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Although leucine zipper tumour suppressor 1 (LZTS1) has been considered a potential tumour suppressor, accumulating evidence suggests that LZTS1 is highly expressed in many cancer types. To unravel the exact role of LZTS1 in colorectal carcinogenesis, we performed the bioinformatic analysis of LZTS1, including expression differences, correlations between expression levels and survival, methylation status of LZTS1 promoter and related cellular pathways based on TCGA dataset, GEO databases and our own CRC patient cohort. Furthermore, we confirmed the oncogenic function of LZTS1 in human mammalian cells by employing a series of assays including tissue microarray, immunoblotting, cell proliferation and migration assay. We found that the expression of LZTS1 is higher in tumour samples compared to paired normal tissue in CRC cancer and its different clinical subtypes, which is, at least in part, due to the low methylation status of LZTS1 promoter in CRC tumour samples. Functional analysis identified the close relationship between high expression of LZTS1 and PI3K‐AKT pathway and the epithelial–mesenchymal transition (EMT) process. Consistently, we found that the expression of LZTS1 positively correlated with the expression PIK3CD, N‐cadherin in CRC tumour samples, while the expression of LZTS1 negatively correlated with the expression of E‐cadherin and PTEN in CRC tumour samples. Experimental data further confirmed that overexpression of LZTS1 upregulated activity of AKT and promoted EMT process. Furthermore, depletion of LZTS1 repressed the proliferation and migration rate of CRC cells. Thus, this study indicates that LZTS1 plays an oncogenic role in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic cancer is a kind of harmful human cancer, rated as the seventh leading cause of global death. Research has shown that in various cancers, the expression of Leucine zipper tumor suppressor 1 (LZTS1) has been found low, but its effects on pancreatic cancer is yet to be elucidated. In this research, the aim was to investigate the biological functions of LZTS1 and the underlying molecular mechanism in pancreatic cancer. Methods: GEPIA database was reported for the relative expression of LZTS1 in pancreatic cancer tissues and cell lines compared to normal ones. Kaplan-Meier analysis was done on GEPIA based on the previous data. Gene expression analysis was performed on human pancreatic cancer cell lines (BXPC3, CFPC-1, Panc-1, AsPC-1 and L3.6pl) as well as a normal cell line HEK-293T by employing RT-qPCR. Transfection procedure was done to up- or down-regulate the expressions of LZTS1 in Panc1 cell line. CCK-8 assay and flow cytometric method were adopted to determine cell viability and apoptosis, respectively. Protein expression levels were determined by Western blot. Results: Expressions of LZTS1 were high in both tumor tissues and cells. Patients with higher LZTS1 had lower 5-year overall survival rate compared to those with lower LZTS1. Overexpressed LZTS1 promoted proliferation and inhibited apoptosis in cancer cell lines. A significant promotion of phosphorylated level of AKT and GSK-3β proteins were achieved through the overexpression of LZTS1. Conclusion: The results from this study revealed that overexpression of LZTS1 increased cell viability and inhibited cell apoptosis, by activation of AKT/GSK-3β signaling pathway. Our findings indicated that LZTS1 might be a prognostic biomarker in pancreatic cancer. [ABSTRACT FROM AUTHOR]

