Acute leukemias (AL) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by co-expression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML M0 or M1), T/myeloid mixed phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell Acute Lymphoblastic Leukemia (T-ALL) (58 ETP, 178 non-ETP, 8 T/M MPAL, 89 not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3,6% of T-ALL) harbouring four types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n=7), t(6;14)(q25.3;q32) (n=9), t(7;14)(q21.2;q32) (n=2) and t(8;14)(q24.2;q32) (n=2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, while the other three rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker, which was present at diagnosis but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently DNMT3A, TET2 and/or WT1 gene. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B positive AL from AML, T-ALL, and ETP-ALL. Remarkably, ex-vivo drug sensitivity profile identified a panel of compounds with effective antileukemic activity.

We aimed to investigate the expression level of long noncoding RNA (lncRNA) zinc finger E-box-binding homeobox two antisense RNA 1 (ZEB2-AS1) in osteosarcoma and explore its possible regulatory mechanisms. Expression of lncRNA ZEB2-AS1 was detected by quantitative real-time PCR in 63 cancerous tissues and 25 adjacent normal mucosal tissues from patients with osteosarcoma. The correlation between the lncRNA ZEB2-AS1 level and clinicopathological characteristics of the osteosarcoma patients were evaluated, and 5-year overall survival (5OS) was also analyzed according to lncRNA ZEB2-AS1 expression. The ZEB2-AS1 and miR-145 recombinant expression vector was used to analyze their relationship in an in vitro cell system. Luciferase reporter gene assays and RNA immunoprecipitation assays were used to verify the interaction between ZEB2-AS1 and miR-145. The proliferation, apoptosis and migration of osteosarcoma cells were determined by Cell counting kit-8 assays, Annexin V-PI assays and transwell assays, respectively. A significantly increased level of lncRNA ZEB2-AS1 with a fold change of 3.86 was found in osteosarcoma tissues compared with control tissues (P < 0.001). The Chi-square test revealed that lncRNA ZEB2-AS1 expression in osteosarcoma was significantly different according to radiology classification (P = 0.018), TNM stage (P = 0.000) and survival status (P = 0.005). The 5OS was 18.4% and 52% in osteosarcoma patients with higher and lower lncRNA ZEB2-AS1 expression, respectively. Significantly increased ZEB2-AS1 expression was found in osteosarcoma cells, while decreased levels of miR-145 were confirmed in osteosarcoma tissues and cell lines compared to controls. Moreover, a negative correlation was found between the expression level of ZEB2-AS1 and miR-145 in osteosarcoma tissues (R = 0.71, P < 0.01). ZEB2-AS1 knockdown resulted in decreased osteosarcoma cell proliferation, increased apoptosis and reduced migration. In addition, negative regulation of miR-145 by ZEB2-AS1 in osteosarcoma cells was also observed, and the effects of ZEB2-AS1 on osteosarcoma cells were found to be regulated by miR-145. Significantly upregulated lncRNA ZEB2-AS1 expression in osteosarcoma patients influences the prognosis of patients, and ZEB2-AS1 accelerates tumorigenesis and osteosarcoma development by downregulating miR-145.

Background: Long noncoding RNAs (lncRNA) represent significant factors of the mammalian transcriptome that mediates varied biological and pathological processes. The liver is the most common site for gallbladder cancer (GBC) distant metastasis and contributes to the majority of GBC-related death. How lncRNA affects GBC metastasis is not completely understood.

Results: A novel lncRNA termed lncGALM (lncRNA in GBC associated with liver metastasis) was discovered to be highly expressed in cancer patients and xenografted tumors with liver metastasis. Elevated lncGALM in GBC patients also correlated to decreased survival. Invasion and migration of GBC cells were enhanced through lncGALM, both in vitro and in vivo. lncGALM functioned as sponges by competitively binding to and inactivating miR-200 family members, which increase epithelial-mesenchymal transition-associated transcription factor ZEB1 and ZEB2, leading to a fibroblastic phenotype and increased expression of N-cadherin. In addition, lncGALM bound to IL-1β mRNA and stabilized the IL-1β gene that mediates liver sinusoidal endothelial cell (LSECs) apoptosis. lncGALM-expressing LiM2-NOZ cells acquired a strong ability to migrate and adhere to LSECs, promoting LSECs apoptosis and therefore facilitating tumor cell extravasation and dissemination.

