Skip to main content

Advertisement

SpringerLink
Log in

Expression and Role of CFTR in Human Esophageal Squamous Cell Carcinoma

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

Abstract

Background

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride (Cl−) anion conducting channel, and its role in esophageal squamous cell carcinoma (ESCC) was examined in the present study.

Methods

Overexpression experiments were conducted on human ESCC cell lines following the transfection of a CFTR plasmid, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. A microarray analysis was performed to examine gene expression profiles. Fifty-three primary tumor samples collected from ESCC patients during esophagectomy were subjected to an immunohistochemical analysis.

Results

Transfection of the CFTR plasmid into the ESCC KYSE 170 and KYSE 70 cell lines suppressed cell proliferation, migration, and invasion and induced apoptosis. The microarray analysis showed the up-regulated expression of genes involved in the p38 signaling pathway in CFTR plasmid-transfected KYSE 170 cells. Immunohistochemical staining revealed a relationship between the CFTR expression pattern at the invasive front and the pN category. A relationship was also observed between the weak expression of CFTR at the invasive front and a shorter postoperative survival in a prognostic analysis.

Conclusions

The overexpression of CFTR in ESCC activated the p38 signaling pathway and was associated with a good patient prognosis. These results indicate the potential of CFTR as a mediator of and/or a biomarker for ESCC.

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
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB. CFTR is a conductance regulator as well as a chloride channel. Physiol Rev. 1999;79(Suppl 1):S145–66. https://doi.org/10.1152/physrev.1999.79.1.S145.

    Article  CAS  PubMed  Google Scholar 

  2. Bear CE, Li C, Kattner N, et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992;68:809–18. https://doi.org/10.1016/0092-8674(92)90155-6.

    Article  CAS  PubMed  Google Scholar 

  3. Than BLN, Linnekamp JF, Starr TK, et al. CFTR is a tumor suppressor in murine and human intestinal cancer. Oncogene. 2016;35(32):4179–87. https://doi.org/10.1038/onc.2015.483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Moskowitz SM, Chmiel JF, Sternen DL, et al. Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders. Genet Med. 2008;10:851–68. https://doi.org/10.1097/GIM.0b013e31818e55a2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yamada A, Komaki Y, Komaki F, Micic D, Zullow S, Sakuraba A. Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis. Lancet Oncol. 2018;19:758–67. https://doi.org/10.1016/S1470-2045(18)30188-8.

    Article  PubMed  Google Scholar 

  6. Mcwilliams RR, Petersen GM, Rabe KG, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer. 2010;116:203–9. https://doi.org/10.1002/cncr.24697.

    Article  CAS  PubMed  Google Scholar 

  7. Peng X, Wu Z, Yu L, et al. Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis. Gynecol Oncol. 2012;125(2):470–6. https://doi.org/10.1016/j.ygyno.2012.02.015.

    Article  CAS  PubMed  Google Scholar 

  8. Sobin L, Gospodarowicz M, Wittekind C. TNM classification of malignant tumors. 7th edn. Hoboken: Wiley; 2009.

    Google Scholar 

  9. Ando N, Kato H, Igaki 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. https://doi.org/10.1245/s10434-011-2049-9.

    Article  PubMed  Google Scholar 

  10. Saigusa Susumu, Tanaka Koji, Mohri Yasuhiko, et al. Clinical significance of RacGAP1 expression at the invasive front of gastric cancer. Gastric Cancer. 2015;18(1):84–92. https://doi.org/10.1007/s10120-014-0355-1.

    Article  CAS  PubMed  Google Scholar 

  11. Rodrigues IS, Lavorato-Rocha AM, de Maia M, et al. Epithelial-mesenchymal transition-like events in vulvar cancer and its relation with HPV. Br J Cancer. 2013;109(1):184–94. https://doi.org/10.1038/bjc.2013.273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu Haiyan, Wenyong Wu, Liu Yang, Zhang Changle, Zhou Zheng. Predictive value of cystic fibrosis transmembrane conductance regulator (CFTR) in the diagnosis of gastric cancer. Clin Invest Med. 2014;37:E226–32. https://doi.org/10.25011/cim.v37i4.21728.

    Article  CAS  PubMed  Google Scholar 

  13. Zhong Xiao, Chen Hong-Qi, Yang Xiu-Ling, Wang Qing, Chen Wenliang, Li Chunfu. CFTR activation suppresses glioblastoma cell proliferation, migration and invasion. Biochem Biophys Res Commun. 2019;508:1279–85. https://doi.org/10.1016/j.bbrc.2018.12.080.

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Zhang JT, Jiang X, et al. The cystic fibrosis transmembrane conductance regulator as a biomarker in non-small cell lung cancer. Int J Oncol. 2015;46:2107–15. https://doi.org/10.3892/ijo.2015.2921.

    Article  CAS  PubMed  Google Scholar 

  15. Xie C, Jiang XH, Zhang JT, et al. CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene. 2013;32(2282–2291):2291.e1-2291.e7. https://doi.org/10.1038/onc.2012.251.

    Article  CAS  Google Scholar 

  16. Tu Z, Chen QU, Zhang JT, Jiang X, Xia Y, Chan HC. CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis. Oncotarget. 2016;7:76955–65. https://doi.org/10.18632/oncotarget.12762.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang JT, Jiang XH, Xie C, et al. Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta. 2013;1833:2961–9. https://doi.org/10.1016/j.bbamcr.2013.07.021.

    Article  CAS  PubMed  Google Scholar 

  18. Xu J, Yong M, Li J, et al. High level of CFTR expression is associated with tumor aggression and knockdown of CFTR suppresses proliferation of ovarian cancer in vitro and vivo. Oncol Rep. 2015. https://doi.org/10.3892/or.2015.3829.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Olson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med. 2004;10(3):125–9. https://doi.org/10.1016/j.molmed.2004.01.007.

