Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

Zhao, Guiqiu; Gong, Liyan; Su, Dan; Jin, Yujuan; Guo, Chenchen; Yue, Meiting; Yao, Shun; Qin, Zhen; Ye, Yi; Tang, Ying; Wu, Qibiao; Zhang, Jian; Cui, Binghai; Ding, Qiurong; Huang, Hsin‐Yi; Hu, Liang; Chen, Yuting; Zhang, Peiyuan; Hu, Guohong; Chen, Luonan; Wong, Kwok-Kin; Gao, Daming; Ji, Hongbin

doi:10.1172/jci122779

Cited by 74 publications

(64 citation statements)

References 80 publications

(103 reference statements)

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“…The ATPindependent FAK inhibitors do not pass through the ATP binding site, but directly targets the FAK site, such as the FAK Y397 phosphorylation site [119]. Experimental results also showed that those small molecule FAK inhibitors could inhabit cell migration [3], survival [120], proliferation [121], and adhesion [122]. FAK inhibitors also can inhibit nuclear active FAK phosphorylation and regulate its related signaling pathways, such as the p53 signaling pathway, the inflammatory signaling pathway, the tumor angiogenesis-related pathway, and the immune escape signaling pathway.…”

Section: Fak Inhibitorsmentioning

confidence: 99%

The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review

Zhou

Qian

Tang

2019

J Exp Clin Cancer Res

235

160

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FAK is a tyrosine kinase overexpressed in cancer cells and plays an important role in the progression of tumors to a malignant phenotype. Except for its typical role as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, related studies have shown new aspects of the roles of FAK in the nucleus. FAK can promote p53 degradation through ubiquitination, leading to cancer cell growth and proliferation. FAK can also regulate GATA4 and IL-33 expression, resulting in reduced inflammatory responses and immune escape. These findings establish a new model of FAK from the cytoplasm to the nucleus. Activated FAK binds to transcription factors and regulates gene expression. Inactive FAK synergizes with different E3 ligases to promote the turnover of transcription factors by enhancing ubiquitination. In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels, affecting the tumor blood supply. This article reviews the roles of nuclear FAK in regulating gene expression. In addition, the use of FAK inhibitors to target nuclear FAK functions will also be emphasized.

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Section: Fak Inhibitorsmentioning

confidence: 99%

The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review

Zhou

Qian

Tang

2019

J Exp Clin Cancer Res

235

160

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“…2a). Cytoplasmic lncRNAs most often function as competing endogenous RNAs (ceRNAs) to regulate downstream mRNAs by sponging miRNAs [31], suggesting that LINC00173.v1 may exert its function in lung cancer in a ceRNA manner. Then, we further analyzed the correlation of LINC00173.v1 with all reported miRNAs in the lung cancer dataset from TCGA, and found that the expression levels of six miRNAs, including miR-126-5p, miR-126-3p, miR-145-3p, miR-511-5p, miR-143-3p and miR-100-5p, were negatively correlated with LINC00173.v1, and were downregulated in SQC tissues compared with those in ANT (Fig.…”

