Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 8/2021

01-08-2021 | Pancreatic Cancer | Translational Research

High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer

Authors: Yosuke Nakao, MD, Shigeki Nakagawa, MD, PhD, Yo-ichi Yamashita, MD, PhD, FACS, Naoki Umezaki, MD, PhD, Yuya Okamoto, BM, Yoko Ogata, BS, Noriko Yasuda-Yoshihara, PhD, Rumi Itoyama, MD, Toshihiko Yusa, MD, Kohei Yamashita, MD, PhD, Tatsunori Miyata, MD, PhD, Hirohisa Okabe, MD, PhD, Hiromitsu Hayashi, MD, PhD, FACS, Katsunori Imai, MD, PhD, FACS, Hideo Baba, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Issue 8/2021

Login to get access

Abstract

Background

Pancreatic cancer has an extremely poor prognosis, even after curative resection. Treatment options for pancreatic cancer remain limited, therefore new therapeutic targets are urgently needed. We searched for genes predictive of poor prognosis in pancreatic cancer using a public database and validated the survival impact of the selected gene in a patient cohort.

Methods

We used a public database to search for genes associated with early pancreatic cancer recurrence. As a validation cohort, 201 patients who underwent radical resection in our institution were enrolled. Expression of the target gene was evaluated using immunohistochemistry (IHC). We evaluated growth and invasiveness using small interfering RNAs, then performed pathway analysis using gene set enrichment analysis.

Results

We extracted ARHGEF2 from GSE21501 as a gene with a high hazard ratio (HR) for early recurrence within 1 year. The high ARHGEF2 expression group had significantly poorer recurrence-free survival (RFS) and poorer overall survival (OS) than the low ARHGEF2 expression group. Multivariate analysis demonstrated that high ARHGEF2 expression was an independent poor prognostic factor for RFS (HR 1.92) and OS (HR 1.63). In vitro, ARHGEF2 suppression resulted in reduced cell growth and invasiveness. Bioinformatic analysis revealed that ARHGEF2 expression was associated with MYC, G2M, E2F, and CDC25A expression, suggesting that c-Myc and cell cycle genes are associated with high ARHGEF2 expression. IHC revealed a positive correlation between ARHGEF2 and c-Myc expression.

