Skip to main content

Advertisement

SpringerLink
Log in

REG1A Expression Status Suggests Chemosensitivity Among Advanced Thoracic Esophageal Squamous Cell Carcinoma Patients Treated with Esophagectomy Followed by Adjuvant Chemotherapy

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

Abstract

Background

Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in the mucous membrane of the gastrointestinal tract. We previously reported that the positive expression status of REG1A was predictive of chemoradiosensitivity in patients treated with preoperative chemoradiotherapy before esophagectomy or with definitive chemoradiotherapy. To further confirm the utility of REG1A as a chemosensitivity marker, we carried out an additional retrospective clinical study aimed at determining whether REG1A is a reliable chemosensitivity marker in patients treated with esophagectomy followed by adjuvant chemotherapy.

Method

A total of 177 patients with T2–4 thoracic esophageal squamous cell carcinoma received curative surgery without preoperative treatment at Akita University Hospital between 2001 and 2011. A tissue microarray was constructed, and REG1A expression status was analyzed immunohistochemically. We then statistically analyzed the relationships between REG1A expression status and 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).

Results

In the adjuvant group (n = 105), REG1A-positive patients showed significantly better prognoses than REG1A-negative patients. (5-year OS, p = .0022; DSS, p = .0004; and DFS, p = .0040). However, there were no significant differences between REG1A-positive and REG1A-negative patients in the surgery group (n = 72). Univariate and multivariate analyses showed REG1A expression status to be a significant prognostic factor affecting 5-year DSS, comparable to lymph node metastatic status.

Conclusion

The present study suggests REG1A expression status has the potential to be a highly reliable and clinically useful chemosensitivity marker in patients treated with advanced thoracic esophageal squamous cell carcinoma. REG1A expression status will provide a good indication of treatment strategy and enable more individualized treatment for patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg. 2002;232:225–32.

    Article  Google Scholar 

  2. Law S, Kwong D, Wong KF, Wong KH, Chu KM, Sham JS, et al. Improvement in treatment results and long-term survival of patients with esophageal cancer: Impact of chemoradiation and change in treatment strategy. Ann Surg. 2003;238:339–47.

    PubMed  Google Scholar 

  3. Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol. 2003;21:4592–6.

    Article  PubMed  Google Scholar 

  4. Kato K, Muro K, Minashi K, Ohtsu A, Ishikura S, Boku N, et al. Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for Stage II–III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906). Int J Radiat Oncol Biol Phys. 2011;81:684–90.

    Article  PubMed  CAS  Google Scholar 

  5. Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19:68–74.

    Article  PubMed  Google Scholar 

  6. Sanuki N, Ishikura S, Shinoda M, Ito Y, Hayakawa K, Ando N. Radiotherapy quality assurance review for a multi-center randomized trial of locally advanced esophageal cancer: the Japan Clinical Oncology Group (JCOG) trial 0303. Int J Clin Oncol. 2012;17:105–11.

    Article  PubMed  Google Scholar 

  7. Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y, et al. A novel gene activated in regenerating islets. J Biol Chem. 1988;263:2111–4.

    PubMed  CAS  Google Scholar 

  8. Watanabe T, Yonekura H, Terazono K, Yamamoto H, Okamoto H. Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. J Biol Chem. 1990;265:7432–9.

    PubMed  CAS  Google Scholar 

  9. Miyaoka Y, Kadowaki Y, Ishihara S, Ose T, Fukuhara H, Kazumori H, et al. Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages. Oncogene. 2004;23:3572–9.

    Article  PubMed  CAS  Google Scholar 

  10. Unno M, Itoh T, Watanabe T, Miyashita H, Moriizumi S, Teraoka H, et al. Islet beta-cell regeneration and reg genes. Adv Exp Med Biol. 1992;321:61–9.

    Article  PubMed  CAS  Google Scholar 

  11. Sekikawa A, Fukui H, Fujii S, Ichikawa K, Tomita S, Imura J, et al. REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. Carcinogenesis. 2008;29:76–83.

    Article  PubMed  CAS  Google Scholar 

  12. Yoshino N, Ishihara S, Rumi MA, Ortega-Cava CF, Yuki T, Kazumori H, et al. Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol. 2005;100:2157–66.

    Article  PubMed  CAS  Google Scholar 

  13. Astrosini C, Roeefzaad C, Dai YY, Dieckgraefe BK, Jöns T, Kemmner W. REG1A expression is a prognostic marker in colorectal cancer and associated with peritoneal carcinomatosis. Int J Cancer. 2008;123:409–13.

    Article  PubMed  CAS  Google Scholar 

  14. Lee WS, Seo G, Shin HJ, Yun SH, Yun H, Choi N, et al. Identification of differentially expressed genes in microsatellite stable HNPCC and sporadic colon cancer. J Surg Res. 2008;144:29–35.

    Article  PubMed  CAS  Google Scholar 

  15. Kimura N, Yonekura H, Okamoto H, Nagura H. Expression of human regenerating gene mRNA and its product in normal and neoplastic human pancreas. Cancer. 1992;70:1857–63.

    Article  PubMed  CAS  Google Scholar 

  16. Cavard C, Terris B, Grimber G, Christa L, Audard V, Radenen-Bussiere B, et al. Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations. Oncogene. 2006;25:599–608.