Conclusions: lncGALM promotes GBC liver metastasis by facilitating GBC cell migration, invasion, liver arrest, and extravasation via the invasion-metastasis cascade. Targeting lncGALM may be protective against the development of liver metastasis in GBC patients.

Keywords: gallbladder cancer; interleukin 1β; liver sinusoidal endothelial cells; lncRNA-lncGALM; miR-200.

Ovarian cancer is a deadly gynecological malignancy with resistance to cisplatin a major clinical problem. We evaluated a role of long non-coding (lnc) RNA HOTTIP (HOXA transcript at the distal tip) in the cisplatin resistance of ovarian cancer cells, using paired cisplatin sensitive and resistant A2780 cells along with the SK-OV-3 cells. HOTTIP was significantly elevated in cisplatin resistant cells and its silencing reversed the cisplatin resistance of resistant cells. HOTTIP was found to sponge miR-205 and therefore HOTTIP silenced cells had higher levels of miR-205. Downregulation of miR-205 could attenuate HOTTIP-silencing effects whereas miR-205 upregulation in resistant cells was found to re-sensitize cells to cisplatin. HOTTIP silencing also led to reduced NF-κB activation, clonogenic potential and the reduced expression of stem cell markers SOX2, OCT4, and NANOG, an effect that could be attenuated by miR-205. Finally, ZEB2 was identified as the gene target of miR-205, thus completing the elucidation of HOTTIP-miR-205-ZEB2 as the novel axis which is functionally involved in the determination of cisplatin resistance in ovarian cancer cells.

Keywords: HOTTIP; ZEB2; cisplatin resistance; miR-205; ovarian cancer.

Background: The clinical relevance of epithelial-to-mesenchymal transition (EMT) in colorectal cancer (CRC) progression has been highlighted over the last decade. Several EMT-inducing transcription factors (EMT-TFs) have been implicated in the regulation of EMT, including Twist, Snail1, Slug, ZEB1, and ZEB2. Here, this meta-analysis aimed to predict the risk of distance metastasis and overall survival in CRC patients with high expression of EMT-TFs.

Materials and methods: All eligible studies were searched in PubMed, Scopus, and Web of Science databases. The search was carried out to include literatures published as late as September 1, 2018. In overall, 16 studies that investigated the relationship between EMT-TFs with distance metastasis and survival in CRC patients were included. In meta-analysis, a pooled hazard ratio (HR) and odds ratio (OR) were estimated for associations.

Results: The results of this review indicated that expressions of all EMT-TFs are significantly correlated with poor overall survival in CRC. Moreover, there are a significant association between Twist (OR, 1.46; 95% confidence interval [CI], 1.03-2.09), Slug (OR, 3.43; 95% CI, 1.98-5.93), and ZEB2 (OR, 2.42; 95% CI, 1.09-5.40) expression with distance metastatic in CRC patients.

Conclusion: These findings suggest that the overexpression of EMT-TFs plays a key role in increasing the risk of distance metastasis as well as decreasing overall survival in CRC patients.

Keywords: Colorectal cancer; distance metastasis; epithelial–mesenchymal transition; overall survival; transcription factors.

