EphA3 promotes malignant transformation of colorectal epithelial cells by upregulating oncogenic pathways

Li, Mingqi; Yang, Cheng; Liu, Xin; Yuan, Long; Zhang, Fubin; Wang, Muhong; Miao, Dazhuang; Gu, Xinyue; Jiang, Shuang; Cui, Binbin; Tong, Jinxue; Yu, Zhiwei

doi:10.1016/j.canlet.2016.10.004

Cited by 20 publications

(24 citation statements)

References 27 publications

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“…However, we observed no changes in the motility or proliferation in these isogenic cell line systems, suggesting that in colon cancer cells EPHA3 mutations are not oncogenic. These results seem at odds with recent data suggesting that wild type, as well as mutant EPHA3 may have oncogenic activity in colon epithelial cells 41 . However, a single mouse cell line model was used in this study by Li and collaborators 41 , and further investigation will be required to clarify the role of EPHA3 in the earlier steps of the oncogenic process.…”

Section: Discussioncontrasting

confidence: 77%

“…However, EPHA3 has been shown to regulate the attachment of melanoma cancer cells 23 and is associated with metastatic dissemination in hepatocellular carcinoma 29 . Moreover, EPHA3 has been suggested to regulate the metastatic spread of colorectal tumors to lymph nodes and distant organs 31 41 . We therefore decided to further investigate the role of EPHA3 in the invasive and metastatic potential of colorectal tumors and found that reintroduction of EPHA3 in colon cancer cells had no effect on their motility/invasion in vitro .…”

Section: Discussionmentioning

confidence: 99%

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Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer

Andretta

Cartón-García

Martínez-Barriocanal

et al. 2017

Sci Rep

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EPH signaling deregulation has been shown to be important for colorectal carcinogenesis and genome-wide sequencing efforts have identified EPHA3 as one of the most frequently mutated genes in these tumors. However, the role of EPHA3 in colorectal cancer has not been thoroughly investigated. We show here that ectopic expression of wild type EPHA3 in colon cancer cells did not affect their growth, motility/invasion or metastatic potential in vivo. Moreover, overexpression of mutant EPHA3 or deletion of the endogenous mutant EPHA3 in colon cancer cells did not affect their growth or motility. EPHA3 inactivation in mice did not initiate the tumorigenic process in their intestine, and had no effects on tumor size/multiplicity after tumor initiation either genetically or pharmacologically. In addition, immunohistochemical analysis of EPHA3 tumor levels did not reveal associations with survival or clinicopathological features of colorectal cancer patients. In conclusion, we show that EPHA3 does not play a major role in colorectal tumorigenesis. These results significantly contribute to our understanding of the role of EPH signaling during colorectal carcinogenesis, and highlighting the need for detailed functional studies to confirm the relevance of putative cancer driver genes identified in sequencing efforts of the cancer genome.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer

Andretta

Cartón-García

Martínez-Barriocanal

et al. 2017

Sci Rep

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“…Previous studies have shown that a reduced expression of CD166 decreases cancer cell tumorigenicity and proliferation, while it favors migration 39 . In addition, several studies have shown that endoA3-expressing cancers have bad prognosis, as it is correlated with an increase in cancer cell proliferation and migration [40][41][42] . Recently, Poudel et al 43 have shown that endoA3 promotes growth and migration of colon cancer cells via two competing mechanisms: an endocytic mechanism that is required for proliferation, and the activation of Rac1 GTPase through interaction with TIAM1 GEF for cell migration.…”

Section: Role Of Cd166/endoa3 In Cancer Cell Adhesion and Migrationmentioning

confidence: 99%

Endophilin-A3 and Galectin-8 control the clathrin-independent endocytosis of CD166

et al. 2020

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While several clathrin-independent endocytic processes have been described so far, their biological relevance often remains elusive, especially in pathophysiological contexts such as cancer. In this study, we find that the tumor marker CD166/ALCAM (Activated Leukocyte Cell Adhesion Molecule) is a clathrin-independent cargo. We show that endophilin-A3-but neither A1 nor A2 isoforms-functionally associates with CD166-containing early endocytic carriers and physically interacts with the cargo. Our data further demonstrates that the three endophilin-A isoforms control the uptake of distinct subsets of cargoes. In addition, we provide strong evidence that the construction of endocytic sites from which CD166 is taken up in an endophilin-A3-dependent manner is driven by extracellular galectin-8. Taken together, our data reveal the existence of a previously uncharacterized clathrin-independent endocytic modality, that modulates the abundance of CD166 at the cell surface, and regulates adhesive and migratory properties of cancer cells.