During neocortical development, many neuronally differentiating cells (neurons and intermediate progenitor cells) are generated at the apical/ventricular surface by the division of neural progenitor cells (apical radial glial cells, aRGs). Neurogenic cell delamination, in which these neuronally differentiating cells retract their apical processes and depart from the apical surface, is the first step of their migration. Since the microenvironment established by the apical endfeet is crucial for maintaining neuroepithelial (NE)/aRGs, proper timing of the detachment of the apical endfeet is critical for the quantitative control of neurogenesis in cerebral development. During delamination, the microtubule–actin–AJ (adherens junction) configuration at the apical endfeet shows dynamic changes, concurrent with the constriction of the AJ ring at the apical endfeet and downregulation of cadherin expression. This process is mediated by transcriptional suppression of AJ-related molecules and multiple cascades to regulate cell adhesion and cytoskeletal architecture in a posttranscriptional manner. Recent advances have added molecules to the latter category: the interphase centrosome protein AKNA affects microtubule dynamics to destabilize the microtubule–actin–AJ complex, and the microtubule-associated protein Lzts1 inhibits microtubule assembly and activates actomyosin systems at the apical endfeet of differentiating cells. Moreover, Lzts1 induces the oblique division of aRGs, and loss of Lzts1 reduces the generation of outer radial glia (oRGs, also called basal radial glia, bRGs), another type of neural progenitor cell in the subventricular zone. These findings suggest that neurogenic cell delamination, and in some cases oRG generation, could be caused by a spectrum of interlinked mechanisms.

Differential Hox gene expression is central for specification of axial neuronal diversity in the spinal cord. Here, we uncover an additional function of Hox proteins in the developing spinal cord, restricted to B cluster Hox genes. We found that members of the HoxB cluster are expressed in the trunk neural tube of chicken embryo earlier than Hox from the other clusters, with poor antero-posterior axial specificity and with overlapping expression in the intermediate zone (IZ). Gain-offunction experiments of HoxB4, HoxB8 and HoxB9, respectively, representative of anterior, central and posterior HoxB genes, resulted in ectopic progenitor cells in the mantle zone. The search for HoxB8 downstream targets in the early neural tube identified the leucine zipper tumor suppressor 1 gene (Lzts1), the expression of which is also activated by HoxB4 and HoxB9. Gain- and loss-of-function experiments showed that Lzts1, which is expressed endogenously in the IZ, controls neuronal delamination. These data collectively indicate that HoxB genes have a generic function in the developing spinal cord, controlling the expression of Lzts1 and neuronal delamination. [ABSTRACT FROM AUTHOR]

The postsynaptic density or PSD is a submembranous compartment containing a wide array of proteins that contribute to both morphology and function of excitatory glutamatergic synapses. In this study, we have analyzed functional aspects of the Fezzin ProSAPiP1, an interaction partner of the well-known PSD proteins Shank3 and SPAR. Using lentiviral-mediated overexpression and knockdown of ProSAPiP1, we found that this protein is dispensable for the formation of both pre- and postsynaptic specializations per se. We further show that ProSAPiP1 regulates SPAR levels at the PSD and the maturation of dendritic spines. In line with previous findings on the ProSAPiP1 homologue PSD-Zip70, we conclude that Fezzins essentially contribute to the maturation of excitatory spine synapses.

Background To study the role of LZTS1 in hepatocellular carcinoma (HCC) proliferation and the molecular mechanism involved. Methods LZTS1 expression was studied in 10 HCC cell lines and 1 normal hepatocyte cell line by western blot analysis and qRT-PCR. One HCC cell line was selected and transfected with LZTS1 lentivirus. Cell proliferation and cell cycle were then determined by CCK-8 assay and flow cytometry, respectively. LZTS1, cyclin D1, CDK1, Cdc25C, pS473 Akt, and pT308 Akt mRNA and protein expressions were measured. PS473 Akt and pT308 Akt expression level was also compared with the HCC cells treated with LY294002. Results Compared with the normal hepatocyte cells, LZTS1 expression in HCC cells was significantly lower. After the transfection with LZTS1 lentivirus, HCC cell proliferation ability decreased markedly and HCC cells were blocked at G2/M phase. Cyclin D1 and CDK1 expression were both decreased but not significantly. Cdc25C expression was increased significantly. PS473 Akt and pT308 Akt expression level was increased significantly as well, which were almost the same with those transfected with LY294002. Conclusion LZTS1 could inhibit HCC cell proliferation by impairing PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-214 is upregulated in human OS tissues and inversely correlated with LZTS1 expression. [•] miR-214 directly targets LZTS1 by binding to its 3′-UTR. [•] miR-214 promotes OS cell proliferation, invasion and tumor growth. [•] Overexpression of LZTS1 reverses miR-214-induced proliferation and invasion of OS cells. [Copyright &y& Elsevier]

