MicroRNA-148a-3p suppresses epithelial-to-mesenchymal transition and stemness properties via Wnt1-mediated Wnt/β-catenin pathway in pancreatic cancer.

Although miR-148a-3p has been reported to function as a tumour suppressor in various cancers, the molecular mechanism of miR-148a-3p in regulating epithelial-to-mesenchymal transition (EMT) and stemness properties of pancreatic cancer (PC) cells remains to be elucidated. In the present study, we demonstrated that miR-148a-3p expression was remarkably down-regulated in PC tissues and cell lines. Moreover, low expression of miR-148a-3p was associated with poorer overall survival (OS) in patients with PC. In vitro, gain-of-function and loss-of-function experiments showed that miR-148a-3p suppressed EMT and stemness properties as well as the proliferation, migration and invasion of PC cells. A dual-luciferase reporter assay demonstrated that Wnt1 was a direct target of miR-148a-3p, and its expression was inversely associated with miR-148a-3p in PC tissues. Furthermore, miR-148a-3p suppressed the Wnt/β-catenin pathway via down-regulation of Wnt1. The effects of ectopic miR-148a-3p were rescued by Wnt1 overexpression. These biological functions of miR-148a-3p in PC were also confirmed in a nude mouse xenograft model. Taken together, these findings suggest that miR-148a-3p suppresses PC cell proliferation, invasion, EMT and stemness properties via inhibiting Wnt1-mediated Wnt/β-catenin pathway and could be a potential prognostic biomarker as well as a therapeutic target in PC.

Fu X ，Hong L ，Yang Z ，Tu Y ，Xin W ，Zha M ，Tu S ，Sun G ，Li Y ，Xiao W ... -  《-》

MicroRNA-148a suppresses epithelial-mesenchymal transition and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/β-catenin signaling pathway.

Peng L ，Liu Z ，Xiao J ，Tu Y ，Wan Z ，Xiong H ，Li Y ，Xiao W ... -  《-》

LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

Emerging evidence suggests that dysregulation of long non-coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up-regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up-regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC-like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR-148a-3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/β-catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC-like properties of BCSCs by as a molecular sponge for miR-148a-3p to increase WNT1 expression, offering a new target for breast cancer therapy.

Han L ，Yan Y ，Zhao L ，Liu Y ，Lv X ，Zhang L ，Zhao Y ，Zhao H ，He M ，Wei M ... -  《-》

LncRNA TUG1 contributes to ESCC progression via regulating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Latest studies report that long noncoding RNAs (LncRNAs) play an essential role in diversified pathological processes of ESCC, although the mechanism by which they do so remains unknown. This study aimed to explore the parts of lncRNA taurine upregulated gene 1 (TUG1) in ESCC tissues and cells, its biofunctional effect and its underlying regulatory mechanism in ESCC. The levels of TUG1 and miR-148a-3p were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in ESCC cells and tissues. The biofunctional effects were examined by MTT, flow cytometry, and transwell assay. The protein expression levels of epithelial-mesenchymal transition (EMT)-related proteins and MCL-1 were determined by western blot analysis. The binding sites between miR-148a-3p and TUG1 or MCL-1 were predicted by online software starBase and confirmed by dual luciferase reporter assay. The mRNA expression of TUG1 was significantly upregulated in ESCC tissues or cells, and was negatively correlated to miR-148a-3p expression in tissues. Knockdown of TUG1 inhibited the proliferation, migration, and invasion, promoted apoptosis, and relieved the EMT progression in EC9706 and OE19 cells. Besides, knockdown of miR-148a-3p inverted positive effects from TUG1 deletion on ESCC cells. Besides, MCL-1 reversed the inhibitive effects from TUG1 deletion on expression of EMT-associated proteins (Wnt1, C-myc, CyclinD1, and β-catenin) above subsequently. TUG1 regulated the biofunction and EMT progression of ESCC by mediating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro.

Tang Y ，Yang P ，Zhu Y ，Su Y ... -  《-》

MicroRNA-1275 induces radiosensitization in oesophageal cancer by regulating epithelial-to-mesenchymal transition via Wnt/β-catenin pathway.

Acquired radioresistance is one of the main obstacles for the anti-tumour efficacy of radiotherapy in oesophageal cancer (EC). Recent studies have proposed microRNAs (miRNAs) as important participators in the development of radioresistance in various cancers. Here, we investigated the role of miR-1275 in acquired radioresistance and epithelial-mesenchymal transition (EMT) in EC. Firstly, a radioresistant cell line KYSE-150R was established, with an interesting discovery was observed that miR-1275 was down-regulated in KYSE-150R cells compared to the parental cells. Functionally, miR-1275 inhibition elevated radioresistance in KYSE-150 cells via promoting EMT, whereas enforced expression of miR-1275 increased radiosensitivity in KYSE-150R cells by inhibiting EMT. Mechanically, we demonstrated that miR-1275 directly targeted WNT1 and therefore inactivated Wnt/β-catenin signalling pathway in EC cells. Furthermore, WNT1 depletion countervailed the promoting effect of miR-1275 suppression on KYSE-150 cell radioresistance through hampering EMT, whereas WNT1 overexpression rescued miR-1275 up-regulation-impaired EMT to reduce the sensitivity of KYSE-150R cells to radiation. Collectively, our findings suggested that miR-1275 suppressed EMT to encourage radiosensitivity in EC cells via targeting WNT1-activated Wnt/β-catenin signalling, providing a new therapeutic outlet for overcoming radioresistance of patients with EC.

Xie C ，Wu Y ，Fei Z ，Fang Y ，Xiao S ，Su H ... -  《-》