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GI cancer
Original research
Bioinformatic analysis of RHO family of GTPases identifies RAC1 pharmacological inhibition as a new therapeutic strategy for hepatocellular carcinoma
  1. Juan Bayo1,2,
  2. Esteban J Fiore1,2,
  3. Luciana María Dominguez1,2,
  4. María Jose Cantero1,2,
  5. Matias S Ciarlantini3,
  6. Mariana Malvicini2,4,
  7. Catalina Atorrasagasti1,2,
  8. Mariana Gabriela Garcia1,2,
  9. Mario Rossi2,5,
  10. Claudio Cavasotto6,7,
  11. Elisabeth Martinez8,9,
  12. Julieta Comin3,10,
  13. Guillermo D Mazzolini1,2
  1. 1Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui, Buenos Aires, Argentina
  2. 2Instituto de Investigaciones en Medicina Traslacional, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Buenos Aires, Argentina
  3. 3Departamento de Ingredientes Activos y Biorrefinerías, INTI, San Martin, Buenos Aires, Argentina
  4. 4Cancer Immunobiology Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui, Buenos Aires, Argentina
  5. 5Laboratorio de Genómica Funcional y Ciencia de Datos, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui, Buenos Aires, Argentina
  6. 6Facultad de Ciencias Biomédicas, Facultad de Ingeniería, and Austral Institute for Applied Artificial Intelligence, Universidad Austral, Derqui, Buenos Aires, Argentina
  7. 7Computational Drug Design and Biomedical Informatics Laboratory, Instituto de Investigaciones en Medicina Traslacional, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Buenos Aires, Argentina
  8. 8Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  9. 9Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  10. 10Departamento de Ingredientes Activos y Biorrefinerías, Consejo Nacional de Investigaciones Cientificas y Tecnicas, San Martin, Buenos Aires, Argentina
  1. Correspondence to Prof Guillermo D Mazzolini, Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui, Buenos Aires, Argentina; gmazzoli{at}austral.edu.ar

Abstract

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.

  • hepatocellular carcinoma
  • cancer genetics
  • drug development
  • fibrosis
  • liver cirrhosis

https://doi.org/10.1136/gutjnl-2020-321454

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    Footnotes

    • JB and EJF contributed equally.

    • Contributors JB and EJF performed experiments, analysed data and wrote the manuscript; LMD, MJC, MM, CA and MGG performed experiments; and MSC design and performed the chemical synthesis; MR helped with TCGA analysis; CC and EDM helped to write the manuscript; MJC guided and design the chemical synthesis; GM guided the work, analysed data and wrote the manuscript.

    • 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).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. Dataset generated from this study are available for scientific community at the Gene Expression Omnibus repository in the GSE125518 serie and can be accessed at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE125518. This data include raw and procesed RNA-Seq data of HuH7 cells treated with 1D-142 or DMSO as control. Data are free to be reused with proper citation of this manuscript.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.