Background: Circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, are involved in a variety of diseases, including several types of cancers. We hypothesized that circRNAs are involved in the tumorigenesis and development of clear cell renal cell carcinoma (ccRCC). Methods: To verify our hypothesis, we explored the circRNA expression profiles in 4 pairs of ccRCC tissues and their adjacent non-carcinoma tissues via microarray analysis. Selected circRNAs were further validated by qPCR. Moreover, hsa_circ_0005875 was selected for further study and the potential clinical values of hsa_circ_0005875 were investigated in 60 pairs of ccRCC tissues and adjacent normal controls. In addition, the role of hsa_circ_0005875 in ccRCC progression were performed using colony formation assay, Transwell assay and Martrigel-Transwell assay respectively. Finally, interactions between the circRNAs and miRNAs were predicted using Arraystar's miRNA target prediction software. Luciferase reporter assays were performed to evaluate the interaction between hsa_circ_0005875 and hsa_miR-145-5p. Results: The microarray data showed 1988 circRNAs were significantly dysregulated circRNAs, including 1033 upregulated and 955 downregulated ones in the ccRCC tissues. Hsa_circ_0005875 was confirmed to be significantly upregulated in the ccRCC tumor tissues and renal carcinoma cells. Further analysis revealed that hsa_circ_0005875 expression was associated with tumor size, pathological TNM stage, histological differentiation, and lymphatic metastasis. Functional experiments demonstrated that overexpression of hsa_circ_0005875 increased proliferation, migration and invasion abilities. Moreover, bioinformatics analysis and luciferase reporter assays suggest that hsa_circ_0005875 may serve as a ceRNA (competing endogenous RNA) of miR-145-5p to relieve the repressive effect of miR-145-5p on target ZEB2. Conclusions: These data indicate that hsa_circ_0005875 might play a role in promoting tumor growth and metastasis and be a potential biomarker of ccRCC.

Keywords: biomarker; circRNAs; clear cell renal cell carcinoma; hsa_circ_0005875; miRNA sponge; microarray analysis.

Endometriosis is a benign disease that shares some malignant features. Epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of endometriosis. Metastasis-associated protein 1 (MTA1) plays an important role in various cancers by promoting EMT, yet there are no studies on its function in endometriosis. In the present study, we found that MTA1 was highly expressed in the ectopic endometrium of endometriosis patients and that the expression of MTA1 was related to the revised American Fertility Society stage. MTA1 facilitated endometrial stroma cell proliferation, migration, and invasion by inducing EMT, and the promotion function and MTA1 expression were suppressed by resveratrol, a natural polyphenol. Moreover, we revealed that MTA1 induced EMT through interaction with ZEB2. The findings in a mouse endometriosis model further showed that MTA1 and ZEB2 were upregulated in ectopic tissues and that resveratrol inhibited the growth of ectopic lesions and expression of MTA1 and ZEB2. Taken together, we demonstrate that MTA1 is a protein that promotes EMT via interacting with ZEB2 in the pathogenesis of endometriosis, and may be a target of resveratrol.

Keywords: MTA1; ZEB2; endometriosis; epithelial-mesenchymal transition; resveratrol.

Objective: Esophageal cancer (EC) is one of the most general malignant tumors in humans. There were few studies researching the connections between lncRNA UCA1 and EC. This study is to research the effect of lncRNA UCA1 adsorbing microRNA-498 (miR-498) as a ceRNA to regulate ZEB2 expression on epithelial mesenchymal transition (EMT), invasion and migration of EC cells. Methods: UCA1, miR-498 and ZEB2 expression in EC tissues and cells was detected by RT-qPCR or western blot analysis. EC cells were transfected with siRNA-UCA1, miR-498 mimics or their controls to determine cell colony, proliferation, cycle distribution, apoptosis, migration and invasion by colony formation assay, CCK-8 assay, flow cytometry, and Transwell assay, respectively. The protein expression of PCNA, c-Myc, E-cadherin, N-cadherin, MMP-2 and MMP-9 was detected by Western blot analysis. The growth rate and weight of transplanted tumor in nude mice were observed. Results: There were overly expressed UCA1 and ZEB2 and lowly expressed miR-498 in EC tissues and cells. LncRNA UCA1 acted as ceRNA to inhibit miR-498 expression and thereby increasing ZEB2 expression. With down-regulated UCA1 and up-regulated miR-498, ZEB2 expression, cell proliferation, colony formation, invasion, migration ability, EMT, tumor growth rate and weight in nude mice were apparently reduced. Conclusion: This study demonstrates that inhibited UCA1 up-regulated miR-498 and down-regulated ZEB2, thereby repressing proliferation activity, invasion, migration, and EMT of EC cells.

