Advertisement

Annals of Surgical Oncology

, Volume 24, Issue 3, pp 850–859 | Cite as

Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma

  • Hisateru Komatsu
  • Tomohiro Iguchi
  • Takaaki Masuda
  • Hidenari Hirata
  • Masami Ueda
  • Shinya Kidogami
  • Yushi Ogawa
  • Kuniaki Sato
  • Qingjiang Hu
  • Sho Nambara
  • Tomoko Saito
  • Shotaro Sakimura
  • Ryutaro Uchi
  • Shuhei Ito
  • Hidetoshi Eguchi
  • Keishi Sugimachi
  • Hidetoshi Eguchi
  • Yuichiro Doki
  • Masaki Mori
  • Koshi Mimori
Translational Research and Biomarkers

ABSTRACT

Background

The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC).

Methods

The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro.

Results

In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells.

Conclusions

Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.

Keywords

Overall Survival Gene Promoter Methylation Electronic Supplementary Table GSE14520 Dataset Biotechnology Information Gene Expression Omnibus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

This research used the supercomputing resource provided by the Human Genome Center at the Institute of Medical Science, University of Tokyo (http://sc.hgc.jp/shirokane.html). HCC clinical samples were provided by the Oita Red Cross Hospital, Hiroshima Red Cross Hospital, Atomic-bomb Survivors Hospital, and Iizuka Hospital.

DISCLOSURES

Hisateru Komatsu, Tomohiro Iguchi, Takaaki Masuda, Hidenari Hirata, Masami Ueda, Shinya Kidogami, Yushi Ogawa, Kuniaki Sato, Qingjiang Hu, Sho Nambara, Tomoko Saito, Shotaro Sakimura, Ryutaro Uchi, Shuhei Ito, Hidetoshi Eguchi, Keishi Sugimachi, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, and Koshi Mimori have no conflicts of interest to disclose.

Funding

This work was supported in part by the following grants and foundations: Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant numbers 24592005 and 15K10168) and the OITA Cancer Research Foundation.

Supplementary material

10434_2016_5573_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)
10434_2016_5573_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 17 kb)
10434_2016_5573_MOESM3_ESM.docx (17 kb)
Supplementary material 3 (DOCX 17 kb)
10434_2016_5573_MOESM4_ESM.docx (17 kb)
Supplementary material 4 (DOCX 18 kb)
10434_2016_5573_MOESM5_ESM.docx (17 kb)
Supplementary material 5 (DOCX 17 kb)
10434_2016_5573_MOESM6_ESM.docx (19 kb)
Supplementary material 6 (DOCX 20 kb)
10434_2016_5573_MOESM7_ESM.tif (34.9 mb)
Supplementary material 7 (TIFF 35703 kb)
10434_2016_5573_MOESM8_ESM.tif (34.9 mb)
Supplementary material 8 (TIFF 35703 kb)
10434_2016_5573_MOESM9_ESM.tif (2.2 mb)
Supplementary material 9 (TIFF 2264 kb)

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Katagiri S, Yamamoto M. Multidisciplinary treatments for hepatocellular carcinoma with major portal vein tumor thrombus. Surg Today. 2014;44:219–26.CrossRefPubMedGoogle Scholar
  3. 3.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.CrossRefPubMedGoogle Scholar
  4. 4.
    Spangenberg HC, Thimme R, Blum HE. Targeted therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2009;6:423–2.CrossRefPubMedGoogle Scholar
  5. 5.
    Braun AC, Olayioye MA. Rho regulation: DLC proteins in space and time. Cell Signal. 2015;27:1643–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Citi S, Spadaro D, Schneider Y, Stutz J, Pulimeno P. Regulation of small GTPases at epithelial cell-cell junctions. Mol Membr Biol. 2011;28:427–44.CrossRefPubMedGoogle Scholar
  7. 7.
    Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16:522–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Okada T, Sinha S, Esposito I, et al. The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling. Nat Cell Biol. 2015;17:81–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12:408–24.CrossRefPubMedGoogle Scholar
  11. 11.
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Roessler S, Jia HL, Budhu A, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010;70:10202–12.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Roessler S, Long EL, Budhu A, et al. Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. Gastroenterology. 2012;142:957–966 e912.CrossRefPubMedGoogle Scholar
  14. 14.
    Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mizuno H, Kitada K, Nakai K, Sarai A. Prognoscan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009;2:18.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Xiang G, Yi Y, Weiwei H, Weiming W. RND1 is up-regulated in esophageal squamous cell carcinoma and promotes the growth and migration of cancer cells. Tumour Biol. 2016;37:773–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Presneau N, Manderson EN, Tonin PN. The quest for a tumor suppressor gene phenotype. Curr Mol Med. 2003;3:605–29.CrossRefPubMedGoogle Scholar
  18. 18.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–28.CrossRefPubMedGoogle Scholar
  19. 19.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Azad N, Zahnow CA, Rudin CM, Baylin SB. The future of epigenetic therapy in solid tumours: lessons from the past. Nat Rev Clin Oncol. 2013;10:256–66.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhou XD, Tang ZY, Yang BH, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479–86.CrossRefPubMedGoogle Scholar
  22. 22.
    Okamura Y, Ashida R, Ito T, Sugiura T, Mori K, Uesaka K. The tumor marker score is an independent predictor of survival in patients with recurrent hepatocellular carcinoma. Surg Today. 2015;45:1513–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Hsu HC, Wu TT, Wu MZ, Sheu JC, Lee CS, Chen DS. Tumor invasiveness and prognosis in resected hepatocellular carcinoma. clinical and pathogenetic implications. Cancer. 1988;61:2095–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Thompson TC, Southgate J, Kitchener G, Land H. Multistage carcinogenesis induced by Ras and Myc oncogenes in a reconstituted organ. Cell. 1989;56:917–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Hipfner DR, Cohen SM. Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol. 2004;5:805–15.CrossRefPubMedGoogle Scholar
  26. 26.
    Campbell PM, Der CJ. Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol. 2004;14:105–14.CrossRefPubMedGoogle Scholar
  27. 27.
    Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. Ras oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 2011;55:838–45.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Hisateru Komatsu
    • 1
    • 2
  • Tomohiro Iguchi
    • 1
  • Takaaki Masuda
    • 1
  • Hidenari Hirata
    • 1
  • Masami Ueda
    • 1
    • 2
  • Shinya Kidogami
    • 1
    • 2
  • Yushi Ogawa
    • 1
  • Kuniaki Sato
    • 1
  • Qingjiang Hu
    • 1
  • Sho Nambara
    • 1
  • Tomoko Saito
    • 1
  • Shotaro Sakimura
    • 1
  • Ryutaro Uchi
    • 1
  • Shuhei Ito
    • 1
  • Hidetoshi Eguchi
    • 1
  • Keishi Sugimachi
    • 1
  • Hidetoshi Eguchi
    • 2
  • Yuichiro Doki
    • 2
  • Masaki Mori
    • 2
  • Koshi Mimori
    • 1
  1. 1.Department of SurgeryKyushu University Beppu HospitalBeppuJapan
  2. 2.Department of Gastroenterological Surgery, Graduate School of MedicineOsaka UniversitySuitaJapan

Personalised recommendations