Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells

Chen, Yu Lin; Yen, Yi Chen; Jang, Chuan Wei; Wang, Ssu Han; Huang, Han Bin; Chen, Chung Hsing; Hsiao, Jenn Ren; Chang, Jang Yang; Lin, Chen‐Yong

doi:10.1038/s41598-020-80060-3

Cited by 13 publications

(15 citation statements)

References 51 publications

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“…A limitation of this study is the lack of molecular mechanisms by which EFNA4 promotes lung cancer metastasis. The present evidence indicates that signaling by EPHA2 and its ligand, EFNA4, promotes hepatocellular carcinoma cell migration and the combination of EFNA4 and EPHA10 promotes proliferation and migration in oral squamous cell carcinoma cells [ 25 , 26 ]. In fact, during the study, we also found the positive relationships between EFNA4 and key glycolytic enzymes (not shown in this paper).…”

Section: Discussionmentioning

confidence: 98%

“…Previous studies have shown that members of the ephrin family play an important role in the pattern of nervous system, vascular system assembly and angiogenesis [ 20 , 21 , 22 , 23 , 24 ]. EFNA4 has also been reported to be involved in the proliferation of oral squamous cell carcinoma, hepatocellular carcinoma and gastric cancer [ 25 , 26 , 27 ]. However, the functions and mechanisms of EFNA4 in lung cancer are still not clear.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic EFNA4 Amplification Promotes Lung Adenocarcinoma Lymph Node Metastasis

Zhao

Chen

Sun

et al. 2022

Cancers

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Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Oncogenic EFNA4 Amplification Promotes Lung Adenocarcinoma Lymph Node Metastasis

Zhao

Chen

Sun

et al. 2022

Cancers

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“…Distinct from the cell-autonomous mechanistic bases for AVE motility suggested by the above approach, our communication analysis and inhibitor experiments identified novel intercellular signalling pathways that might be involved in the unidirectional migration of the AVE. Ephrins, Semaphorins and their respective cognate receptors are mainly membrane-tethered molecules, that were first identified as axon guidance cues, but have since been shown to regulate migration of other cell types by direct intercellular signalling (Alto and Terman, 2017;Chen et al, 2021;Kania and Klein, 2016;Toyofuku et al, 2004). Given the large number of Ephrin and Semaphorin family members expressed in the early embryo at this stage, a certain degree of functional redundancy is possible.…”

Section: Discussionmentioning

confidence: 99%

“…The analysis of intercellular communication in the scRNAseq data at E5.5 and E6.25 has been performed using a curated list of 2,548 ligand-receptor pairs (LRPs) (Caruso et al, 2020), to which we added the following LRPs based on previously reported direct interactions: CER1-MRC2 (Vento-Tormo et al, 2018), CER1-BMP2/BMP4 (Chi et al, 2011), CER1-NODAL (Aykul and Martinez-Hackert, 2016), LEFTY1-NODAL (Chen and Shen, 2004), LEFTY1-BMPR2 (Zabala et al, 2020). We selected only AVE, emVE and Epi cells, and we filtered out genes detected in fewer than 10 cells or with log-normalized mean expression computed on non-zero values smaller than 1.…”

Section: Cell-cell Communication Analysismentioning

confidence: 99%

Characterisation of the transcriptional dynamics underpinning the function, fate, and migration of the mouse Anterior Visceral Endoderm

Thowfeequ

Fiorentino

et al. 2021

Preprint

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During early post-implantation development of the mouse embryo, the Anterior Visceral Endoderm (AVE) differs from surrounding visceral endoderm (VE) in its migratory behaviour and ability to restrict primitive streak formation to the opposite side of the egg cylinder. In order to characterise the molecular basis for the unique properties of the AVE, we combined single-cell RNA-sequencing of the VE prior to and during AVE migration, with high-resolution imaging, short-term lineage labelling, phosphoproteomics and pharmacological intervention. This revealed the transient nature of the AVE, the emergence of heterogeneities in AVE transcriptional states relative to position of cells, and its prominence in establishing gene expression asymmetries within the spatial constraints of the embryo. We identified a previously unknown requirement of Ephrin- and Semaphorin-signalling for AVE migration. These findings point to a tight coupling of transcriptional state and position in the AVE and reveal molecular heterogeneities underpinning its migratory behaviour and function.

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“…Previous studies have shown that members of ephrin family play an important role in the pattern of nervous system, vascular system assembly and angiogenesis [20][21][22][23][24]. EFNA4 has also been reported to be involved in the proliferation of oral squamous cell carcinoma, hepatocellular carcinoma and gastric cancer [25][26][27]. However, the functions and mechanisms of EFNA4 in lung cancer are still not clear.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis

Zhao

Chen

Sun

et al. 2022

Preprint

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Lymph nodes metastases are common in patients with lung cancer. And those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. So-matic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are a major type of DNA alteration that promotes lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung cancer metastasis related gene, EFNA4. EFNA4 genome locus was significantly amplified and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 over-expression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis and suggests EFNA4 as a potential target in metastatic lung cancer therapy.Simple SummaryLymph nodes are likely to be the first stop for lung cancer metastasis. To further investigate the mechanism of lung cancer lymph node metastasis, we performed cancer genome analysis and found that EFNA4, a member of the ephrin (EPH) family, is amplified and up-regulated in lung tumor patients, especially in patients with lymph node metastases. In vitro and in vivo experiments show that overexpression of EFNA4 promotes lung tumor cell proliferation and migration, while knockdown or knockout of EFNA4 inhibits cell proliferation and migration. Altogether, our results suggest that the DNA amplification of EFNA4 genome locus could play an oncogenic function in promoting lung cancer lymph node metastasis.

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Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells

Cited by 13 publications

References 51 publications

Oncogenic EFNA4 Amplification Promotes Lung Adenocarcinoma Lymph Node Metastasis

Oncogenic EFNA4 Amplification Promotes Lung Adenocarcinoma Lymph Node Metastasis

Characterisation of the transcriptional dynamics underpinning the function, fate, and migration of the mouse Anterior Visceral Endoderm

Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis

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