Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression

Lin, Xiao; Hu, Liang; Gu, Jin; Wang, Ruo–Yu; Li, Liang; Tang, Jing; Zhang, Baohua; Xing, Yan; Zhu, Yanjing; Hu, Congli; Zhou, Weiping; Li, Shao; Liu, Jingfeng; Gonzalez, Frank J.; Wu, Mengchao; Wang, Hongyang; Chen, Lei

doi:10.1053/j.gastro.2016.12.033

Cited by 57 publications

(53 citation statements)

References 42 publications

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“…However, only EDI3 affected cell migration, indicating that this ratio is not predictive of migratory capacity. Interestingly, our findings differ from those of previous studies where silencing CHKA decreased motility and invasion (9)(10)(11)(12). In two studies (9,10), the authors reported reduced proliferation, but no direct effect on apoptosis, or on MAPK and PI3K/Akt signaling pathways, as published by others after CHKA inhibition in other cell lines (30)(31)(32)(33).…”

Section: Discussioncontrasting

confidence: 99%

“…In two studies (9,10), the authors reported reduced proliferation, but no direct effect on apoptosis, or on MAPK and PI3K/Akt signaling pathways, as published by others after CHKA inhibition in other cell lines (30)(31)(32)(33). Furthermore, a recent study describing a role for CHKA in migration observed no direct effect on proliferation (12). Altogether, the role of CHKA in processes such as migration and proliferation requires further evaluation and may be cell type and context dependent.…”

Section: Discussionmentioning

confidence: 80%

“…1A), respectively. CHKA has been previously linked to migration (9)(10)(11)(12); however, a role for GPAM in this process has never been described.…”

Section: ) To Elucidate Edi3mentioning

confidence: 99%

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Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

et al. 2017

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Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-a (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 80%

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Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

et al. 2017

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“…The lung metastases assay was performed as previously reported (Lin et al, 2017). Briefly, six mice in the experiment group were injected intravenously with 1 9 10 6 tumor cells suspended in phosphate-buffered saline via the lateral tail vein, while six mice in the control group were injected intravenously with the same volume phosphate-buffered saline via the lateral tail vein.…”

Section: Lung Metastases Assay In Vivomentioning

confidence: 99%

FAM134B induces tumorigenesis and epithelial‐to‐mesenchymal transition via Akt signaling in hepatocellular carcinoma

et al. 2019

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Fam134b (JK‐1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of FAM 134B during tumorigenesis of hepatocellular carcinoma ( HCC ) and in epithelial‐to‐mesenchymal transition ( EMT ) were previously unclear. In this study, we investigated the function of FAM 134B in HCC and the related tumorigenesis mechanisms, as well as how FAM 134B induces EMT . We detected the expression of FAM 134B in a normal hepatic cell line, HCC cell lines, fresh specimens, and a HCC tissue microarray. A retrospective study of 122 paired HCC tissue microarrays was used to analyze the correlation between FAM 134B and clinical features. Gain‐ and loss‐of‐function experiments, rescue experiments, Akt pathway activator/inhibitors, nude mice xenograft models, and nude mice lung metastasis models were used to determine the underlying mechanisms of FAM 134B in inducing tumorigenesis and EMT in vitro and in vivo . The expression level of FAM 134B was highly elevated in HCC , as compared with that in normal liver tissues and normal hepatic cells. Overexpression of FAM 134B was significantly associated with tumor size ( P = 0.025), pathological vascular invasion ( P = 0.026), differentiation grade ( P = 0.023), cancer recurrence ( P = 0.044), and portal vein tumor thrombus ( P = 0.036) in HCC . Patients with high expression of FAM 134B had shorter overall survival and disease‐free survival than patients with non‐high expression of FAM 134B. Furthermore, knockdown of FAM 134B with sh RNA s inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of FAM 134B. Our study demonstrated that Fam134b is an oncogene that plays a crucial role in HCC via the Akt signaling pathway with subsequent glycogen synthase kinase‐3β phosphorylation, accumulation of β‐catenin, and stabilization of Snail, which promotes tumorigenesis, EMT , and tumor metastasis in HCC .

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“…However, those anti-EGFR agents have not been proved positive evaluation in hepatocellular carcinoma (HCC) despite the expression of EGFR is commonly high [4][5][6]. Lin et al reported that the anti-EGFR drug resistance in HCC is caused by the promoted interaction of EGFR with mTORC2, this shows that the complex signaling pathways is the main reason of drug resistance in liver cancer cells [7]. At present, the unique international recognized drug could benefit HCC patients is Sorafenib.…”

Section: Introductionmentioning

confidence: 99%

An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy

Huang

Fan

Liu

et al. 2020

Cancers

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The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from Ganoderma lucidum was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter into Hepatoma cells, abrogate endosomal recycling and induce HCC cell death. Surprisingly, we screened a monoclonal antibody which possesses competitive binding site with rLZ-8, it also trigger catastrophic EGFR internalization. This result suggests that it is necessary to investigate the interface of EGFR and rLZ-8 complex. An internalization related epitope (S222/K269) was identified on the dimerization arm of EGFR extracellular domain (ECD). These results suggest vulnerability of HCC cells to catastrophic EGFR internalization that can be targeted by a novel epitope and point to the possible exploitation in the design of anti-EGFR therapeutic biologics for HCC therapy.

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Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression

Cited by 57 publications

References 42 publications

Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

FAM134B induces tumorigenesis and epithelial‐to‐mesenchymal transition via Akt signaling in hepatocellular carcinoma

An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy

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