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Conference Paper: Dysregulation of RalGAPA2 in hepatocellular carcinoma

TitleDysregulation of RalGAPA2 in hepatocellular carcinoma
Authors
Issue Date2020
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Proceedings of the 111th Annual Meeting of the American Association for Cancer Research (AACR), Virtual Meeting II, 22-24 June 2020. In Cancer Research, 2020, v. 80 n. 16, Suppl., Abstract 2589 How to Cite?
AbstractRalGTPases are Ras-like G-proteins which cycle between the active GTP-bound and the inactive GDP-bound forms. Elevation of expression and activity of RalGTPase has been demonstrated to play an oncogenic role in human cancers. RalA activity could be positively regulated by RalGEF and negatively regulated by RalGAP. The functional RalGAP complex consists of either one of the catalytic subunits, RalGAPA1 or RalGAPA2, together with the regulatory subunit, RalGAPB. In this study, we aimed to investigate the potential role of RalGAPA2 dysregulation and its functional significance in hepatocellular carcinoma (HCC). By RNA-sequencing analysis in human HCC tissues and cell lines, we found that RalGAPA2 was the predominantly expressed RalGAP catalytic subunit in the liver. To examine the RalGAPA2 expression in HCC, we performed qPCR analysis in paired HCC tissues (n=90), and 37.8% of the HCC samples showed a 2-fold downregulation of RalGAPA2. Clinically, downregulation of RalGAPA2 was significantly correlated with a lower cellular differentiation (P=0.034) and a shorter overall survival rate (P=0.045). Interestingly, HCC tumors showing combined upregulation of RalA and downregulation of RalGAPA2 tended to be associated with more aggressive tumor behaviour, including higher occurrence of venous invasion (P=0.001) and more advanced TNM stage (P=0.007). On the other hand, by targeted-DNA sequencing, RalGAPA2 was identified to be recurrently mutated in 7.4% of the patients in a HBV-associated HCC cohort (n=95). Functionally, CRISPR/Cas9-mediated RalGAPA2 knockout HCC cells showed an enhanced migratory ability when compared to the control cells, underlying an upregulation of RalA activity. In HCC, expression of RalA isoform was found to be specifically upregulated and functionally supporting HCC metastasis. Also, inhibition of RalGAP has been demonstrated to promote RalA activity and enhance cell invasion in several cancer types, including oral squamous cell carcinoma, prostate and bladder cancer. Consistently, the inverse correlation between the RalA activity and RalGAPA2 expression was also observed in a panel of HCC cell lines. Furthermore, HCC cells possessing a higher RalA activity were demonstrated to be more prone to RBC8 treatment, a RalGTPase-specific inhibitor. Taken together, our results suggested that RalGAPA2 might play a potential tumor suppressive role in HCC by negatively regulating RalA activity.
DescriptionE-Posters - Session PO.MCB01.03 - Signaling through Immune Receptors, G-Protein-Coupled Receptors, G Proteins, Ras, and Rho GTPases in Cancer - no. 2589 / 16
Persistent Identifierhttp://hdl.handle.net/10722/294672
ISSN
2020 Impact Factor: 12.701
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTian, L-
dc.contributor.authorChan, LK-
dc.contributor.authorHo, DWH-
dc.contributor.authorZhao, L-
dc.contributor.authorNg, IOL-
dc.date.accessioned2020-12-08T07:40:15Z-
dc.date.available2020-12-08T07:40:15Z-
dc.date.issued2020-
dc.identifier.citationProceedings of the 111th Annual Meeting of the American Association for Cancer Research (AACR), Virtual Meeting II, 22-24 June 2020. In Cancer Research, 2020, v. 80 n. 16, Suppl., Abstract 2589-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/294672-
dc.descriptionE-Posters - Session PO.MCB01.03 - Signaling through Immune Receptors, G-Protein-Coupled Receptors, G Proteins, Ras, and Rho GTPases in Cancer - no. 2589 / 16-
dc.description.abstractRalGTPases are Ras-like G-proteins which cycle between the active GTP-bound and the inactive GDP-bound forms. Elevation of expression and activity of RalGTPase has been demonstrated to play an oncogenic role in human cancers. RalA activity could be positively regulated by RalGEF and negatively regulated by RalGAP. The functional RalGAP complex consists of either one of the catalytic subunits, RalGAPA1 or RalGAPA2, together with the regulatory subunit, RalGAPB. In this study, we aimed to investigate the potential role of RalGAPA2 dysregulation and its functional significance in hepatocellular carcinoma (HCC). By RNA-sequencing analysis in human HCC tissues and cell lines, we found that RalGAPA2 was the predominantly expressed RalGAP catalytic subunit in the liver. To examine the RalGAPA2 expression in HCC, we performed qPCR analysis in paired HCC tissues (n=90), and 37.8% of the HCC samples showed a 2-fold downregulation of RalGAPA2. Clinically, downregulation of RalGAPA2 was significantly correlated with a lower cellular differentiation (P=0.034) and a shorter overall survival rate (P=0.045). Interestingly, HCC tumors showing combined upregulation of RalA and downregulation of RalGAPA2 tended to be associated with more aggressive tumor behaviour, including higher occurrence of venous invasion (P=0.001) and more advanced TNM stage (P=0.007). On the other hand, by targeted-DNA sequencing, RalGAPA2 was identified to be recurrently mutated in 7.4% of the patients in a HBV-associated HCC cohort (n=95). Functionally, CRISPR/Cas9-mediated RalGAPA2 knockout HCC cells showed an enhanced migratory ability when compared to the control cells, underlying an upregulation of RalA activity. In HCC, expression of RalA isoform was found to be specifically upregulated and functionally supporting HCC metastasis. Also, inhibition of RalGAP has been demonstrated to promote RalA activity and enhance cell invasion in several cancer types, including oral squamous cell carcinoma, prostate and bladder cancer. Consistently, the inverse correlation between the RalA activity and RalGAPA2 expression was also observed in a panel of HCC cell lines. Furthermore, HCC cells possessing a higher RalA activity were demonstrated to be more prone to RBC8 treatment, a RalGTPase-specific inhibitor. Taken together, our results suggested that RalGAPA2 might play a potential tumor suppressive role in HCC by negatively regulating RalA activity.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.relation.ispartof111th American Association Cancer Research (AACR) Annual Meeting-
dc.titleDysregulation of RalGAPA2 in hepatocellular carcinoma-
dc.typeConference_Paper-
dc.identifier.emailChan, LK: lkchan1@hku.hk-
dc.identifier.emailHo, DWH: dwhho@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.authorityChan, LK=rp02289-
dc.identifier.authorityHo, DWH=rp02285-
dc.identifier.authorityNg, IOL=rp00335-
dc.description.natureabstract-
dc.identifier.doi10.1158/1538-7445.AM2020-2589-
dc.identifier.hkuros320544-
dc.identifier.volume80-
dc.identifier.issue16, Suppl.-
dc.identifier.spageAbstract 2589-
dc.identifier.epageAbstract 2589-
dc.identifier.isiWOS:000590059304418-
dc.publisher.placeUnited States-
dc.identifier.issnl0008-5472-

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