A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations

Background Breast cancer is the most common cancer type in female. As microRNAs play vital role in breast cancer, this study aimed to explore the molecular mechanism and clinical value of miR-21 in breast cancer. Methods qRT-PCR was performed to detect miR-21 levels in plasma of 127 healthy controls, 82 benign breast tumor, 252 breast cancer patients, as well as in breast cancer cell lines. Transwell and wound healing assay were used to analyze breast cancer metastasis in response to miR-21 inhibitor. Colony formation and eFluor™ 670 based flow cytometric analysis were used to test breast cancer proliferation following miR-21 inhibitor treatment. Leucine zipper transcription factor-like 1 (LZTFL1), the target gene of miR-21 was predicted by MIRDB, TargetScan 5.1, PicTar and miRanda. Survival analysis of LZTFL1 levels in breast cancer prognosis was estimated with the Kaplan–Meier method by log-rank test according to data from the Cancer Genome Atlas. Luciferase activity assay was performed to confirm the regulation of miR-21 on LZTFL1. LZTFL1 siRNA and miR-21 inhibitor were co-transfected to breast cancer cells, then cell proliferation, migration and epithelial–mesenchymal transition (EMT) makers were tested. BALB/c nude mice were injected in situ with Hs578T cells stably overexpressing miR-21. Breast tumor growth, metastasis and the expression of EMT markers or LZTFL1 were detected in vivo. Results Plasma miR-21 levels were elevated in breast cancer patients compared with healthy controls and benign breast tumor patients, and the miR-21 levels were significantly decreased after surgery comparing with pre operation in 44 patients. Inhibition of miR-21 suppressed cell proliferation and metastasis in breast cancer cells. LZTFL1 was identified as a novel target gene of miR-21. Knockdown of LZTFL1 overcame the suppression of miR-21 inhibitor on cell proliferation, metastasis and the expression of EMT markers in breast cancer cells. miR-21 overexpression promoted breast cancer cell proliferation and metastasis in vivo. Conclusions These results indicate that plasma miR-21 level is a crucial biomarker for breast cancer diagnosis and targeting miR-21–LZTFL1–EMT axis might be a promising strategy in breast cancer therapy. Trial registration Retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s12885-019-5951-3) contains supplementary material, which is available to authorized users.

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“…IHC was performed as previously described [37]. Staining intensity and proportion were viewed and expression scores were calculated [38].…”

Section: Methodsmentioning

confidence: 99%

microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1

et al. 2019

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“…CRISPR/Cas9-mediated narfl knockout was described in our previous work [9]. Two independent mutant lines, respectively containing 4 bp insertion and 5 bp deletion plus 4 bp insertion in the target region, were obtained and confirmed by sequencing (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It was reported that NARFL knockdown in mammalian cells causes increased levels of hypoxia-inducible factor-1α (HIF-1α) protein under normoxic and hypoxic conditions [7], and recent study has shown that NARFL is a key element in cellular defense against oxidative stress [8]. In our previous work, NARFL (Ser161Ile) was identified as a causative gene in a family with diffuse pulmonary arteriovenous malformations (dPAVMs), in which the proband died of pulmonary hypertension at a young age, and we observed abnormal development of the subintestinal vessels using a narfl -knockout zebrafish model [9]. Previous studies provide insights regarding the interaction between oxidative stress, angiogenesis and vascular diseases, indicating that oxidative stress plays a positive role during angiogenesis [[10], [11], [12], [13]].…”

Section: Introductionmentioning

confidence: 87%

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Deletion of narfl leads to increased oxidative stress mediated abnormal angiogenesis and digestive organ defects in zebrafish

Luo

Zhang

et al. 2020

Redox Biology

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Nuclear prelamin A recognition factor-like (NARFL) is a human protein that participates in cytosolic iron-sulfur (Fe–S) protein biogenesis and cellular defense against oxidative stress. Previous studies of Narfl knockout mice did not reveal well the regulatory mechanisms of embryonic development mediated by Narfl because the homozygous mice die in utero. Here, we investigated the function of narfl in an established zebrafish knockout model by taking advantage of zebrafish external fertilization and ease of embryonic development examination. Our experiments showed that narfl deletion resulted in larvae lethality, subintestinal vessel (SIV) malformation and digestive organ defects in the early stages of embryonic development. Biochemical analyses and western blot revealed increased oxidative stress and upregulated hypoxia-inducible factor-1α (HIF-1α) expression in narfl−/− fish. The use of HIF-1α inhibitor 2-methoxyestradiol (2ME2) for the treatment of mutants partially rescued the SIV sprouting. These results suggest that narfl deletion causes increased oxidative stress and subintestinal vessel malformation, which further influence the development of digestive organs and might contribute to the lethality of the narfl knockout fish.

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“…Furthermore, our understanding of lung cancer is very limited, which has resulted in poor patient outcomes. Discovery of new targeted biomarkers for prognosis is important in cancer research (4)(5)(6). Recently, accumulating studies have revealed that angiogenesis-related genes, including DLL4 are dysregulated in lung cancer and they act as oncogenes or tumor suppressors.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of DLL4 predicts poor survival in non‑small cell lung cancer patients due to promotion of lymph node metastasis

et al. 2018

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Delta-like 4 (DLL4) is a membrane‑bound ligand, which belongs to the Notch signaling pathway and plays important roles in angiogenesis and vascular development. The expression of DLL4 in non‑small cell lung cancer (NSCLC) remains unclear. Therefore, DLL4 expression was detected in clinical specimens using quantum dots (QDs)‑immunohistochemistry (IHC) and lung cancer cell lines by quantitative real‑time polymerase chain reaction. The protein levels of DLL4 were decreased in the tumor tissues of NSCLC patients and lung cancer cell lines. Kaplan‑Meier analysis indicated that low expression of DLL4 predicted poor survival rate of NSCLC patients. A549 and A427 cells transfected with pCMV‑DLL4 exhibited reduced cell proliferation, migration and invasion using MTT assay, wound healing assay and Transwell assay. These data indicate that DLL4 represents a new prognostic biomarker for NSCLC, and DLL4 overexpression inhibits cell proliferation and metastasis in vitro.

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A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations

Cited by 10 publications

References 34 publications

microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1

microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1

Deletion of narfl leads to increased oxidative stress mediated abnormal angiogenesis and digestive organ defects in zebrafish

Downregulation of DLL4 predicts poor survival in non‑small cell lung cancer patients due to promotion of lymph node metastasis

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