Conclusions

High ARHGEF2 expression is associated with cell cycle progression, and predicts early recurrence and poor survival in patients with pancreatic cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.PubMedCrossRef
3.
Hartwig W, Werner J, Jager D, Debus J, Buchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14(11):e476–e85.PubMedCrossRef
4.
Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022.PubMedCrossRef
5.
Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.
6.
Wartenberg M, Cibin S, Zlobec I, Vassella E, Eppenberger-Castori S, Terracciano L, et al. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin Cancer Res. 2018;24(18):4444–54.PubMedCrossRef
7.
Jenkinson C, Elliott VL, Evans A, Oldfield L, Jenkins RE, O’’rien DP, et al. Decreased serum thrombospondin-1 levels in pancreatic cancer patients up to 24 months prior to clinical diagnosis: association with diabetes mellitus. Clin Cancer Res. 2016;22(7):1734–43.PubMedCrossRef
8.
Heeg S, Das KK, Reichert M, Bakir B, Takano S, Caspers J, et al. ETS-transcription factor ETV1 regulates stromal expansion and metastasis in pancreatic cancer. Gastroenterology. 2016;151(3):540–53 e14.
9.
Radon TP, Massat NJ, Jones R, Alrawashdeh W, Dumartin L, Ennis D, et al. Identification of a three-biomarker panel in urine for early detection of pancreatic adenocarcinoma. Clin Cancer Res. 2015;21(15):3512–21.PubMedPubMedCentralCrossRef
10.
Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33(28):3124–9.PubMedCrossRef
11.
12.
Aznar S, Fernandez-Valeron P, Espina C, Lacal JC. Rho GTPases: potential candidates for anticancer therapy. Cancer Lett. 2004;206(2):181–91.PubMedCrossRef
13.
Sahai E, Olson MF, Marshall CJ. Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J. 2001;20(4):755–66.PubMedPubMedCentralCrossRef
14.
Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005;118(Pt 5):843–6.PubMedCrossRef
15.
16.
Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10(12):842–57.PubMedPubMedCentralCrossRef
17.
18.
Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005;6(2):167–80.PubMedCrossRef
19.
Cook DR, Rossman KL, Der CJ. Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease. Oncogene. 2014;33(31):4021–35.PubMedCrossRef
20.
21.
Chen JC, Zhuang S, Nguyen TH, Boss GR, Pilz RB. Oncogenic Ras leads to Rho activation by activating the mitogen-activated protein kinase pathway and decreasing Rho-GTPase-activating protein activity. J Biol Chem. 2003;278(5):2807–18.PubMedCrossRef
22.
Cullis J, Meiri D, Sandi MJ, Radulovich N, Kent OA, Medrano M, et al. The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer Cell. 2014;25(2):181–95.PubMedCrossRef
23.
Ren Y, Li R, Zheng Y, Busch H. Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases. J Biol Chem. 1998;273(52):34954–60.PubMedCrossRef
24.
Cheng IK, Tsang BC, Lai KP, Ching AK, Chan AW, To KF, et al. GEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling. J Pathol. 2012;228(4):575–85.PubMedCrossRef
25.
Frolov A, Chahwan S, Ochs M, Arnoletti JP, Pan ZZ, Favorova O, et al. Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. Mol Cancer Ther. 2003;2(8):699–709.PubMed
26.
Birkenfeld J, Nalbant P, Yoon SH, Bokoch GM. Cellular functions of GEF-H1, a microtubule-regulated Rho-GEF: is altered GEF-H1 activity a crucial determinant of disease pathogenesis? Trends Cell Biol. 2008;18(5):210–9.PubMedCrossRef
27.
Nakagawa S, Okabe H, Sakamoto Y, Hayashi H, Hashimoto D, Yokoyama N, et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann Surg Oncol. 2013;20 Suppl 3:S667–75.PubMedCrossRef
28.
Izumi D, Ishimoto T, Miyake K, Sugihara H, Eto K, Sawayama H, et al. CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin beta1 clustering and invasiveness in gastric cancer. Int J Cancer. 2016;138(5):1207–19.PubMedCrossRef
29.
Umezaki N, Nakagawa S, Yamashita YI, Kitano Y, Arima K, Miyata T, et al. Lysyl oxidase induces epithelial-mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma. Cancer Sci. 2019;110(6):2033–43.PubMedPubMedCentral
30.
Okabe H, Beppu T, Ueda M, Hayashi H, Ishiko T, Masuda T, et al. Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int J Cancer. 2012;131(10):2234–41.PubMedCrossRef
31.
Nakagawa S, Sakamoto Y, Okabe H, Hayashi H, Hashimoto D, Yokoyama N, et al. Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol Rep. 2014;31(2):983–8.PubMedCrossRef
32.
Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53(4):549–54.PubMedCrossRef
33.
34.
Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988;16(16):7773–82.PubMedPubMedCentralCrossRef
