Dataset Information

The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma.

ABSTRACT: Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer after hepatocellular carcinoma. Antiangiogenic therapy has been administered to patients with CCA, but the benefits of this therapy remain unsatisfactory. Improved understanding of the molecular mechanisms underlying angiogenesis in CCA is required. In the present study, the expression of GATA?binding protein 6 (GATA6), lysyl oxidase?like 2 (LOXL2) and vascular endothelial growth factor A (VEGFA), in addition to the microvessel density (MVD), were evaluated by performing immunohistochemical staining of human CCA microarrays. The expression of GATA6/LOXL2 was associated with poor overall survival (P=0.01) and disease?free survival (P=0.02), and was positively associated with VEGFA expression (P=0.02) and MVD (P=0.04). In vitro, western blotting, reverse transcription?quantitative PCR analysis and ELISAs revealed that altered GATA6 and LOXL2 expression regulated the expression levels of secreted VEGFA. Co?immunoprecipitation demonstrated a physical interaction between GATA6 and LOXL2 in CCA cell lines, and the scavenger receptor cysteine?rich domain of LOXL2 interacted with GATA6, which regulated VEGFA mRNA expression and protein secretion, and promoted tube formation. In vivo analyses further revealed that GATA6/LOXL2 promoted VEGFA expression, angiogenesis and tumor growth. The GATA6/LOXL2 complex represents a novel candidate prognostic marker for stratifying patients with CCA. Drugs targeting this complex may possess great therapeutic value in the treatment of CCA.

SUBMITTER: Peng T

PROVIDER: S-EPMC6685595 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma.

Peng Tao T Deng Xiang X Tian Feng F Li Zhonghu Z Jiang Peng P Zhao Xin X Chen Guangyu G Chen Yan Y Zheng Ping P Li Dajiang D Wang Shuguang S

International journal of oncology 20190715 3

Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer after hepatocellular carcinoma. Antiangiogenic therapy has been administered to patients with CCA, but the benefits of this therapy remain unsatisfactory. Improved understanding of the molecular mechanisms underlying angiogenesis in CCA is required. In the present study, the expression of GATA‑binding protein 6 (GATA6), lysyl oxidase‑like 2 (LOXL2) and vascular endothelial growth factor A (VEGFA), in addition to the microves ...[more]

PMID: 31322171

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Project description:PurposeAngiogenesis actively contributes to tumor growth and metastasis. MACC1 was reported to be associated with tumor progression. In the present study, we aimed to investigate the expression and role of MACC1 in cholangiocarcinoma (CCA) and its correlation with angiogenesis.Patients and methodsWe investigated the expression and correlation of MACC1 and VEGFA in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and in 7 paired frozen CCA and matched paracarcinoma tissues. Immunohistochemistry (IHC) was used to examine MACC1 and VEGFA expression as well as microvessel density (MVD) in 122 paraffin-embedded CCA samples. Western blotting, real-time qPCR and ELISA were performed to investigate the effect of MACC1 knockdown on VEGFA expression and secretion in CCA cells. Subsequently, we collected conditioned medium from cells with MACC1 knockdown and used it in angiogenesis assays.ResultsThe expression levels of both MACC1 and VEGFA were significantly upregulated in the TCGA and GEO datasets and in the 7 paired frozen CCA tissues compared to the matched paracarcinoma tissues, and MACC1 was significantly correlated with VEGFA. IHC showed that high expression of MACC1 and VEGFA was significantly correlated with lymph node metastasis (P<0.05 and P<0.01) and worse survival (P<0.01, P<0.05) in patients with CCA. We further verified that MACC1 was significantly correlated with VEGFA (P<0.01) and MVD (P<0.01) in clinical samples. Western blotting, real-time qPCR and ELISA results showed that MACC1 knockdown in CCA cells significantly decreased the protein and mRNA expression of VEGFA and reduced the VEGFA concentration in conditioned medium. Moreover, angiogenesis assays showed that conditioned medium from CCA cells with MACC1 knockdown decreased the number of tubes formed.ConclusionOur results indicate that MACC1 and VEGFA expression are upregulated in CCA. Moreover, MACC1 is an independent predictor of overall survival and facilitates angiogenesis in CCA by upregulating of VEGFA.

Project description:Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression.LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients.Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors.These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression, and that these effects are driven by LOXL2-mediated activation of ErbB2. LOXL2 may also be a beneficial marker for breast cancer patients that could benefit most from anti-ErbB2 therapy.

Dataset Information

The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma.

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The interaction of LOXL2 with GATA6 induces VEGFA expression and angiogenesis in cholangiocarcinoma.

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