Dysfunction of vascular smooth muscle cells (VSMCs) mediates intracranial aneurysm (IA). KDR is reported to alleviate IA progression via promoting VSMC proliferation, while the upstream reg...

https://tandfonline.com/doi/pdf/10.1080/19336918.2019.1619432

Decreased expression of circ_0020397 in intracranial aneurysms may be contributing to decreased vascular smooth muscle cell proliferation via increased expression of miR-138 and subsequent decreased KDR expression.

336 The homeobox (HOX) gene family consists of 39 genes organized in four clusters (A-D) on four chromosomes in 13 paralogous groups. HOX genes specify positional identity during development and regulate differentiation and proliferation in adult tissues. We demonstrated previously by expression array analysis that HOXA4 is overexpressed in most serous ovarian adenocarcinomas. The aim of this study was to examine the influence of HOXA4 on the phenotype of cultured normal ovarian surface epithelium (OSE) and ovarian cancer cell lines. HOXA4 expression was high in OSE cells and variable among ovarian cancer cell lines, as assessed by RT-PCR and Western blot analysis. siRNA-mediated down-regulation of HOXA4 expression in OSE cells significantly enhanced EGF (20ng/mL)-stimulated migration, despite having no effect on basal migration, as measured by wound-healing assay. In contrast, basal migration of OVCAR-8 and OVCAR-3 cells, which express high levels of HOXA4, was enhanced by HOXA4 siRNA, though migration of SKOV-3 cells, which exhibit low HOXA4 levels, was not. Similar to the wound-healing results, knockdown of HOXA4 significantly enhanced the migration of OVCAR-8 and OVCAR-3 cells in transwell assays using modified Boyden chambers. In contrast, invasion of the cells through Matrigel (1mg/mL)-coated filters was not affected. The EGF receptor inhibitor AG1478 inhibited the stimulatory effect of HOXA4 siRNA on migration of OVCAR-8 cells. Interestingly, OVCAR-8 cells transfected with HOXA4 siRNA displayed increased cell spreading on plastic. Image analysis revealed an increase in spread cell area, independent of colony size. siRNA-induced increases in cell motility and spreading do not appear to be associated with a significant decrease in E-cadherin mediated cell-cell adhesion. Western blot analysis and immunofluorescence were used to examine E-cadherin expression and localization in siRNA treated OVCAR-8 cells. HOXA4 knockdown did not affect total cellular levels of E-cadherin, nor did it alter its primarily junctional localization. Instead, down-regulation of HOXA4 significantly reduced integrin β1 levels, as assessed by Western blot and immunofluorescence. Conversely, preliminary experiments in CaOV-3 cells, which exhibit moderate HOXA4 levels, indicate that transient overexpression of full-length HOXA4 increases integrin β1 levels. These results suggest that HOXA4 suppresses cellular motility and spreading, in part, by antagonizing the pro-migratory effects of EGF receptor ligands. Mechanistically, this may be achieved by modulating the expression of adhesion molecules such as integrin β1. Thus, the role of HOXA4 in ovarian neoplastic progression may be homeostatic, by counteracting cell spreading and migration. Supported by NCIC Canada.

Cell motility and spreading are suppressed by HOXA4 in ovarian cancer cells: Possible involvement of integrin β1

Vasculogenic mimicry (VM) is a novel cancer hallmark in which malignant cells develop matrix-associated 3D tubular networks with a lumen under hypoxia to supply nutrients needed for tumor growth. Recent studies showed that microRNAs (miRNAs) may have a role in VM regulation. In this study, we examined the relevance of hypoxia-regulated miRNAs (hypoxamiRs) in the early stages of VM formation. Data showed that after 48 h hypoxia and 12 h incubation on matrigel SKOV3 ovarian cancer cells undergo the formation of matrix-associated intercellular connections referred hereafter as 3D channels-like structures, which arose previous to the apparition of canonical tubular structures representative of VM. Comprehensive profiling of 754 mature miRNAs at the onset of hypoxia-induced 3D channels-like structures showed that 11 hypoxamiRs were modulated (FC>1.5; p < 0.05) in SKOV3 cells (9 downregulated and 2 upregulated). Bioinformatic analysis of the set of regulated miRNAs showed that they might impact cellular pathways related with tumorigenesis. Moreover, overall survival analysis in a cohort of ovarian cancer patients (n = 485) indicated that low miR-765, miR-193b, miR-148a and high miR-138 levels were associated with worst patients outcome. In particular, miR-765 was severely downregulated after hypoxia (FC < 32.02; p < 0.05), and predicted to target a number of protein-encoding genes involved in angiogenesis and VM. Functional assays showed that ectopic restoration of miR-765 in SKOV3 cells resulted in a significant inhibition of hypoxia-induced 3D channels-like formation that was associated with a reduced number of branch points and patterned tubular-like structures. Mechanistic studies confirmed that miR-765 decreased the levels of VEGFA, AKT1 and SRC-α transducers and exerted a negative regulation of VEGFA by specific binding to its 3'UTR. Finally, overall survival analysis of a cohort of ovarian cancer patients (n = 1435) indicates that high levels of VEGFA, AKT1 and SRC-α and low miR-765 expression were associated with worst patients outcome. In conclusion, here we reported a novel hypoxamiRs signature which constitutes a molecular guide for further clinical and functional studies on the early stages of VM. Our data also suggested that miR-765 coordinates the formation of 3D channels-like structures through modulation of VEGFA/AKT1/SRC-α axis in SKOV3 ovarian cancer cells.

