RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC)

Ezzeldin, Mohamad; Borrego-Diaz, Emma; Taha, Mohammad; Esfandyari, Tuba; Wise, Amanda L.; Peng, Warner; Rouyanian, Alex; Kermani, Atabak Asvadi; Soleimani, M.; Patrad, Elham; Lialyte, Kristina; Wang, Kun; Williamson, Stephen K.; Abdulkarim, Bashar; Olyaee, Mojtaba; Farassati, Faris

doi:10.1016/j.molonc.2014.03.020

Cited by 39 publications

(38 citation statements)

References 30 publications

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“…RALGPS2 has highest expression in the testis or brain [56, 57]. It is suggested that RALGPS2 functions as an inhibitor of RalA signaling and thereby decreases tumor cell proliferation and induces apoptosis [58, 59]. The role of RALGPS2 in endothelial cells is probably different, because no cell death was observed during our 7-day tube formation assay.…”

Section: Discussionmentioning

confidence: 99%

Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro

et al. 2016

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During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9527-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro

et al. 2016

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“…The interplay between pathways is related to the ability of the Ras protein to activate, besides Raf, several other downstream effectors such as, for instance, the PI3 kinase, the RalGDS, the PLCε and the TIAM1 proteins. Activation of these effectors may be implicated in hepatocarcinogenesis as an enhanced expression of RalGDS and its downstream effector RalA is described in HCC cell lines and in HCC mouse models . Moreover, TIAM1 is associated with a poor prognosis in patients with HCC and contributes to tumour invasion and metastasis .…”

Section: Signalling Crosstalk Influencing Ras/mapk Pathway Activity Imentioning

confidence: 99%

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

Delire

Stärkel

2015

Eur J Clin Investigation

220

179

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Background Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications.

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“…A role for RalB was not addressed. Finally, in a transgenic mouse model for HCC (farnesoid X receptor–deficiency induced) elevated RalA-GTP was detected in the liver tumors [111]. …”

Section: Ral and Cancermentioning

confidence: 99%

Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame

Gentry

Martin

Reiner

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

112

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Since their discovery in 1986, Ral (Ras-like) GTPases have emerged as critical regulators of diverse cellular functions. Ral-selective guanine nucleotide exchange factors (RalGEFs) function as downstream effectors of the Ras oncoprotein, and the RalGEF-Ral signaling network comprises the third best characterized effector of Ras-dependent human oncogenesis. Because of this, Ral GTPases as well as their effectors are being explored as possible therapeutic targets in the treatment of RAS mutant cancer. The two Ral isoforms, RalA and RalB, interact with a variety of downstream effectors and have been found to play key and distinct roles in both normal and neoplastic cell physiology including regulation of vesicular trafficking, migration and invasion, tumor formation, metastasis, and gene expression. In this review we provide an overview of Ral biochemistry and biology, and we highlight recent discoveries.

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RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC)

Cited by 39 publications

References 30 publications

Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro

Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame

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