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

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Acknowledgment

The authors thank Hiroko Taniguchi for her valuable technical assistance, and Joe Barber Jr, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.

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Correspondence to Hideo Baba MD, PhD, FACS.

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Disclosures

Yosuke Nakao, Shigeki Nakagawa, Yo-ichi Yamashita, Naoki Umezaki, Yuya Okamoto, Yoko Ogata, Noriko Yasuda-Yoshihara, Rumi Itoyama, Toshihiko Yusa, Kohei Yamashita, Tatsunori Miyata, Hirohisa Okabe, Hiromitsu Hayashi, Katsunori Imai, and Hideo Baba have no conflicts of interest in association with this study. No financial support was received for the work described in this manuscript.

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Nakao, Y., Nakagawa, S., Yamashita, Yi. et al. High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer. Ann Surg Oncol 28, 4733–4743 (2021). https://doi.org/10.1245/s10434-020-09383-9

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