Adenocarcinoma is the most common type of lung cancer. Epithelial-mesenchymal transition (EMT) is required for tumor invasion/metastasis and the components that control this process are potential therapeutic targets. This study we examined the role of Gli in lung adenocarcinoma and whether its activation regulates metastasis through EMT in lung adenocarcinoma. We found that tumors with high Gli expression had significantly lower E-Cadherin expression in two independent cohorts of patients with lung adenocarcinoma that we studied. In vitro up-regulation of SHh resulted in increased cell migration while small molecule inhibitors of Smo or Gli significantly reduced cell mobility both in a wound healing assay and in a 3D cell invasion assay. Inhibition of Gli in vivo decreased tumor growth and induced an increase in E-Cadherin expression. Our results indicate that Gli may be critical for lung adenocarcinoma metastasis and that a novel Gli inhibitor shows promise as a therapeutic agent by preventing cell migration and invasion in vitro and significantly reducing tumor growth and increasing E-Cadherin expression in vivo.

Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC.

Exosomes have recently emerged as a pivotal mediator of many physiological and pathological processes. However, the role of exosomes in proliferative vitreoretinopathy (PVR) has not been reported. In this study, we aimed to investigate the role of exosomes in PVR. Transforming growth factor beta 2 (TGFß-2) was used to induce epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, as an in vitro model of PVR. Exosomes from normal and EMTed RPE cells were extracted and identified. We incubated extracted exosomes with recipient RPE cells, and co-cultured EMTed RPE cells and recipient RPE cells in the presence of the exosome inhibitor GW4869. Both experiments suggested that there are further EMT-promoting effects of exosomes from EMTed RPE cells. MicroRNA sequencing was also performed to identify the miRNA profiles in exosomes from both groups. We identified 34 differentially expressed exosomal miRNAs (P <. 05). Importantly, miR-543 was found in exosomes from EMTed RPE cells, and miR-543-enriched exosomes significantly induced the EMT of recipient RPE cells. Our study demonstrates that exosomal miRNA is differentially expressed in RPE cells during EMT and that these exosomal miRNAs may play pivotal roles in EMT induction. Our results highlight the importance of exosomes as cellular communicators within the microenvironment of PVR.

The proliferation of retinal pigment epithelium (RPE) cells resulting from an epithelial-mesenchymal transition (EMT) plays a key role in proliferative vitreoretinopathy (PVR), which leads to complex retinal detachment and the loss of vision. Genes of Snail family encode the zinc finger transcription factors that have been reported to be essential in EMT during embryonic development and cancer metastasis. However, the function of Snail in RPE cells undergoing EMT is largely unknown.

The role of microRNA (miRNA) in proliferative vitreoretinopathy (PVR) progression has not been studied extensively, especially in retinal pigment epithelial-mesenchymal transition (EMT) which is the main reason for formation of PVR. In this study, we first investigated the miRNA expression profile in transforming growth factor beta 1 (TGF-β1) mediated EMT of ARPE-19 cells. Among the five changed miRNAs, miR-29b showed the most significant downregulation. Enhanced expression of miR-29b could reverse TGF-β1 induced EMT through targeting Akt2. Akt2 downregulation could inhibit TGF-β1-induced EMT. Furthermore, inhibition of miR-29b in ARPE-19 cells directly triggered EMT process, which characterized by the phenotypic transition and the upregulation of α-smooth muscle actin (α-SMA) and downregulation of E-cadherin and zona occludin-1 (ZO-1) with increased cell migration. Akt2-shRNA also inhibited miR-29 inhibitor-induced EMT process. These data indicate that miR-29b plays an important role in TGF-β1-mediated EMT in ARPE-19 cells by targeting Akt2.