The current study aimed to summarize the clinical manifestations and identify the epigenetic mechanisms of gastric mucosa associated lymphoid tissue (MALT) lymphoma, as well as evaluate the long-term effects of Helicobacter pylori (H. pylori) eradication. A total of 122 patients with marginal zone B-cell lymphoma of primary gastric MALT lymphoma were enrolled in the present study. The clinical manifestations of gastric MALT lymphoma, including symptoms, H. pylori state and endoscopic type, were summarized. The response to therapy was evaluated in patients that underwent H. pylori eradication. Survival analysis was estimated using the Kaplan-Meier method. The expression of microRNA-383 (miR-383) in tumor tissues and cell lines was determined using reverse transcription quantitative polymerase chain reaction. Furthermore, bioinformatic analyses, luciferase reporter assays. and western blot analysis identified zinc finger E-box binding homeobox 2 (ZEB2) as a direct target gene of miR-383. An MTT assay was used to examine the function of miR-383 and ZEB2 in MALT lymphoma. The clinical symptoms of patients with gastric MALT lymphoma were non-specific and included epigastric pain, abdominal discomfort and bleeding. The majority of endoscopic types were classified as ulcer, erosion and mucosa edema. The H. pylori infection rate was 79.5% (97/122) and a total of 47 patients underwent eradication therapy. Lymphoma remission was achieved in 93.6% (44/47) of patients and complete remission (CR) was achieved in 74.4% (35/47). The median follow-up time was 38 months (range, 10-132 months) and the median time taken to achieve CR was 4 months (range, 3-7 months). The estimated 3-year survival rate was 90.3% and the 5-year survival rate was 76.2%. Therefore, it was determined that patients with stage I or II gastric MALT lymphoma are able to undergo H. pylori eradication as a first-line treatment and that the survival rate of patients undergoing this treatment is high. Furthermore, it was determined that the mechanism by which miR-383 and ZEB2 contribute to MALT lymphoma progression is by the targeting of ZEB2 by miR-383, which inhibits the proliferation of cancer cells.

The hepatitis B virus (HBV) regulatory HBx protein is required for infection, and its binding to cellular damaged DNA binding protein 1 (DDB1) is critical for this function. DDB1 is an adaptor protein for the cullin 4A Really Interesting New Gene (RING) E3 ubiquitin ligase (CRL4) complex and functions by binding cellular DDB1 cullin associated factor (DCAF) receptor proteins that recruit substrates for ubiquitination and degradation. We compared the proteins found in the CRL4 complex immunoprecipitated from uninfected versus HBV-infected hepatocytes from human liver chimeric mice for insight into mechanisms by which HBV and the cell interact within the CRL4 complex. Consistent with its role as a viral DCAF, HBx was found in the HBV CRL4 complexes. In tissue culture transfection experiments, we showed that HBx expression led to decreased levels of known restriction factor structural maintenance of chromosomes protein 6 (SMC6) and putative restriction factors stromal interaction molecule 1 (STIM1, zinc finger E-box binding homeobox 2 (ZEB2), and proteasome activator subunit 4 (PSME4). Moreover, silencing of these proteins led to increased HBV replication in the HepG2-sodium taurocholate cotransporting polypeptide (NTCP) infection model. We also identified cellular DCAF receptors in CRL4 complexes from humanized mice. Increasing amounts of HBx did not reveal competitive DCAF binding to cullin4 (CUL4)-DDB1 in plasmid-transfected cells. Our results suggest a model in which HBx benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.

