TY - JOUR
T1 - Bioinformatic analysis of RHO family of GTPases identifies RAC1 pharmacological inhibition as a new therapeutic strategy for hepatocellular carcinoma
AU - Bayo, Juan
AU - Fiore, Esteban J.
AU - Dominguez, Luciana María
AU - Cantero, María Jose
AU - Ciarlantini, Matias S.
AU - Malvicini, Mariana
AU - Atorrasagasti, Catalina
AU - Garcia, Mariana Gabriela
AU - Rossi, Mario
AU - Cavasotto, Claudio
AU - Martinez, Elisabeth
AU - Comin, Julieta
AU - Mazzolini, Guillermo D.
N1 - Funding Information:
Funding This work was partly supported by ANPCyT (PICTO-2016-0101 and PICT-2018-04053 to GM, PICT-2018-1036 to JB). IIMT-Universidad Austral-CONICET (PUE0102-2017 to GM). Additional support was by Universidad Austral (UA 2018 to GDM and JB) and NIH, CPRIT Program and The Welch Foundation (P50CA70907, RP160493 and I-1878 to EDM).
Publisher Copyright:
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Objective The RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC). Design We studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated. Results Among the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo. Conclusions The bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers.
AB - Objective The RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC). Design We studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated. Results Among the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo. Conclusions The bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers.
KW - cancer genetics
KW - drug development
KW - fibrosis
KW - hepatocellular carcinoma
KW - liver cirrhosis
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U2 - 10.1136/gutjnl-2020-321454
DO - 10.1136/gutjnl-2020-321454
M3 - Article
C2 - 33106353
AN - SCOPUS:85096750907
SN - 0017-5749
VL - 70
SP - 1362
EP - 1374
JO - Gut
JF - Gut
IS - 7
ER -