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“…EPHA3 is highly expressed during the embryonic development of the brain and spinal cord, lungs, kidneys and heart, and then drops to a low level in most normal adult tissues (1). However, its expression is also elevated in a wide range of malignancies, including gastric cancer (2,3), melanoma (4)(5)(6), hepatocellular carcinoma (7) and glioblastoma (8), and is correlated with tumorigenicity, tumor angiogenesis and cancer progression (7)(8)(9). It was found that blocking the activation of the EPHA3 receptor with soluble EPHA3-Fc inhibited tumor growth in the 4T1 model of metastatic mammary adenocarcinoma (10).…”

Section: Androgen Receptor Induces Epha3 Expression By Interacting Wimentioning

confidence: 99%

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Xiao-wei

Chen

et al. 2018

Oncol Rep

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Erythropoietin‑producing hepatocellular carcinoma cell surface type‑A receptor 3 (EPHA3) has been found to promote the proliferation and survival of prostate cancer (PCa) cell lines and prostate tumor development in nude mice. However, the regulation of EPHA3 in PCa remains largely unknown. This study is aimed to investigate the association between EPHA3 expression and androgen receptor (AR) signaling and the potential mechanism. We determined mRNA and protein levels of EPHA3 and AR signaling‑related genes in the PCa cell line 22Rv1 by reverse transcription‑polymerase chain reaction (RT‑PCR) and western blotting, respectively. The EPHA3 mRNA and protein levels were both found to be elevated by dihydrotestosterone (DHT) hormone in a dose‑ and time‑dependent manner, as AR and prostate‑specific antigen (PSA) expression were increased. Similarly, EPHA3 protein levels were also increased in the PCa cell line LNCaP stimulated with DHT or mibolerone (Mib). Overexpression of pEGFP‑AR in 22Rv1 cells significantly increased the EphA3 level, while AR knockdown with small interfering RNA (siRNA) for AR (siAR) markedly decreased the expression of EPHA3. The key EPHA3 promoter region associated with AR regulation was evaluated by co‑transfection of various pGL3‑basic‑luciferase reporter plasmids, containing EPHA3 core promoter fragments differing in length, with the AR plasmid or siAR into 22Rv1 cells. AR overexpression in 22Rvl cells raised the EphA3 promoter transcription activity of pGL3‑EPHA3‑Luc (EPHA3‑Luc)‑789, and vice versa. Similarly, luciferase activity of EPHA3‑Luc‑317 was also clearly affected. However, truncated EPHA3‑Luc‑237 without the transcription factor specific protein 1 (SP1) binding sites or EPHA3‑Luc‑789ΔSP1 with modified SP1 binding sites clearly decreased EPHA3 promoter activity regardless of whether AR was overexpressed or blocked. Treatment of 22Rv1 cells with 10 and 100 nM of the SP1 inhibitor mithramycin A for 24 and 48 h significantly reduced EPHA3 mRNA and protein levels. Additionally, selective inhibition of SP1 with siRNA SP1 (siSP1) at various concentration from 25 to 75 nM, reduced the EPHA3 protein level in PCa LNCaP cells, accordingly. Co‑immunoprecipitation (co‑IP) and chromatin IP (ChIP) assays were performed to determine whether AR forms a transcription factor complex with Sp1 that binds the EPHA3 core promoter region to sense androgen induction. The result suggests that the interaction of AR and SP1 contributes to regulate EPHA3 expression, and the SP1 binding sites (‑295~‑261) in the EPHA3 core promoter region is crucial to the regulation of EPHA3 expression in response to androgen hormone stimuli.

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EphA3 promotes malignant transformation of colorectal epithelial cells by upregulating oncogenic pathways

Cited by 20 publications

References 27 publications

Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer

Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer

Endophilin-A3 and Galectin-8 control the clathrin-independent endocytosis of CD166

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

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