406894

MIR101-2

Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-beta-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-beta-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.

BACKGROUND: Ovarian cancer (OvCa) is one of the most common malignant diseases of the female reproductive system in the world. The majority of OvCa is diagnosed with metastasis in the abdominal cavity. epithelial-to-mesenchymal transition (EMT) plays a key role in tumor cell metastasis. However, it is still unclear whether long non-coding RNA (lncRNA) is implicated in EMT and influences cell invasion and metastasis in OvCa. RESULTS: In this study, using bioinformatcis analysis, we constructed a lncRNA-mediated competing endogenous RNA (ceRNA) network for mesenchymal OvCa and identified lncRNA AP000695.4, which we named pro-transition associated RNA (PTAR). PTAR was significantly up-regulated in the mesenchymal subtype samples compared with the epithelial subtype samples from the TCGA OvCa data sets. In addition, our study showed that PTAR expression was positively correlated with the expression level of ZEB1 in the mesenchymal OvCa samples. Meanwhile, we found that silencing miR-101 promoted cell migration, whereas the overexpression of miR-101 suppressed EMT and cell migration in OvCa cell lines through the regulation of ZEB1. Further analysis showed that enhanced expression of PTAR promoted EMT and metastasis through the regulation of miR-101, whereas silencing PTAR led to the attenuation of TGF-beta1-induced tumorigenicity in ovarian cancer cells. Mechanistically, we found that PTAR acted as a ceRNA of miR-101, as forced expression of PTAR reduced the expression and activity of miR-101. More importantly, the knockdown of PTAR reduced tumorigenicity and metastasis in vivo. CONCLUSIONS: Taken together, the results from our study highlight a role for the PTAR-miR-101-ZEB1 axis in OvCa, which offers novel strategies for the prevention of metastasis in OvCa.