Cullin4B (CUL4B) is a scaffold protein of the CUL4B-Ring E3 ligase (CRL4B) complex. However, the role of CUL4B in the development of breast cancer remains poorly understood. Here it is shown that CRL4B interacts with multiple histone deacetylase (HDAC)-containing corepressor complexes, including MTA1/NuRD, SIN3A, CoREST, and NcoR/SMRT complexes. It is demonstrated that CRL4B/NuRD(MTA1) complexes cooccupy the E-cadherin and AXIN2 promoters, and could be recruited by transcription factors including Snail and ZEB2 to promote cell invasion and tumorigenesis both in vitro and in vivo. Remarkably, CUL4B responded to transformation and migration/invasion stimuli and is essential for multiple epithelial-mesenchymal transition (EMT) signaling pathways such as hypoxia. Furthermore, the transcription of CUL4B is directedly activated by hypoxia-inducible factor 1α (HIF1α) and repressed by the ERα-GATA3 axis. Overexpressing of CUL4B successfully induced CSC-like properties. Strikingly, CUL4B expression is markedly upregulated during breast cancer progression and correlated with poor prognosis. The results suggest that CUL4B lies at a critical crossroads between EMT and stem cell properties, supporting CUL4B as a potential novel target for the development of anti-breast cancer therapy.

Keywords: CUL4B; HIF1A; breast cancer; cancer stem cell; epithelial‐mesenchymal transition.

Tumor buds in colorectal cancer are hypothesized to undergo a (partial) epithelial-mesenchymal transition (EMT). If so, cytokeratin (CK) and vimentin (VIM) co-expression is expected. CK+/VIM+ can also be found in some stromal cells; however, their origin remains unclear. Here, we determine the frequency of CK+/VIM+ tumor cells and characterize the CK+/VIM+ stroma in colorectal cancer. Three cell populations (CK+, VIM+, CK+/VIM+) were sorted using DepArray and fluorescence-activated cell sorting (FACS). Tumor areas were selected to include tumor center, stroma and tumor budding. Fluorescence microscopy was used to visualize co-expressing cells on whole slides. A next-generation tissue microarray (ngTMA) of matched Pan-CK-positive and -negative stroma was constructed and stained for E-cadherin, VIM, Snail1, Twist1, Zeb1 and Zeb2, COL11A1, SPARC, CD90, α-SMA, FAP and WT1. CK+/VIM+ co-expressing tumor cells were detected using all three methods. With DepArray, only tumor budding areas contained CK+/VIM+ cells. The proportion of CK+/VIM+ tumor cells was low (1.5%-22%). CK+ stroma was associated with aggressive tumor features like distant metastasis (P = .0003), lymphatic invasion (P = .0009) and tumor budding (P = .0084). CK+/VIM+ stroma was characterized by positive WT1 (P < .001), ZEB2 (P < .001), TWIST1 (P = .009), and FAP (P = .003). Our data suggest that CK+/VIM+ tumor cells exist, albeit in low numbers and could represent a subgroup of tumor buds in partial EMT. CK+/VIM+ stroma may be of mesothelial origin and shows features of mesenchymal cells and cancer-associated fibroblasts. These results, together with the association with metastasis point to cells in mesothelial-mesenchymal transition (MMT). This atypical stroma may be a potential target for therapy.

Aim: Understanding the cell types and cell compositions in tumor environment (TME) and the gene changes in lung adenocarcinoma (LUAD) may provide insights on immune profiles and treatment targets for LUAD patients. Materials & methods: The RNA-Seq data from The Cancer Genome Atlas database were used to calculate the stromal scores and immune scores and analyzed the fractions of tumor infiltrating immune cells in LUAD samples with ESTIMATE and CIBERSORT algorithm. Results: We extracted a list of TME-related differentially expressed genes and performed the functional enrichment analysis. We found these genes were mainly enriched in immune response and cancer-related signal pathways. The prognosis analysis indicated that LINC00211, MUC2, LINC00426, LY86-AS1 ZEB2-AS1 and EREG were associated with prognosis in LUAD patients. Conclusion: The current study provides novel insights into immune files and gene changes in TME in LUAD patients.