Proliferative vitreoretinopathy (PVR), a serious vision-threatening complication of retinal detachment (RD), is characterized by the formation of contractile fibrotic membranes, in which epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a major event. Recent studies suggest an important role of bone morphogenetic protein 4 (BMP4) in the suppression of fibrosis. In this study, we aimed to investigate the role of BMP4 in the pathological process of PVR, particularly in the EMT of RPE cells. We found that BMP4 and its receptors were co-labelled with cytokeratin and α-SMA positive cells within the PVR membrane. Moreover, the mRNA and protein expression levels of BMP4 were decreased whereas BMP4 receptors ALK2, ALK3 and ALK6 were increased during TGF-β-induced EMT in primary RPE cells. Exogenous BMP4 inhibited TGF-β-induced epithelial marker down-regulation, as well as mesenchymal marker up-regulation at both the mRNA and protein levels in RPE cells. In addition, BMP4 treatment attenuated the TGF-β-induced gel contraction, cell migration and Smad2/3 phosphorylation. However, knockdown of endogenous BMP4 stimulated changes in EMT markers. Our results confirm the hypothesis that BMP4 might inhibit TGF-β-mediated EMT in RPE cells via the Smad2/3 pathway and suppress contraction. This might represent a potential treatment for PVR.

Proliferative vitreoretinopathy (PVR) is a disease that causes severe blindness and is characterized by the formation of contractile fibrotic subretinal or epiretinal membranes. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a hallmark of PVR. This work aims to examine the role of a long noncoding RNA (lncRNA) named EMT-related lncRNA in RPE (ERLR, LINC01705-201 (ENST00000438158.1)) in PVR and to explore the underlying mechanisms. In this study, we found that ERLR is upregulated in RPE cells stimulated with transforming growth factor (TGF)-β1 as detected by lncRNA microarray and RT-PCR. Further studies characterized full-length ERLR and confirmed that it is mainly expressed in the cytoplasm. In vitro, silencing ERLR in RPE cells attenuated TGF-β1-induced EMT, whereas overexpressing ERLR directly triggered EMT in RPE cells. In vivo, inhibiting ERLR in RPE cells reduced the ability of cells to induce experimental PVR. Mechanistically, chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor TCF4 directly binds to the promoter region of ERLR and promotes its transcription. ERLR mediates EMT by directly binding to MYH9 protein and increasing its stability. TCF4 and MYH9 also mediate TGF-β1-induced EMT in RPE cells. Furthermore, ERLR is also significantly increased in RPE cells incubated with vitreous PVR samples. In clinical samples of PVR membranes, ERLR was detected through fluorescent in situ hybridization (FISH) and colocalized with the RPE marker pancytokeratin (pan-CK). These results indicated that lncRNA ERLR is involved in TGF-β1-induced EMT of human RPE cells and that it is involved in PVR. This finding provides new insights into the mechanism and treatment of PVR.

To study the role of long non-coding RNA (lncRNA) MALAT1 in transforming growth factor beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells.

Neuropilin-1 (NRP1) binds to many ligands and co-receptors and affects cell survival and migration, which is essential for tumor progression. However, there are still largely unknowns about how NRP1 affects the epithelial-mesenchymal transition (EMT)-related malignant progression in gastric cancer.

BRD7 is a tumor suppressor known to inhibit cell proliferation and cell cycle progression and initiate apoptosis in breast cancer. However, the function and underlying molecular events of BRD7 in tumor invasion and metastasis in breast cancer are not fully understood.

Metastasis is the major cause of prostate cancer (PCa)-related mortality. Epithelial-mesenchymal transition (EMT) is a vital characteristic feature that empowers cancer cells to adapt and survive at the beginning of metastasis. Therefore, it is essential to identify the regulatory mechanism of EMT in metastatic prostate cancer (mPCa) and to develop a novel therapy to block PCa metastasis. Here, we discovered a novel PCa metastasis oncogene, DEP domain containing 1B (DEPDC1B), which was positively correlated with the metastasis status, high Gleason score, advanced tumor stage, and poor prognosis. Functional assays revealed that DEPDC1B enhanced the migration, invasion, and proliferation of PCa cells in vitro and promoted tumor metastasis and growth in vivo. Mechanistic investigations clarified that DEPDC1B induced EMT and enhanced proliferation by binding to Rac1 and enhancing the Rac1-PAK1 pathway. This DEPDC1B-mediated oncogenic effect was reversed by a Rac1-GTP inhibitor or Rac1 knockdown. In conclusion, we discover that the DEPDC1B-Rac1-PAK1 signaling pathway may serve as a multipotent target for clinical intervention in mPCa.