35.
Kent OA, Sandi MJ, Burston HE, Brown KR, Rottapel R. An oncogenic KRAS transcription program activates the RHOGEF ARHGEF2 to mediate transformed phenotypes in pancreatic cancer. Oncotarget. 2017;8(3):4484–500.PubMedCrossRef
36.
Kent OA, Sandi MJ, Rottapel R. Co-dependency between KRAS addiction and ARHGEF2 promotes an adaptive escape from MAPK pathway inhibition. Small GTPases. 2019;10(6):441–8.PubMedCrossRef
37.
Krendel M, Zenke FT, Bokoch GM. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol. 2002;4(4):294–301.PubMedCrossRef
38.
Birukova AA, Adyshev D, Gorshkov B, Bokoch GM, Birukov KG, Verin AD. GEF-H1 is involved in agonist-induced human pulmonary endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2006;290(3):L540–8.PubMedCrossRef
39.
Liao YC, Ruan JW, Lua I, Li MH, Chen WL, Wang JR, et al. Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling. Oncogene. 2012;31(25):3086–97.PubMedCrossRef
40.
Ridgway LD, Wetzel MD, Ngo JA, Erdreich-Epstein A, Marchetti D. Heparanase-induced GEF-H1 signaling regulates the cytoskeletal dynamics of brain metastatic breast cancer cells. Mol Cancer Res. 2012;10(6):689–702.PubMedPubMedCentralCrossRef
41.
Cao J, Yang T, Tang D, Zhou F, Qian Y, Zou X. Increased expression of GEF-H1 promotes colon cancer progression by RhoA signaling. Pathol Res Pract. 2019;215(5):1012–9.PubMedCrossRef
42.
Ridgway LD, Wetzel MD, Marchetti D. Modulation of GEF-H1 induced signaling by heparanase in brain metastatic melanoma cells. J Cell Biochem. 2010;111(5):1299–309.PubMedPubMedCentralCrossRef
43.
Sauzeau V, Berenjeno IM, Citterio C, Bustelo XR. A transcriptional cross-talk between RhoA and c-Myc inhibits the RhoA/Rock-dependent cytoskeleton. Oncogene. 2010;29(26):3781–92.PubMedPubMedCentralCrossRef
44.
45.
Shiio Y, Donohoe S, Yi EC, Goodlett DR, Aebersold R, Eisenman RN. Quantitative proteomic analysis of Myc oncoprotein function. EMBO J. 2002;21(19):5088–96.PubMedPubMedCentralCrossRef
46.
Fukasawa T, Enomoto A, Miyagawa K. Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint. Cell Signal. 2015;27(8):1569–75.PubMedCrossRef
47.
Yuan P, Li J, Zhou F, Huang Q, Zhang J, Guo X, et al. NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell Death Dis. 2017;8(3):e2704.PubMedPubMedCentralCrossRef
48.
Siu MK, Chan HY, Kong DS, Wong ES, Wong OG, Ngan HY, et al. p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. Proc Natl Acad Sci U S A. 2010;107(43):18622–7.PubMedPubMedCentralCrossRef
49.
Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci U S A. 1999;96(3):1002–7.PubMedPubMedCentralCrossRef
50.
Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998;282(5393):1497–501.PubMedCrossRef
51.
Gao X, Wang Q, Wang Y, Liu J, Liu S, Liu J, et al. The REGgamma inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells. Nat Commun. 2020;11(1):3904.PubMedPubMedCentralCrossRef
52.
Vigneron A, Cherier J, Barre B, Gamelin E, Coqueret O. The cell cycle inhibitor p21waf1 binds to the myc and cdc25A promoters upon DNA damage and induces transcriptional repression. J Biol Chem. 2006;281(46):34742–50.PubMedCrossRef
Metadata
Title
High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer
Authors
Yosuke Nakao, MD
Shigeki Nakagawa, MD, PhD
Yo-ichi Yamashita, MD, PhD, FACS
Naoki Umezaki, MD, PhD
Yuya Okamoto, BM
Yoko Ogata, BS
Noriko Yasuda-Yoshihara, PhD
Rumi Itoyama, MD
Toshihiko Yusa, MD
Kohei Yamashita, MD, PhD
Tatsunori Miyata, MD, PhD
Hirohisa Okabe, MD, PhD
Hiromitsu Hayashi, MD, PhD, FACS
Katsunori Imai, MD, PhD, FACS
Hideo Baba, MD, PhD, FACS
Publication date
01-08-2021
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 8/2021
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-09383-9

Other articles of this Issue 8/2021

Annals of Surgical Oncology 8/2021 Go to the issue

Peritoneal Surface Malignancy

The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases

ASO Author Reflections

ASO Author Reflections: Evidence for Limiting Perioperative Allogenic Blood Transfusions for Patients Undergoing CRS/HIPEC

Melanoma

Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA–D Melanoma

ASO Author Reflections

ASO Author Reflections: Gene Expression Profiling for Melanoma: Is it Ready for Prime Time?

Endocrine Tumors

Total Thyroidectomy and Low-Risk Thyroid Cancer: Are We Treating the Surgeon or Patient?

ASO Author Reflections

ASO Author Reflections: Proposed Nodal Categories for Future Editions of the TNM Classification of Non-small Cell Lung Cancer