    Article  PubMed  CAS  Google Scholar 

  17. Minamiya Y, Kawai H, Saito H, Ito M, Hosono Y, Motoyama S, et al. REG1A expression is an independent factor predictive of poor prognosis in patients with non-small cell lung cancer. Lung Cancer. 2008;60:98–104.

    Article  PubMed  Google Scholar 

  18. Sasaki Y, Minamiya Y, Takahashi N, Nakagawa T, Katayose Y, Ito A, et al. REG1A expression is an independent factor predictive of poor prognosis in patients with breast cancer. Ann Surg Oncol. 2008;15:3244–51.

    Article  PubMed  Google Scholar 

  19. Geng J, Fan J, Wang P, Fang ZJ, Xia GW, Jiang HW, et al. REG1A predicts recurrence in stage Ta/T1 bladder cancer. Eur J Surg Oncol. 2009;35:852–7.

    Article  PubMed  CAS  Google Scholar 

  20. Motoyama S, Sugiyama T, Ueno Y, Okamoto H, Takasawa S, Nanjo H, et al. REG I expression predicts long-term survival among locally advanced thoracic squamous cell esophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Ann Surg Oncol. 2006;13:1724–31.

    Article  PubMed  Google Scholar 

  21. Hayashi K, Motoyama S, Sugiyama T, Izumi J, Anbai A, Nanjo H, et al. REG Ialpha is a reliable marker of chemoradiosensitivity in squamous cell esophageal cancer patients. Ann Surg Oncol. 2008;15:1224–31.

    Article  PubMed  Google Scholar 

  22. Hayashi K, Motoyama S, Koyota S, Koizumi Y, Wang J, Takasawa S, et al. REG I enhances chemo- and radiosensitivity in squamous cell esophageal cancer cells. Cancer Sci. 2008;99:2491–5.

    Article  PubMed  CAS  Google Scholar 

  23. Sato Y, Motoyama S, Maruyama K, Yoshino K, Sasaki T, Wakita A, et al. CMV reactivation caused by methylprednisolone therapy for ARDS after esophagectomy. Esophagus. 2012;9:141–6.

    Article  Google Scholar 

  24. Motoyama S, Saito R, Kitamura M, Ogawa J. Outcome of active surgery during intensive follow-up for second primary malignancy after esophagectomy for thoracic squamous cell esophageal carcinoma. J Am Coll Surg. 2003;197:914–20.

    Article  PubMed  Google Scholar 

  25. Sato Y, Motoyama S, Maruyama K, Okuyama M, Ogawa J, et al. A second malignancy is the major cause of death among thoracic squamous cell esophageal cancer patients negative for lymph node involvement. J Am Coll Surg. 2005;201:188–93.

    Article  PubMed  Google Scholar 

  26. Camp RL, Neumeister V, Rimm DL. A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers. J Clin Oncol. 2008;26:5630–7.

    Article  PubMed  Google Scholar 

  27. Camp RL, Charette LA, Rimm DL. Validation of tissue microarray technology in breast carcinoma. Lab Invest. 2000;80:1943–9.

    Article  PubMed  CAS  Google Scholar 

  28. Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Köchli OR, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001;159:2249–56.

    Article  PubMed  CAS  Google Scholar 

  29. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.

    Article  PubMed  CAS  Google Scholar 

  30. Miyata H, Doki Y, Shinozaki H, Inoue M, Yano M, Fujiwara Y, et al. CDC25B and p53 are independently implicated in radiation sensitivity for human esophageal cancers. Clin Cancer Res. 2000;6:4859–65.

    PubMed  CAS  Google Scholar 

  31. Takasawa S, Ikeda T, Akiyama T, Nata K, Nakagawa K, Shervani NJ, et al. CyclinD1 activation through ATF-2 in Reg-induced pancreatic b-cell regeneration. FEBS Lett. 2006;580:585–91.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by Takeda Science Foundation.

Author information

Authors and Affiliations

  1. Department of Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan

    Yusuke Sato MD, PhD, Satoru Motoyama MD, PhD, Kei Yoshino MD, PhD, Tomohiko Sasaki MD, PhD, Kuniaki Kuribayashi MD, Yushi Nagaki MD, Kazuhiro Imai MD, PhD, Hajime Saito MD, PhD, Yoshihiro Minamiya MD, PhD & Jun-ichi Ogawa MD, PhD

  2. Department of Pathology, Akita University Graduate School of Medicine, Akita, 010-8543, Japan

    Hiroshi Nanjo MD, PhD & Satoru Ito

Authors
  1. Yusuke Sato MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoru Motoyama MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroshi Nanjo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoru Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kei Yoshino MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomohiko Sasaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kuniaki Kuribayashi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yushi Nagaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuhiro Imai MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hajime Saito MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshihiro Minamiya MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jun-ichi Ogawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusuke Sato MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sato, Y., Motoyama, S., Nanjo, H. et al. REG1A Expression Status Suggests Chemosensitivity Among Advanced Thoracic Esophageal Squamous Cell Carcinoma Patients Treated with Esophagectomy Followed by Adjuvant Chemotherapy. Ann Surg Oncol 20, 3044–3051 (2013). https://doi.org/10.1245/s10434-013-2983-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-2983-9

Keywords

Search

Navigation