Keywords: bioinformatics; ceRNA; differentially expressed genes; gene ontology; immune; lung adenocarcinoma; lung cancer; non-small-cell lung cancer; prognosis; tumor microenvironment.

Environmental contaminants exposure may lead to detrimental changes to the microRNAs (miRNAs) expression resulting in several health effects. miRNAs, small non-coding RNAs that regulate gene expression, have multiple transcript targets and thereby regulate several signalling molecules. Even a minor alteration in the abundance of one miRNA can have deep effects on global gene expression. Altered patterns of miRNAs can be responsible for changes linked to various health outcomes, suggesting that specific miRNAs are activated in pathophysiological processes. In this review, we provide an overview of studies investigating the impact of air pollution, organic chemicals, and heavy metals on miRNA expression and the potential biologic effects on humans.Abbreviations: AHRR, aryl-hydrocarbon receptor repressor; AHR, aryl-hydrocarbon receptor; As, arsenic; BCL2, B-cell lymphoma 2; BCL2L11, B-cell lymphoma 2 like 11; BCL6, B-cell lymphoma 6; BPA, bisphenol A; CVD, cardiovascular diseases; CD40, cluster of differentiation 40; CCND1, Cyclin D1; CDKN1A, cyclin-dependent kinase inhibitor 1A; Cr, chromium; CTBP1, C-terminal binding protein 1; CXCL12, C-X-C motif chemokine ligand 12; DAZAP1, deleted in azoospermia associated protein 1; DEP, diesel exhaust particles; EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; EVs, extracellular vesicles; FAK, focal adhesion kinase; FAS, fas cell surface death receptor; FOXO, forkhead box O; HbA1c, glycated hemoglobin; Hg, mercury; HLA-A, human leukocyte antigen A; HMGB, high-mobility group protein B; IFNAR2, interferon alpha receptor subunit 2; IL-6, interleukin-6; IRAK1, interleukin 1 receptor associated kinase 1; JAK/STAT, janus kinase/signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; miRNAs, microRNAs; MVs, microvesicles; NCDs, noncommunicable diseases; NFAT, nuclear factor of activated T cells; NFkB, nuclear factor kappa B; NRF2, nuclear factor, erythroid-derived 2; NRG3, neuregulin 3; O₃, ozone; OP, organophosphorus pesticides; PAHs, polycyclic aromatic hydrocarbons; Pb, lead; PCBs, polychlorinated biphenyls; PDCD4, programmed cell death 4; PDGFB, platelet derived growth factor subunit beta; PDGFR, platelet-derived growth factor receptor; PI3K/Akt, phosphoinositide-3-kinase/protein kinase B; PKA, protein kinase A; PM, particulate matter; PRKCQ, protein kinase C theta; PTEN, phosphatase and tensin homolog; SORT1, sortilin 1; TGFβ, transforming growth factor-β; TLR, toll-like receptor; TNF, tumor necrosis factors; TRAF1, tumor necrosis factors-receptor associated factors 1; TRAP, traffic-related air pollution; TREM1, triggering receptor expressed on myeloid cells 1; TRIAP1, TP53 regulated inhibitor of apoptosis 1; VCAM-1, vascular cell adhesion molecule 1; VEGFA, vascular endothelial growth factor A; XRCC2, X-ray repair cross complementing 2; YBX2, Y-box-binding protein 2; ZEB1, zinc finger E-box-binding homeobox 1; ZEB2, zinc finger E-box-binding homeobox 2; 8-OH-dG, 8-hydroxy-guanine.

Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Dihydroartemisinin (DHA) exhibits potent anti-cancer activities. CMTs is a potential suitable model for studies in human breast cancer research. In the present study, we separated DHA-untreated cells from CMTs cells to be a control group, the rest of the CMTs cells treated by DHA which were composed of three concentrations 5,10 as well as 20 μM. After that we cultivate the cells severally under the condition of 24, 48 and 72 h at 37 °C. CMTs cells were evaluated by Cell viability assay, Wound healing assay, Invasion assay and RT-PCR analysis for the expression of Slug, ZEB1, ZEB2 and Twist. Our results showed that DHA increased the inhibitory rate of CMTs cell and restrain TGF-β1-induced migration and invasion of cells in a time and concentration reliant manner efficaciously. Our result also show DHA inhibits the expression of Slug, ZEB1, ZEB2 and Twist at the mRNA in vitro, the media concentration DHA (10 μM) decreased the expression level of the Slug, ZEB1, ZEB2 mRNA significantly. In conclusion, DHA inhibits canine mammary tumours cells migration and invasiveness by regulating the expression of EMT-related genes.

OBJECTIVE

To review and summarize the newest update on ocular sebaceous gland carcinoma (SGC) focusing on diagnosis and treatment.

METHODS

A PubMed search was carried out using the terms "Sebaceous Carcinoma", "Meibomian Gland Carcinoma", "Sebaceous Cell Carcinoma", and "Sebaceous Gland Carcinoma". All studies published in English up to October 2017 were included in this review.

RESULTS

Globally, the overall incidence of SGC is increasing making it the third most common eyelid malignancy after basal cell carcinoma (BCC) and squamous cell carcinoma. The mainstay of treatment of ocular SGC is wide surgical resection under frozen section or Moh's micrographic surgery control followed by eyelid reconstruction. Based on histopathological features, SGC can be classified according to growth pattern, cell type, and cytoarchitecture. Based on the growth pattern, they can be classified as trabecular, lobular, papillary, and BCC-like. The cell type can be classified as basaloid, basosquamous, and epidermoid. The SGC cytoarchitecture presents either as a nodular or as an infiltrative lesion. Based on immunohistochemistry, the overexpression of ZEB2, BAG3, androgen receptor, and C-erbB-2 oncoprotein is associated with poor prognosis. The tumor is associated with systemic metastasis in 8-14% and death in 10-30%.

CONCLUSIONS

Ocular SGC is an aggressive tumor associated with poor prognosis. Early identification and appropriate treatment may help improve the prognosis. New insight into its pathogenesis and the immunohistochemical profile may lead to the development of new effective treatment strategies, along with traditional therapies.

Mowat-Wilson syndrome is a rare genetic condition characterized by intellectual disability, structural anomalies, and dysmorphic features. It is caused by haploinsufficiency of the ZEB2 gene in chromosome 2q22.3. Over 180 distinct mutations in ZEB2 have been reported, including nonsense and missense point mutations, deletions, and large chromosomal rearrangements. We report on a 14-year-old female with a clinical diagnosis of Mowat-Wilson syndrome. Chromosomal microarray identified a novel de novo 69-kb duplication containing exons 1 and 2 of the ZEB2 gene. Sequence analysis identified no other variants in this gene. This is the first report of a partial duplication of the ZEB2 gene resulting in Mowat-Wilson syndrome.

We aimed to investigate whether resveratrol (RSV) could sensitize human triple-negative breast cancer (TNBC) cells to FL118-induced cell death, epithelial to mesenchymal transition (EMT), invasion, and migration. The effects of sequential administration of RSV and FL118 on MDA-MB-436 and MDA-MB-468 cells were evaluated in terms of cell viability, cytotoxicity, apoptosis, cell cycle distribution, active caspase-3/7 levels, migration and invasion. Furthermore, mRNA and protein levels of EMT associated genes and proteins were also evaluated. Sequential administration of RSV and FL118 inhibited the cell viability in both TNBC cell lines. Meanwhile sequential administration of RSV and FL118 also dramatically reduced the migratory and invasive capabilities, it also reversed the EMT process in both TNBC cells. Moreover, sequential administration of RSV and FL118 led to a significant increase of apoptotic cells, as well as active Caspase-3/7 levels. Sequential administration of RSV and FL118 caused TNBC cells accumulating in the G1 phase, and markedly suppressed the mRNA and protein levels of N-cadherin, β-catenin, Vimentin, Snail, and Slug, and also significantly downregulated mRNA levels of Fibronectin, Twist1, Twist2, Zeb1, and Zeb2 genes, while enhanced the mRNA and protein levels of E-cadherin genes. RSV sensitized TNBC cells to FL118 via facilitating apoptosis, migration, invasion, and EMT and enhancing intracellular entrapment of FL118. Thus, our results suggest that since RSV enhanced the in vitro anticancer activity of FL118 in BC, it may be a potential therapeutic agent in advanced BC.