Background: Neuronal circuit assembly comprises a number of developmental processes that ultimately underlie function. Identifying the molecular events that dictate these processes can give key insights into how neuronal circuit formation is coordinated. To begin to identify such molecular mechanisms, we have analysed the expression of a candidate gene of entirely unknown function within the nervous system. Here we reveal the spatial and temporal distribution of Lzts1 in mouse and chick embryonic spinal cord and propose potential biological functions. Results: Lzts1 mRNA is transiently expressed at the border of the ventricular and mantle zones in subsets of sensory and motor spinal neurons. The protein is localized to the cell body, axon, and trailing process of motor, commissural, and dorsal root neurons during development. Conclusions: Taken together, the spatial and temporal distribution of Lzts1 is consistent with a potential function(s) in cell cycle regulation, axon growth or guidance, and/or migration of neurons. Developmental Dynamics 241:984-994, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purposes: To determine the relationship between immunohistochemical reactivity to osteopontin, vimentin, keratin 8/18, LZTS1, and beta-catenin and clinical and histopathological prognostic factors for metastasis and death in archival specimens of primary uveal melanomas, and the prognostic value of the evaluated study variables for death from metastasis. Methods: Retrospective analysis of clinical records and formalin-fixed, paraffin-embedded slides of primary uveal melanomas treated by enucleation during May 1 1999, through June 30 2009. Immunofluorescent staining of each tumor was assessed on newly prepared histologic slides after the application of antibodies directed against five biomarkers associated with unfavorable prognosis in uveal melanoma. Results: After exclusions, our study group consisted of 82 cases. Immunofluorescence was observed in 40.2% of specimens evaluated for keratin, 50.0% evaluated for osteopontin, 26.8% evaluated for β-catenin, 65.9% evaluated for vimentin, and 70.7% evaluated for LZTS1. Through available follow-up, 27 patients (32.9%) were dead of confirmed or suspected metastatic uveal melanoma. None of the patients whose tumor exhibited strong immunoreactivity to β-catenin died of metastasis. In contrast, patients whose tumor exhibited immunoreactivity of any intensity to LZTS1 were more likely to develop metastasis. In multivariate Cox proportional hazards modeling, a composite variable that took into account the immunostaining for both β-catenin and LZTS1 had a statistically significant relationship with patient's survival time. Conclusions: Our study suggests that conventional clinical and histopathological prognostic factors, and immunoexpression of β-catenin and LZTS1 combined may allow better prognostication of metastasis than clinical and histomorphological factors alone. [ABSTRACT FROM AUTHOR]

Summary: Leucine zipper putative tumor suppressor 1 is down-regulated by promoter methylation, but not frequently, in human malignancies, including breast cancer. Recent studies suggest that leucine zipper putative tumor suppressor 1 is a candidate for the metastasis modifier locus on human chromosome 8p in melanoma. In this study, we evaluated whether leucine zipper putative tumor suppressor 1 plays a role in breast cancer metastasis. We found that leucine zipper putative tumor suppressor 1 protein expression was significantly reduced or absent in a series of 340 invasive breast carcinomas compared to normal breast tissue. Lower levels of leucine zipper putative tumor suppressor 1 correlated with high histologic grade, lymph node metastasis, and poor prognosis. Functional studies demonstrated that ectopic expression of leucine zipper putative tumor suppressor 1 in the highly malignant MDA-MB-231 breast cancer cell line suppressed cell proliferation, migration, and invasion in vitro. Expression of leucine zipper putative tumor suppressor 1 in MDA-MB-231 cells also induced a series of changes that are characteristic of mesenchymal-to-epithelial transition, including phenotypic change, up-regulation of epithelial markers E-cadherin, β-catenin, and cytokeratin and down-regulation of the mesenchymal marker vimentin. Expression of leucine zipper putative tumor suppressor 1 also repressed the transcription of Slug and Snail, which both repress E-cadherin expression during epithelial-to-mesenchymal transition. These findings suggest that epithelial-to-mesenchymal transition likely inhibits breast cancer metastasis by intervening in epithelial-to-mesenchymal transition in breast cancer. [ABSTRACT FROM AUTHOR]

