Fas signaling induces stemness properties in colorectal cancer by regulation of Bmi1.

Fas signaling promotes colorectal cancer (CRC) metastasis by inducing epithelial-mesenchymal transition (EMT). The acquisition of EMT properties in turn induces stemness but the mechanism by which Fas signaling contributes to it still remains unclear. Hence, the aim of this study was to investigate how Fas signaling regulates CRC stemness. For this purpose, soft agar assay, sphere formation assay, cell survival analysis, immunoblot, qRT-PCR, chromatin immunoprecipitation, and luciferase reporter assay were performed. Expression of FasL, Bmi1, and the miR-200c in CRC specimens was examined through immunohistochemistry, qRT-PCR, and immunoblot. In our study, Fas signaling induced stem cell properties in CRC specimens, relying on ERK1/2 MAPK pathway, with Bmi1 being mainly responsible for FasL-induced stemness. FasL treatment promoted Bmi1 expression by inhibiting miR-200c, which targets Bmi1 3'UTR region. Furthermore, FasL-induced Zeb1 binded with miR-200c promoter and inhibited its expression. Moreover, FasL-induced β-catenin nuclear expression promoted Zeb1 expression by binding with Zeb1 promoter. GSK-3β, which regulates β-catenin, was inhibited by FasL-induced ERK1/2 MAPK signaling. Finally, FasL and Bmi1 expression in clinical samples increased during CRC progression, and a positive correlation between them was observed. Patients with high FasL and Bmi1 expression had a worse prognosis than patients with low expression. In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK-3β/β-catenin/Zeb1/miR-200c axis, suggesting that Fas signaling-based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.

Chen J ，Wang Y ，Zhuo L ，Liu Z ，Liu T ，Li W ，Cai Y ，Zheng H ... -  《-》

Glycogen synthase kinase-3 beta regulates Snail and β-catenin expression during Fas-induced epithelial-mesenchymal transition in gastrointestinal cancer.

Fas signalling has been shown to induce the epithelial-mesenchymal transition (EMT) to promote gastrointestinal (GI) cancer metastasis, but its mechanism of action is still unknown. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signalling on GI cancer cells were tested using invasion assay, immunofluorescence, immunoblot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), quantitative Real-time PCR (qRT-PCR), immunoprecipitation and luciferase reporter assay. Immunohistochemistry was used to analyse the EMT-associated molecules in GI cancer specimens. FasL treatment inhibited E-cadherin transcription by upregulation of Snail in GI cancer cells. The nuclear expression and transcriptional activity of Snail and β-catenin were increased by inhibitory phosphorylation of glycogen synthase kinase-3 beta (GSK-3β) at Ser9 by FasL-induced extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling. Snail associated with β-catenin in the nucleus and, thus, increased β-catenin transcriptional activity. Evaluation of human GI cancer specimens showed that the expression of FasL, phospho-GSK-3β, Snail and β-catenin increase during GI cancer progression. An EMT phenotype was shown to correlate with an advanced cancer stage, and a non-EMT phenotype significantly correlated with a better prognosis. Collectively, these data indicate that GSK-3β regulates Snail and β-catenin expression during Fas-induced EMT in gastrointestinal cancer.

Zheng H ，Li W ，Wang Y ，Liu Z ，Cai Y ，Xie T ，Shi M ，Wang Z ，Jiang B ... -  《-》

Down regulation of miR200c promotes radiation-induced thymic lymphoma by targeting BMI1.

The miR-200c has recently been implicated in the epithelial to mesenchymal transition (EMT) process by directly target the EMT related transcriptional factors ZEB1 and ZEB2. The expression of this miRNA is inversely correlated with tumorgenecity and invasiveness in several human cancers. However, little is known about the expression and targets of the miR-200c in radiation carcinogenesis. Here in this study, using a split radiation induced thymic lymphoma (RITL) model in BALB/c mice, we found that miR-200c is down-regulated in RITL samples. Cell death and apoptosis in lymphoma cells was induced by miR-200c mimic while decreased by miR-200c inhibitor. Computational analysis found a putative target site of miR-200c in the 3'UTR of one of the polycomb group (PcG) protein BMI1 mRNA, which was verified by a luciferase reporter assay. Forced over-expression of miR-200c decreased the level of BMI1 protein and moreover, over-expression of BMI1 rescued the biological effects of miR-200c, indicating BMI1 is a direct mediator of miR-200c functions. Furthermore, the BMI1 expression level was up-regulated and inversely correlated with miR-200c in RITL samples. Finally, our data also indicates that Adenovirus over-expression of pre-miR-200c reduced tumorgenesis in vivo. Taken together, we conclude that down-regulated expression of miR-200c and up-regulation of its direct target BMI1 in radiation-induced thymic lymphoma, which may indicate a novel therapeutic method for RITL through induction of miR-200c or inhibition of BMI1.

Cui J ，Cheng Y ，Zhang P ，Sun M ，Gao F ，Liu C ，Cai J ... -  《-》

RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1.

Zhang M ，Miao F ，Huang R ，Liu W ，Zhao Y ，Jiao T ，Lu Y ，Wu F ，Wang X ，Wang H ，Zhao H ，Ju H ，Miao S ，Wang L ，Song W ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Long noncoding RNA SNHG12 induces proliferation, migration, epithelial-mesenchymal transition, and stemness of esophageal squamous cell carcinoma cells via post-transcriptional regulation of BMI1 and CTNNB1.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors around the world. Numerous studies have revealed the function of long noncoding RNAs (lncRNAs) in cancers, including ESCC. In this study, lncRNA small nucleolar RNA host gene 12 (SNHG12), mainly distributed in ESCC cell cytoplasm, was overexpressed in ESCC specimens and CD133+ cells. In CD133- ESCC cells, SNHG12 overexpression promoted cell proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness and SNHG12 silencing led to opposite results. Furthermore, SNHG12 sequestered miR-6835-3p and induced the proto-oncogene, polycomb ring finger (BMI1). SNHG12 also enhanced the stability of CTNNB1, the mRNA encoding β-catenin, via recruiting insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in ESCC. Rescue assays indicated that CTNNB1 and BMI1 were targets for SNHG12 to regulate ESCC cell proliferation, migration, EMT, and stemness. Furthermore, SOX4 (sex-determining region Y-box 4) bound with the SNHG12 promoter to transcriptionally activate SNHG12 in ESCC. Finally, in vivo data showed SNHG12 knockdown retarded tumorigenesis and metastasis in ESCC. In summary, SNHG12 induces proliferation, migration, EMT, and stemness of ESCC cells via post-transcriptional regulation of BMI1 and CTNNB1, indicating that targeting SNHG12 might be a novel target for ESCC treatment.

Wu D ，He X ，Wang W ，Hu X ，Wang K ，Wang M ... -  《-》