Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis

Cui, Xiang-Dan; Lee, Mi-Jin; Kim, Jong-Hyun; Hao, Peipei; Liu, Lan; Yu, Goung-Ran; Kim, Dae‐Ghon

doi:10.1002/hep.26253

Cited by 34 publications

(35 citation statements)

References 64 publications

(42 reference statements)

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“…Inhibition of mTOR has been demonstrated to suppress liver tumor growth and metastasis (9,10). Several clinical and preclinical studies have demonstrated that the mTOR inhibitor rapamycin and its analogues can be used to treat various types of solid tumor, including esophageal squamous cell carcinoma (11), lung cancer (12), renal cell carcinoma (13) and prostate cancer (14).…”

Section: Introductionmentioning

confidence: 99%

Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

Ling

Tian

Zhang

et al. 2014

Molecular Medicine Reports

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Metformin exhibits anti-proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel-7402/5-fluorouracil (5-Fu; Bel/Fu) cells. The synergistic anti-proliferative effect of metformin combined with 5-Fu was evaluated using a Cell Counting kit-8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti-proliferative effect with 5-Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia-inducible factor-1α (HIF-1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF-1α/P-gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.

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Section: Introductionmentioning

confidence: 99%

Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

Ling

Tian

Zhang

et al. 2014

Molecular Medicine Reports

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“…Two prominent oncogenic pathways, FAK and AKT, have been associated with EphA2 overexpression (30,(44)(45)(46). FAK pathway has been reported to be inversely correlated with miR-200a expression in ovarian tumors, the seed sequence of which is the same as that of the miR-141 (23).…”

Section: Discussionmentioning

confidence: 99%

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

Chen

Wang

Ruan

et al. 2014

Clinical Cancer Research

124

117

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Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis.Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues.Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G 0 -G 1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9.

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“…Among Eph receptors, EphA2 and EphB2 were increased in CCA tumors and correlated with the metastatic status of patients and poorer tumor differentiation [91,92].…”

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

“…Eph Receptors and their ligands are expressed at very low levels in normal cholangiocytes [91,92]. Among Eph receptors, EphA2 and EphB2 were increased in CCA tumors and correlated with the metastatic status of patients and poorer tumor differentiation [91,92].…”

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis

Cited by 34 publications

References 64 publications

Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

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