Keywords: Apoptosis; Epithelial to mesenchymal transition; FL118; Resveratrol; Triple-negative breast cancer.

Diabetic osteoporosis (DOP) is attributed to the aberrant physiological function of bone marrow mesenchymal stem cells (BMSCs) under high glucose (HG) environment. MicroRNAs (miRNAs) are involved in the pathological processes of DOP. We aimed to explore the underlying mechanism of miRNA in DOP. BMSCs were cultured in osteogenic medium with HG to induce osteogenic differentiation, and the interaction between miR-493-5p and ZEB2 was assessed by luciferase assay. Herein, we found miR-493-5p is gradually reduced during osteogenic differentiation in BMSCs. HG treatment inhibits osteogenic differentiation and induces an up-regulation of miR-493-5p leading to reduced level of its downstream target ZEB2. Inhibition of miR-493-5p attenuates HG-induced osteogenic differentiation defects by upregulation of ZEB2. Mechanistically, miR-493-5p/ZEB2 signalling mediates HG-inhibited osteogenic differentiation by inactivation of Wnt/β-catenin signalling. More importantly, knockdown of miR-493-5p therapeutically alleviated the DOP condition in mice. HG prevents BMSCs osteogenic differentiation via up-regulation of miR-493-5p, which results in reduced level of ZEB2 by directly targeting its 3'-untranslated region of mRNA. Thus, miR-493-5p/ZEB2 is a potential therapeutic target and provides novel strategy for the treatment and management of DOP.

Keywords: ZEB2; bone marrow mesenchymal stem cells; high glucose; miR-493-5p osteogenic differentiation.

Increasing evidence has confirmed long non-coding RNAs (lncRNAs) as important regulators involved in several pathophysiological processes in many diseases. The aim of this study was to investigate the roles of lncRNA ZEB2-AS1 (ZEB2-AS1) in osteosarcoma (OS). The levels of ZEB2-AS1 in OS tissues and cells were detected using RT-PCR. The clinical significance of ZEB2-AS1 expressions in OS patients was statistically analyzed. The functional effects of ZEB2-AS1 on the proliferation, apoptosis, invasion, and metastasis of OS cells was determined by a series of cellular experiments. Bioinformatic analysis, dual-luciferase reporter assays and pull-down assays were carried out for the confirmation of the molecular binding. We found that ZEB2-AS1 expression was distinctly upregulated in OS specimens and cell lines. Higher levels of ZEB2-AS1 in OS patients were associated with clinical stage, distant metastasis and unfavorable survivals. A multivariate Cox model revealed that ZEB2-AS1 expression was an independent prognostic factor for OS patients. Cellular experiments revealed that knockdown of ZEB2-AS1 inhibited proliferation and metastasis, and induced apoptosis in vitro. Mechanistic investigation revealed that ZEB2-AS1 acted as a sponge for miR-107 and blocked the inhibition of spalt like transcription factor 4 (SALL4) via miR-107 in OS cells. Rescue experiments suggested that up-regulation of ZEB2-AS1 could partly attenuate the miR-107 mediated inhibition of SALL4 expression in OS cells. To sum up, our data revealed that ZEB2-AS1 played an oncogenic role in OS progression, and could serve as a novel molecular target for treating this tumor.

Keywords: LncRNA ZEB2-AS1; SALL4; invasion; miR-107; osteosarcoma; prognosis.