Epithelial-mesenchymal transition (EMT) is characterized by a decreased expression of E-cadherin and an increased expression of vimentin, which is associated with poor prognosis in rectal cancer. This study aimed to explore the feasibility of using multi-parameter diffusion and perfusion magnetic resonance imaging (MRI) to evaluate the expression of E-cadherin and vimentin.

Although recent evidence shows that long noncoding RNAs (lncRNAs) are involved in the regulation of gene expression and cancer progression, the understanding of the role of lncRNAs in lung cancer metastasis is still limited. To identify novel lncRNAs in non-small cell lung cancer (NSCLC), we profile NSCLC tumor and matched normal samples using GeneChip® Human Gene 2.0 ST Array, which provides the most accurate, sensitive, and comprehensive measurement of protein coding and lncRNA transcripts. We identified a panel of key factors dysregulated in lung cancer. Among them, the expression of FOXF1-AS1 was significantly downregulated in lung cancer. Stable overexpression of FOXF1-AS1 inhibits lung cancer cell migration and invasion by regulating EMT. Meanwhile, loss of FOXF1-AS1 mediates stem-like properties of lung cancer cells. Interestingly, we found that FOXF1-AS1 physically associates with PRC2 components EZH2 and loss of FOXF1-AS1 mediates cell migration and stem-like properties require EZH2. Loss of FOXF1-AS1 is also correlated with downregulation of FOXF1 in lung cancer. These results suggested that FOXF1-AS1 might regulate EMT, stemness and metastasis of NSCLC cells via EZH2, indicating it as a therapeutic target for future treatment of NSCLC.

Methionine sulfoxide reductase B1 (MsrB1) is a member of the selenoprotein family, which contributes to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS) by redox processes in energy pathways. However, few studies have examined the role of MsrB1 in human hepatocellular carcinoma (HCC). We observed that MsrB1 is highly expressed in HCC tissues and that its expression correlated with the prognoses of patients with HCC after hepatectomy. In vitro, knockdown of MsrB1 inhibits HCC cell growth by MTT and EdU proliferation assay, and MsrB1 interference enhances H2O2/trx-induced apoptosis. We observed that phosphorylation of the key proteins of the MAPK pathway, namely, ERK, MEK, and p53, was inhibited, but PARP and caspase 3 were increased, thus infecting mitochondrial integrity. In vivo, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown reduced HCC cell migration and invasion in a transwell assay through inhibition of cytoskeletal rearrangement and spread. This change was linked to epithelial-mesenchymal transition (EMT) inhibition resulting from increases in E-cadherin expression and decreases in expression in TGF-β1, Slug, MMP-2/9, and so on. MsrB1 regulates HCC cell proliferation and migration by modulating the MAPK pathway and EMT. Thus, MsrB1 may be a novel therapeutic target with respect to the treatment of HCC.

Methionine sulfoxide reductase B1 (MsrB1), a member of the selenoprotein family and contributes significantly to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS). However, few studies have examined the role of MsrB1 in tumors. Here We tested the proliferation and invasion in MsrB1 knockdown u2os cells under H2O2/thioredoxin. As shown in our result, knockdown of MsrB1 inhibited the proliferation of u2os cells and regulates mitogen-activated protein kinase (MAPK) pathway by down-regulation of Erk, MeK phosphorylation and p53 expression in u2os cells. In a xenograft tumorigenicity mice, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown resulted in migration and invasion reducement of u2os cells. MsrB1 regulates epithelial-mesenchymal transition (EMT) via affecting cytoskeleton by increasing E-cadherin expression and decreasing N-cadherin, TGF-β1, slug, fibronectin, vimentin, c-myc, snail and β-catenin expressions. In vivo, MsrB1 shRNAi can inhibit lung metastasis in metastasis model. In conclusion, MsrB1 regulates proliferation and invasion of u2os cells by affecting MAPK pathway and EMT, and MsrB1 gene may be a novel therapeutic target against tumors.

