Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses β-catenin nuclear translocation and decreases the occupancy of β-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3β. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH2-terminal domain can completely abolish NDRG2-dependent differentiation induction. Supporting the biological significance of the reciprocal relationship between NDRG2 and Skp2, an NDRG2low/Skp2high gene expression signature correlates with poor CRC patient outcome and could be considered as a diagnostic marker of CRCs.

Increasing studies showed that long noncoding RNAs (lncRNAs) had crucial regulatory roles in various tumors, including gastric cancer (GC). Recent studies demonstrated that lncRNA nicotinamide nucleotide transhydrogenase‐antisense RNA1 (NNT‐AS1) played an important role in several tumors. However, the role and expression of NNT‐AS1 in GC progression remain unknown. In our study, we indicated that NNT‐AS1 expression was upregulated in GC samples compared with the nontumor tissues. We also showed that NNT‐AS1 expression was upregulated in the GC cell lines. Ectopic expression of NNT‐AS1 promoted GC cell line HGC‐27 cell proliferation, cell cycle progression, and invasion. In addition, we showed that NNT‐AS1 acted as a sponge competing endogenous RNA for microRNA‐363 (miR‐363), which was downregulated in the GC samples and cell lines. miR‐363 expression was negatively related with NNT‐AS1 expression in GC samples. Upregulated expression of miR‐363 suppressed GC cell growth, cycle, and invasion. Furthermore, we reported that elevated expression of NNT‐AS1 promoted GC cell proliferation, cycle, and invasion partly by suppressing miR‐363 expression. These results indicated that lncRNA NNT‐AS1 acted as an oncogene in the development of GC partly by inhibiting miR‐363 expression.

No abstract

miR-26a is known to play an important oncosuppressive role in HCC. However, its regulatory role and relationship with other non-coding RNAs is less clear. In the present study, we report that the expression levels of miR-26a and long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) were frequently downregulated in HCC tissues compared to matched non-malignant tissues. In addition, the expression levels of miR-26a and MEG3 were negatively correlated with the tumor sizes and TNM clinical stage in HCC patients. Overexpression of miR-26a significantly reduced the capacity of proliferation, invasion and migration of HCC cells. Moreover, we demonstrated that DNA methyltransferase 3b (DNMT3B) was a direct target gene of miR-26a. Overexpression of miR-26a suppressed the expression level of DNMT3B. Inhibited expression of DNMT3B showed similar tumor suppressive effects induced by miR-26a upregulation, and resulted in the upregulation of MEG3. Furthermore, we found that the expression levels of DNMT3B were upregulated in the HCC tissues compared with non-malignant tissues, and it was inversely correlated with miR-26a and MEG3 in HCC tissues. Thus, these results provided a plausible link between the observed reduction of miR-26a and MEG3 in HCCs. Together, the present study added miR-26a/DNMT3B/MEG3 axis to the complex mechanisms of HCC development.