EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop

Lin, Junhao; Zeng, Chunting; Zhang, Jiakang; Song, Zhenghui; Qi, Na; Liu, Xinhui; Zhang, Ziyan; Li, Aimin; Chen, Fengsheng

doi:10.1016/j.omtn.2021.06.002

Cited by 19 publications

(29 citation statements)

References 28 publications

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“…EFNA3 helps in proliferation, invasion of peripheral nerve sheath tumors, and tumor angiogenesis [ 44 , 45 ]. EFNA4 potentially promotes hepatocellular carcinoma invasion and migration via the GSK3β signaling pathway [ 15 ], and is involved in the invasion of glioma via Akt signaling [ 46 ]. Furthermore, EFNA5 promotes the malignant progression of pancreatic cancer [ 47 ] but played a tumor suppressor role in glioma by inhibiting EGFR [ 48 ], tumor invasiveness, and metastasis in hepatoma and colorectal cancer [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…EFNA1 overexpression is linked to low DFS of hepatoma [ 70 ]. EFNA4 expression is linked to poor prognosis in hepatoma [ 15 ]. High EFNA5 expression is associated with lower OS in ovarian carcinoma [ 71 ] and pancreatic cancer [ 47 ] but associated with a better prognosis in prostate cancer [ 17 ], hepatoma [ 49 ], and glioblastoma [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…EFNA2 and EFNA3 have been linked to CD8 + T cells, Treg cells, and other immune cells [14]. Several recent studies have confirmed the role of EFNA4 in the progression of proliferation and metastasis of various cancers [15,16]. Also, EFNA5 is implicated in several tumorigenic processes [17,18].…”

Section: Introductionmentioning

confidence: 95%

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Expression characteristic, immune signature, and prognosis value of EFNA family identified by multi-omics integrative analysis in pan-cancer

et al. 2022

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Background EphrinA (EFNA) are Eph receptor ligands that regulate various disease processes. Nonetheless, the expression characteristics of EFNAs in pan-cancer, their relationship with tumor immune microenvironment, and prognostic value landscape remain unknown. Methods A comprehensive landscape of EFNAs was created using various statistical data extracted from 33 cancers. Subsequently, we identified differential expression, genetic variations, potential function enrichment, tumor immune-related analysis, and drug sensitivity. Further, we investigated the clinical features and diagnostic prognostic value of EFNAs. RT-qPCR, western blot and immunohistochemistry (IHC) were used to validate the expression level and significant clinical value of EFNA5 in lung adenocarcinoma cell lines and tissues. Results EFNAs were highly mutated in various cancers. Genomic and epigenetic alterations of EFNAs were observed in various tumors, where an oncogenic mutation in specific cancer types potentially affected EFNA expression. Moreover, tumor-derived EFNAs were significantly related to the tumor immune microenvironment, suggesting that they are promising therapeutic targets. The majority of EFNA family genes were significantly linked to patient prognosis. Eventually, EFNA5 was an independent prognostic factor in lung adenocarcinoma. Conclusion In summary, EFNAs are crucial in tumor immune regulation, and EFNA5 is a prognostic marker in lung adenocarcinoma. Our findings provide new insights into EFNAs from a bioinformatics standpoint and highlight the significance of EFNAs in cancer diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression characteristic, immune signature, and prognosis value of EFNA family identified by multi-omics integrative analysis in pan-cancer

et al. 2022

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“…EFNA4 is up-regulated in hepatocellular carcinoma correlating to a poor prognosis. Its overexpression mainly affects the PIK3R2/GSK3β/β -catenin pathway which significantly promotes the progression (proliferation and migration) of hepatocellular carcinoma ( Lin et al, 2021 ). In recent years, there has also been reports on EphA1 and EphA2 in the field of gastric cancer ( Rudno-Rudzińska et al, 2017 ; Peng C et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

Xie

Yuan

Jiang

2022

Front. Cell Dev. Biol.

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Background:EFNA1–5 have important physiological functions in regulating tumorigenesis and metastasis. However, correlating EFNA genes in the tumor immune microenvironment (TIME), and the prognosis of patients with gastric cancer remains to be determined.Methods: Using public databases, the expression of EFNA1-5 in pan-cancer and gastric cancer was comprehensively analyzed using UCSC Xena, the Oncomine dataset and UALCAN. We further completed survival analysis by Kaplan-Meier plotter to evaluate the prognosis of the high and low expression groups of the EFNAs gene in patients with gastric cancer. The TIMER tool was used to reveal the correlation between immune cell infiltration and genes of interest. Spearman correlation was used to find an association between the EFNA genes and tumor stem cells, TIME, microsatellite instability (MSI) or tumor mutational burden (TMB). We also used cBioportal, GeneMANIA and STRINGS to explore the types of changes in these genes and the protein interactions. Finally, we described the TIME based on QUANTISEQ algorithm, predicted the relationship between the EFNA genes and half-maximal inhibitory concentration (IC50), and analyzed the relationship between the EFNA family genes and immune checkpoints.Results: The expression of EFNA1, EFNA3, EFNA4, and EFNA5 was elevated in pan-cancer. Compared with normal adjacent tissues, EFNA1, EFNA3, and EFNA4 were up-regulated in gastric cancer. In terms of the influence on the survival of patients, the expression of EFNA3 and EFNA4 were related to overall survival (OS) and disease-free survival (DFS) for patients with gastric cancer. High expression of EFNA5 often predicted poor OS and DFS. In gastric cancer, the expression of EFNA3 and EFNA4 showed a significant negative correlation with B cells. The higher the expression of EFNA5, the higher the abundance of B cells, CD4+T cells and macrophages. CD8+T cells, dendritic cells infiltration and EFNA1-4 expression were negatively correlated. The infiltration of CD4+T cells, macrophages and neutrophils was negatively correlated with the expression of EFNA1, EFNA3, and EFNA4. TMB and MSI were positively correlated with EFNA3/EFNA4 expression. In the tumor microenvironment and drug sensitivity, EFNA3/4/5 also showed a significant correlation. In addition, we explored the relationship between the EFNA family genes and the immune microenvironment (B cells, M2 macrophages, monocytes, CD8+ T cells, regulatory T cells, myeloid dendritic cells, natural killer cells, non-regulatory CD4+ T cells), immune checkpoint (PDCD1, PDCD1LG2, CD274, CTLA4), and IC50 of common chemotherapeutic drugs for gastric cancer (5-fluorouracil, cisplatin, docetaxel and gemcitabine).Conclusions: Our study provides new ideas for tumor treatment and prognosis from the perspective of TIME, and nominates EFNA1–5 to become potential therapeutic targets for gastric cancer.

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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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EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop

Cited by 19 publications

References 28 publications

Expression characteristic, immune signature, and prognosis value of EFNA family identified by multi-omics integrative analysis in pan-cancer

Expression characteristic, immune signature, and prognosis value of EFNA family identified by multi-omics integrative analysis in pan-cancer

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis

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