G protein nucleolar 3 (GNL3), a nucleolar GTP-binding protein, is highly expressed in progenitor cells, stem cells, and various types of cancer cells. Therefore, it is considered to have an important role in cancer pathogenesis. GNL3 has been reported to play crucial roles in cell proliferation, cell cycle regulation, inhibition of differentiation, ribosome biogenesis, and the maintenance of stemness, genome stability and telomere integrity. Furthermore, GNL3 has recently been shown to be involved in cancer invasion and metastasis. However, the biological significance of GNL3 in the invasion and metastasis of colon cancer remains unclear. This study was performed to address this gap in knowledge. GNL3 expression was upregulated in colon cancer tissue specimens and correlated with tumor differentiation, invasion and metastasis. GNL3 overexpression promoted cell proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) in colon cancer cells. Moreover, inhibition of the EMT and the Wnt/β‑catenin signaling pathway induced by GNL3 knockdown was partially reversed by lithium chloride (LiCl). Based on these data, GNL3 promotes the EMT in colon cancer by activating the Wnt/β‑catenin signaling pathway. In summary, GNL3 is upregulated in colon cancer and plays an important role in tumor growth, invasion and metastasis. Strategies targeting GNL3 are potential treatments for colon cancer.

To explore whether dihydroartemisinin (DHA) can block interleukin (IL)-6-induced epithelial-mesenchymal transition (EMT) in laryngeal squamous cell carcinoma (LSCC).

Most of advanced hypopharyngeal squamous cell carcinoma (HSCC) are resistant to chemotherapy, and there is still lack of effective treatment for HSCC now. The present study aimed to investigate whether downregulation of RNA-binding motif protein 17 (RBM17) could enhance cisplatin sensitivity and inhibit cell invasion in HSCC and the underlying mechanism. We observed that RBM17 was upregulated in tumor tissues and associated with poor progression. Treatment of FaDu cells with cisplatin increased RBM17 expression in mRNA levels. Downregulation of RBM17 enhanced cisplatin-mediated inhibition of FaDu cells. In addition, downregulation of RBM17 effectively suppressed tumor cell migration and invasion through the reversion of epithelial-mesenchymal transition. Moreover, downregulation of RBM17 could significantly slow tumor growth in FaDu xenograft tumor model. Liquid chromatography-mass spectrometry/mass spectrometry detection and independent PRM analysis showed that 21 differentially expressed proteins were associated with the downregulation of RBM17. Taken together, our study implied that downregulation of RBM17 could serve as a novel approach to enhance cisplatin sensitivity in HSCC.

Ginsenoside Rh2 (Rh2) is one of the pharmacologically active components of ginseng with an antitumor effect. However, its effect on non-small-cell lung cancer (NSCLC), especially on aerobic glycolysis, which plays a crucial role in the proliferation and progression of tumor cells, has not been characterized. Here, we demonstrated that Rh2 inhibited the proliferation and metastasis of NSCLC cells by promoting apoptosis and suppressing epithelial-mesenchymal transition, respectively. Notably, Rh2 exerted a glycolysis inhibition effect through regulating GLUT1, PKM2, and LDHA, which are key enzymes of the glycolysis process. Furthermore, the metabolic shift function of Rh2 was dependent on the STAT3/c-Myc axis in NSCLC. This novel regulatory role of Rh2 provides a new perspective for NSCLC treatment and highlights the potentiality of Rh2 to be used as a tumor energy blocker. The combination of Rh2 with an STAT3 or c-Myc inhibitor revealed a promising therapeutic approach for patients with NSCLC.

RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.