Leucine zipper putative tumor suppressor 1 (LZTS1) is a tumor suppressor gene located on chromosome 8p22, and the expression is usually decreased in different types of cancers. Here we analyze the correlation between LZTS1 and paclitaxel sensitivity to breast cancer. LZTS1 expression was investigated in MDA-MB-231 cell line by reverse transcriptase-polymerase chain reaction(RT-PCR) and western blot. Cell cycle and apoptosis were detected using flow cytometry. Cell proliferation/viability assays to test drug sensitivity in breast cancer cell line. Human tumor xenograft models to measure chemo-sensitivity in LZTS1 over-expression tumor. The expression of LZTS1 was detected using immunohistochemistry in breast cancer, and the correlation between the LZTS1expression and the effect of chemotherapy was analyzed. In vitro cell proliferation assays revealed that LZTS1 expression was correlated with paclitaxel sensitivity in breast cancer cells. Cell cycle analysis and apoptosis experiments have demonstrated that LZTS1 could enhance the inhibitory effect of paclitaxel on the breast cancer cell cycle and the ability to induce apoptosis. Overexpression of LZTS1 could sensitize human breast carcinoma xenografts to paclitaxel. In addition, tumor with high LZTS1 expression was more sensitive to chemotherapy with paclitaxel in breast cancer. For the first time, we evaluated the relationship between LZTS1 expression and chemotherapy sensitivity using the Collagen gel droplet drug sensitivity test(CD-DST) in primary cell culture of breast cancer. LZTS1 may play an important role in improving the sensitivity of paclitaxel-based breast cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: LZTS1 has been shown to have tumour suppressor activities against prostate and breast cancer and is located within a region of frequent loss of heterozygosity (LOH) at 8p22 in ovarian cancer. We have analysed the expression of LZTS1 in ovarian cancer and found no evidence of loss of expression relative to normal ovarian surface epithelial cells. We have also analysed the coding region of the LZTS1 gene in 87 primary ovarian adenocarcinomas by DHPLC and detected a single silent somatic mutation. These data indicate that LZTS1 is not the target of LOH at 8p22 in ovarian cancer. [Copyright &y& Elsevier]

Abstract: Genomic deletions of the short arm of chromosome 8 are common in many human cancers and are frequently associated with a more aggressive tumour phenotype. One of the regions of loss of heterozygosity (LOH) on 8p22 identified in bladder cancer contains two genes, LZTS1 (FEZ1) and DBC2 (RHOBTB2) that have been shown to be mutated at low frequency in other cancers. We screened a panel of bladder tumours and bladder tumour-derived cell lines for mutations in these genes. Forty two percent of the tumours were found to have LOH in the 8p22 region and many of the cell lines have known loss of 8p. Several known polymorphisms and novel polymorphisms were detected. One possible mutation of LZTS1 (G374S) was found in a cell line. The functional significance of this is unknown but the novel serine residue created may represent a novel phosphorylation site. In DBC2, we found a single somatic mutation in a tumour (E349D) that lies in a highly conserved region of the protein. mRNA levels for both genes were reduced in the majority of bladder cancer cell lines. We conclude that neither LZTS1 nor DBC2 is commonly mutated in bladder cancer. However, neither can yet be excluded as the target of 8p22 LOH. The finding of a somatic mutation of DBC2 in a tumour sample and the down-regulation of both gene transcripts in bladder tumour cell lines may indicate that an alternative mechanism of inactivation of the second allele, for example promoter hypermethylation, is more common than mutation and this must now be examined. [Copyright &y& Elsevier]