Section: Linc00173v1 Functions As a Competing Endogenous Rna For Mirmentioning

confidence: 99%

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression

et al. 2020

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Background Anti-angiogenic therapy represents a promising strategy for non-small-cell lung cancer (NSCLC) but its application in lung squamous cell carcinoma (SQC) is limited due to the high-risk adverse effects. Accumulating evidence indicates that long noncoding RNAs (lncRNAs) mediate in tumor progression by participating in the regulation of VEGF in NSCLC, which might guide the development of new antiangiogenic strategies. Methods Differential lncRNA expression in SQC was analyzed in AE-meta and TCGA datasets, and further confirmed in lung cancer tissues and adjacent normal tissues with RT-qPCR and in-situ hybridization. Statistical analysis was performed to evaluate the clinical correlation between LINC00173.v1 expression and survival characteristics. A tube formation assay, chick embryo chorioallantoic membrane assay and animal experiments were conducted to detect the effect of LINC00173.v1 on the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC in vivo. Bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the downstream target of LINC00173.v1. The therapeutic efficacy of antisense oligonucleotide (ASO) against LINC00173.v1 was further investigated in vivo. Chromatin immunoprecipitation and high throughput data processing and visualization were performed to identify the cause of LINC00173.v1 overexpression in SQC. Results LINC00173.v1 was specifically upregulated in SQC tissues, which predicted poorer overall and progression-free survival in SQC patients. Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo. Our results further revealed that LINC00173.v1 promoted the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells by upregulating VEGFA expression by sponging miR-511-5p. Importantly, inhibition of LINC00173.v1 via the ASO strategy reduced the tumor growth of SQC cells, and enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo. Moreover, our results showed that squamous cell carcinoma-specific factor ΔNp63α contributed to LINC00173.v1 overexpression in SQC. Conclusion Our findings clarify the underlying mechanism by which LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC, demonstrating that LINC00173.v1-targeted drug in combination with cisplatin may serve as a rational regimen against SQC.

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“…and Apaf1, involved in SCLC signaling pathway and induction of lung inflammation in animals exposed to 2,4-D. These data are important because SCLC is the dominant cause of patient death [60] and 2,4D is linked to pulmonary cancer. These descriptive data set the stage for mechanistic studies involving methods such as gene-knockout mice and in vitro methods such as siRNA.…”

Section: Discussionmentioning

confidence: 97%

Exposures to 2,4-Dichlorophenoxyacetic Acid With or Without Endotoxin Upregulate Small Cell Lung Cancer Pathway

Kaur

Kumar

Singh

et al. 2020

Preprint

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Background: Pesticide residues in food and environment along with airborne contaminants such as endotoxins pose health risk. Although herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) has been associated with increased risk of lung cancers such as small cell lung cancer (SCLC) among agricultural workers, there are no data on the SCLC signaling pathway upon 2,4-D exposure alone or in combination with endotoxin. Methods: We exposed Swiss albino mice (N=48) orally to high (9.58 mg kg -1 ) and low (5.12 mg kg -1 ) dosages of 2,4-D dissolved in corn oil for 90 days followed by E. coli lipopolysaccharide (LPS) or normal saline solution (80µl/animal. Lung samples and broncho-alveolar fluid (BALF) were subjected to Total histological score (THS) and TLC and DLC analyses, respectively. We used microarray and bioinformatics tools for transcriptomic analyses and differentially expressed genes were analyzed to predict the top canonical pathways followed by validation of selected genes qPCR and immunohistochemistry. Results: Total histological score (THS) along with broncho-alveolar fluid (BALF) analyses showed lung inflammation following long term dietary exposure to high or low doses of 2,4-D individually or in combination with LPS. Microarray analysis revealed exposure to high dose of 2,4-D alone or with endotoxin upregulated 2178 and 2142 and downregulated 1965 and 1719 genes, respectively (p<0.05; minimum cut off 1.5 log fold change). The low dose alone or with LPS upregulated 2133 and 2054 and downregulated 1838 and 1625 genes, respectively. Bioinformatics analysis showed SCLC as topmost dysregulated pathway along with differential expression of Itgb1, NF-kB1, p53, Cdk6 and Apaf1. Immunohistological and qPCR analyses also supported the transcriptomic data. Conclusions: Taken together, the data show exposures to high and low dose of 2,4-D with/without LPS induced lung inflammation and altered pulmonary transcriptome profile with the involvement of the SCLC pathway. The data from the study provides the insights of the potential damage on lungs caused by 2,4-D and endotoxin interaction and helps to better understand the mechanism of this complex relation.

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Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

Cited by 74 publications

References 80 publications

The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review

The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression

Exposures to 2,4-Dichlorophenoxyacetic Acid With or Without Endotoxin Upregulate Small Cell Lung Cancer Pathway

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