC). However, the function and mechanisms responsible for these molecules in GC are not fully understood. In our previous study, we found that GC associated lncRNA HOXA11-AS is significantly upregulated in GC tissues. Over-expressed HOXA11-AS promotes GC cells proliferation and invasion through scaffolding the chromatin modification factors PRC2, LSD1 and DNMT1.MethodsHOXA11-AS expression levels in GC cells was detected by quantitative real-time PCR (qPCR). HOXA11-AS siRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate HOXA11-AS expression. In vitro and in vivo assays were performed to investigate the functional role of HOXA11-AS in GC cells cell cycle progression, invasion and metastasis. RIP and ChIP assays were used to determine the mechanism of HOXA11-AS’s regulation of underlying targets.ResultsWe found that knockdown of HOXA11-AS induced GC cells G0/G1 phase arrest and suppressed GC cells migration, invasion and metastasis in vivo. Moreover, mechanistic investigation showed that HOXA11-AS could interact with WDR5 and promote β-catenin transcription, bind with EZH2 and repress P21 transcription, and induce KLF2 mRNA degradation via interacting with STAU1.ConclusionsTaken together, these findings show that HOXA11-AS not only could promote GC cells migration and invasion in vitro, but also promotes GC cells metastasis in vivo, at least in part, by regulating β-catenin and KLF2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0651-6) contains supplementary material, which is available to authorized users.

Lad is an SH2 domain-containing adaptor protein that binds MEK kinase 2 (MEKK2), a mitogen-activated protein kinase (MAPK) kinase kinase for the extracellular signal-regulated kinase 5 (ERK5) and JNK pathways. Lad and MEKK2 are in a complex in resting cells. Antisense knockdown of Lad expression and targeted gene disruption of MEKK2 expression results in loss of epidermal growth factor (EGF) and stress stimuli-induced activation of ERK5. Activation of MEKK2 and the ERK5 pathway by EGF and stress stimuli is dependent on Src kinase activity. The Lad-binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2, and expression of this motif blocks Lad-MEKK2 interaction, resulting in inhibition of Src-dependent activation of MEKK2 and ERK5. JNK activation by EGF is similarly inhibited by loss of Lad or MEKK2 expression and by blocking the interaction of MEKK2 and Lad. Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF, MEKK2 expression is required for ERK5 activation by Src, Lad and MEKK2 association is required for Src activation of ERK5, and EGF and Src stimulation of ERK5-regulated MEF2-dependent promoter activity requires a functional Lad-MEKK2 signaling complex.Extracellular signal-regulated kinase 5 (ERK5)/big mitogenactivated kinase 1 is a member of the mitogen-activated protein kinase (MAPK) family. Efforts to define the ERK5 signaling module have led to the identification of MEK5 as a specific ERK5 kinase (61). Sequence comparisons indicate that MEK5 is most related to the ERK1/2 kinases MEK1 and MEK2 (42). However, MEK5 is not significantly phosphorylated by the MEK1/2 kinase Raf-1 or MEKK1, nor does MEK5 phosphorylate ERK1/2 or JNK (13), indicating that MEK5/ ERK5 represents a distinct MAPK signaling cascade. The ERK5 pathway has been implicated in stress response and growth factor-promoted cell growth and survival (1,20). In neurons, blocking ERK5 activation diminished retrograde survival responses initiated by neurotrophin stimulation of axon terminals (56). A recent study showed that expression of an activated form of MEK5 resulted in serial assembly of sarcomeres in cardiomyocytes and eccentric cardiac hypertrophy in transgenic mice, suggesting a role for the MEK5/ERK5 module in mediating cytokine signaling associated with cardiac hypertrophy (36). ERK5 activates the MADS box transcription factors MEF2A, -C, and -D (19, 21, 28) and the Ets-domain transcription factor Sap1a (18). One consequence of activation of the MEF2 proteins is to induce c-jun expression that is essential for cell growth and cell cycle progression (7,19,21,23,28). Additionally, ERK5 regulates muscle cell differentiation via a mechanism probably involving MEF2 proteins and myocyte-specific activators such as MyoD (12).We and others have recently demonstrated that the two highly homologous MEK kinases, MEKK2 and -3, specifically interact with MEK5 and activate the ERK5 pathway (8, 49). Significantly, we found that MEKK2 is much more potent than MEKK3 in ERK5 activa...

Background/Aims: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs, a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tRNA-derived fragments and trastuzumab resistance is still unknown. Methods: We detected the levels of tRNA-derived fragments expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed fragments in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tRNA-derived fragments. Progression-free survival (PFS) was analyzed using Cox-regression. Results: Our sequence results showed that tRNA-derived fragments were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression were associated with significantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Conclusion: Our results suggest that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN play important roles in trastuzumab resistance. Patients with high levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these molecules. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.