    Article  CAS  PubMed  Google Scholar 

  20. Bulavin DV, Fornace AJ. p38 MAP kinase’s emerging role as a tumor suppressor. Adv Cancer Res. 2004;92:95–118. https://doi.org/10.1016/S0065-230X(04)92005-2.

    Article  CAS  PubMed  Google Scholar 

  21. Wen Guorong, Deng Shili, Song Wenfeng, et al. Helicobacter pylori infection downregulates duodenal CFTR and SLC26A6 expressions through TGFβ signaling pathway. BMC Microbiol. 2018;18:87. https://doi.org/10.1186/s12866-018-1230-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Miyazaki H, Shiozaki A, Niisato N, et al. Chloride ions control the G1/S cell-cycle checkpoint by regulating the expression of p21 through a p53-independent pathway in human gastric cancer cells. Biochem Biophys Res Commun. 2008;366(2):506–12. https://doi.org/10.1016/j.bbrc.2007.11.144.

    Article  CAS  PubMed  Google Scholar 

  23. Ohsawa R, Miyazaki H, Niisato N, et al. Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells. J Cell Physiol. 2010;223(3):764–70. https://doi.org/10.1002/jcp.22088.

    Article  CAS  PubMed  Google Scholar 

  24. Shiozaki A, Otsuji E, Marunaka Y. Intracellular chloride regulates the G(1)/S cell cycle progression in gastric cancer cells. World J Gastrointest Oncol. 2011;3(8):119–22. https://doi.org/10.4251/wjgo.v3.i8.119.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tanaka S, Miyazaki H, Shiozaki A, Ichikawa D, Otsuji E, Marunaka Y. Cytosolic Cl- affects the anticancer activity of paclitaxel in the gastric cancer cell line, MKN28 cell. Cell Physiol Biochem. 2017;42(1):68–80. https://doi.org/10.1159/000477116.

    Article  CAS  PubMed  Google Scholar 

  26. Li W, Wang C, Peng X, Zhang H, Huang H, Liu H. CFTR inhibits the invasion and growth of esophageal cancer cells by inhibiting the expression of NF-κB. Cell Biol Int. 2018;42(12):1680–7. https://doi.org/10.1002/cbin.11069.

    Article  CAS  PubMed  Google Scholar 

  27. Maggiora P, Marchio S, Stella MC, et al. Overexpression of the RON gene in human breast carcinoma. Oncogene. 1998;16(22):2927–33. https://doi.org/10.1038/sj.onc.1201812.

    Article  CAS  PubMed  Google Scholar 

  28. Baljinnyam E, Umemura M, De Lorenzo MS, et al. Gβγ subunits inhibit Epac-induced melanoma cell migration. BMC Cancer. 2011;17(11):256. https://doi.org/10.1186/1471-2407-11-256.

    Article  CAS  Google Scholar 

  29. Krenzer S, Peterziel H, Mauch C, et al. Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment. J Invest Dermatol. 2011;131(11):2281–8. https://doi.org/10.1038/jid.2011.190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lou X, Han X, Jin C, et al. SOX2 targets fibronectin 1 to promote cell migration and invasion in ovarian cancer: new molecular leads for therapeutic intervention. OMICS. 2013;17(10):510–8. https://doi.org/10.1089/omi.2013.0058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang Chenlei, Liu Tieqin, Wang Gebang, et al. Rac3 regulates cell invasion, migration and EMT in lung adenocarcinoma through p38 MAPK pathway. J Cancer. 2017;8(13):2511–22. https://doi.org/10.7150/jca.18161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fang CX, Ma CM, Jiang L, et al. p38 MAPK is crucial for Wnt1- and Licl-induced epithelial mesenchymal transition. Curr Med Sci. 2018. https://doi.org/10.1007/s11596-018-1903-4.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by Grants-in-Aid for Scientific Research (C) (17K10602, 17K10710, 18K08628, 18K08689, 19K09202, and 19K09182) and a Grant-in-Aid for Young Scientists (19K18160) from the Japan Society for the Promotion of Science.

Author information

Author notes

  1. Yoshihisa Matsumoto and Atsushi Shiozaki have contributed equally to this work.

Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yoshihisa Matsumoto MD, Atsushi Shiozaki MD, PhD, Toshiyuki Kosuga MD, PhD, Michihiro Kudou MD, PhD, Hiroki Shimizu MD, PhD, Tomohiro Arita MD, PhD, Hirotaka Konishi MD, PhD, Shuhei Komatsu MD, PhD, Takeshi Kubota MD, PhD, Hitoshi Fujiwara MD, PhD, Kazuma Okamoto MD, PhD & Eigo Otsuji MD, PhD

  2. Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

    Mitsuo Kishimoto MD, PhD & Eiichi Konishi MD, PhD

Authors
  1. Yoshihisa Matsumoto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Shiozaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshiyuki Kosuga MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michihiro Kudou MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroki Shimizu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomohiro Arita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirotaka Konishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shuhei Komatsu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takeshi Kubota MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hitoshi Fujiwara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazuma Okamoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mitsuo Kishimoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eiichi Konishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eigo Otsuji MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Atsushi Shiozaki MD, PhD.

Ethics declarations

Disclosures

There are no conflicts of interest or financial ties to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsumoto, Y., Shiozaki, A., Kosuga, T. et al. Expression and Role of CFTR in Human Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 28, 6424–6436 (2021). https://doi.org/10.1245/s10434-021-09752-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-021-09752-y

Search

Navigation