/pdf/hypoxamirs-profiling-identify-mir-765-as-a-regulator-of-the-48vjvbewwa.pdf

HypoxamiRs Profiling Identify miR-765 as a Regulator of the Early Stages of Vasculogenic Mimicry in SKOV3 Ovarian Cancer Cells

Kidney renal clear cell carcinoma (KIRC) is one of the most common lethal cancers in the human urogenital system. As members of the Homeobox (HOX) family, Homeobox-A (HOXA) cluster genes have been reported to be involved in the development of many cancer types. However, the expression and clinical significance of HOXA genes in KIRC remain largely unknown. In this study, we comprehensively analyzed the mRNA expression and prognostic values of HOXA genes in KIRC using The Cancer Genome Atlas (TCGA) analysis databases online. Colony formation assay, flow cytometry and Western blot were used to detect cell proliferation, apoptosis, cell cycle, and protein level of the indicated gene. We found that the HOXA genes were differentially expressed in KIRC tissues when compared with normal tissues. The expression of HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were down-regulated in KIRC. High mRNA levels of HOXA2, HOXA3 and HOXA13, and low level of HOXA7 predicted poor overall survival (OS) of KIRC patients. High mRNA level of HOXA13 further indicated a poor disease-free survival (DFS) of KIRC patients. Functionally, knockdown of HOXA13 significantly suppressed cell proliferation of KIRC in vitro, increased the protein level of p53 and decreased the protein level of cyclin D1 in KIRC cells. Over-expression of HOXA13 had the opposite effects on KIRC cells. Collectively, our findings suggest that HOXA13 functions as a novel oncogene in KIRC and may be a potential biomarker for this malignancy.

Comprehensive analysis of the HOXA gene family identifies HOXA13 as a novel oncogenic gene in kidney renal clear cell carcinoma.

Lung cancer is the leading cause of cancer-related deaths worldwide, but effective therapeutics is limited. This study aims to identify novel anticancer strategy from a Food and Drug Administration (FDA)-approved drug library consisting of 528 compounds. Benzethonium Chloride (BZN), a FDA-approved drug for anti-infective, was found to markedly induce apoptosis and inhibit proliferation and colony formation ability of lung cancer cells in dose- and time-dependent manners. BZN also enhanced the sensitivity of lung cancer cells to gefitinib, the first-line treatment strategy for selected lung cancer patients. Furthermore, BZN significantly delayed the growth of tumor xenografts in nude mice by increasing apoptosis and decreasing Ki-67 proliferation index, without obvious toxic effects to the vital organs of animals. Mechanistically, quantitative proteomics coupled with bioinformatics analyses and a series of functional assays demonstrated that BZN induced cell cycle arrest at G1 phase, and this was associated with an increase in p38-mediated phosphorylation at threonine 286 (T286) and accelerated degradation of cyclin D1. Our findings provide the first evidence that BZN could be a promising therapeutic agent in lung cancer treatment.

Benzethonium chloride suppresses lung cancer tumorigenesis through inducing p38-mediated cyclin D1 degradation.

Many non-small cell lung cancer (NSCLC) patients initially benefiting from gefitinib are confronted with acquired resistance MiR-138 was previously stated as a growth inhibitor of several cancer cell lines including NSCLC cells and its expression level was significantly lower in gefitinib-resistant cells The role of miR-138 in NSCLC cell lines PC9 and A549 was verified using methyl thiazolyl tetrazolium (MTT) assay and colony formation assay Quantitative real-time PCR (RT-PCR) was employed to assess the level of miR-138 in gefitinib-sensitive PC9 cells and gefitinib-resistant PC9GR cells Bioinformatic algorithms (TargetScan) and rVISTA 20 were used to predict binding sites on miR-138 and its target genes MiR-138 inhibited cell proliferation of PC9 and A549 cells In PC9GR cells, miR-138 expression was inhibited Gefitinib treatment negatively regulated miR-138 in PC9 cells Transfection of PC9GR cells with miR-138 mimics significantly reduced cell viability MiR-138 was directly regulated by Homeobox A4 (HOXA4) via an HOXA4-binding site on the promoter region TargetScan predicted numerous miR-138 target genes and EGFR was found to be the functional downstream effector of miR-138 We demonstrated that miR-138 is regulated by HOXA4 and exerts its functions via inhibiting EGFR expression in NSCLC cells

HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer

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HOXA4-regulated miR-138 suppresses proliferation and gefitinib resistance in non-small cell lung cancer