Expression and Role of CFTR in Human Esophageal Squamous Cell Carcinoma

Overview

Journal Ann Surg Oncol

Publisher Springer

Specialty Oncology

Date 2021 Mar 12

PMID 33710504

Citations 7

Authors

Yoshihisa Matsumoto

Atsushi Shiozaki

Toshiyuki Kosuga

Michihiro Kudou

Hiroki Shimizu

Tomohiro Arita

Hirotaka Konishi

Shuhei Komatsu

Takeshi Kubota

Hitoshi Fujiwara

Kazuma Okamoto

Mitsuo Kishimoto

Eiichi Konishi

Eigo Otsuji

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Schwiebert E, Benos D, Egan M, Stutts M, Guggino W . CFTR is a conductance regulator as well as a chloride channel. Physiol Rev. 1999; 79(1 Suppl):S145-66. DOI: 10.1152/physrev.1999.79.1.S145. View

Bear C, Li C, Kartner N, Bridges R, Jensen T, Ramjeesingh M . Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992; 68(4):809-18. DOI: 10.1016/0092-8674(92)90155-6. View

Than B, Linnekamp J, Starr T, Largaespada D, Rod A, Zhang Y . CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene. 2016; 35(32):4179-87. PMC: 4940277. DOI: 10.1038/onc.2015.483. View

Moskowitz S, Chmiel J, Sternen D, Cheng E, Gibson R, Marshall S . Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders. Genet Med. 2008; 10(12):851-68. PMC: 2810953. DOI: 10.1097/GIM.0b013e31818e55a2. View

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(6):758-767. DOI: 10.1016/S1470-2045(18)30188-8. View

McWilliams R, Petersen G, Rabe K, Holtegaard L, Lynch P, Bishop M . Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer. 2009; 116(1):203-9. PMC: 2807917. DOI: 10.1002/cncr.24697. View

Peng X, Wu Z, Yu L, Li J, Xu W, Chan H . 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. DOI: 10.1016/j.ygyno.2012.02.015. View

Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H . 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. 2011; 19(1):68-74. DOI: 10.1245/s10434-011-2049-9. View

Saigusa S, Tanaka K, Mohri Y, Ohi M, Shimura T, Kitajima T . Clinical significance of RacGAP1 expression at the invasive front of gastric cancer. Gastric Cancer. 2014; 18(1):84-92. DOI: 10.1007/s10120-014-0355-1. View

10.

Rodrigues I, Lavorato-Rocha A, de M Maia B, Stiepcich M, de Carvalho F, Baiocchi G . Epithelial-mesenchymal transition-like events in vulvar cancer and its relation with HPV. Br J Cancer. 2013; 109(1):184-94. PMC: 3721089. DOI: 10.1038/bjc.2013.273. View

11.

Liu H, Wu W, Liu Y, Zhang C, Zhou Z . Predictive value of cystic fibrosis transmembrane conductance regulator (CFTR) in the diagnosis of gastric cancer. Clin Invest Med. 2014; 37(4):E226-32. DOI: 10.25011/cim.v37i4.21728. View

12.

Zhong X, Chen H, Yang X, Wang Q, Chen W, Li C . CFTR activation suppresses glioblastoma cell proliferation, migration and invasion. Biochem Biophys Res Commun. 2018; 508(4):1279-1285. DOI: 10.1016/j.bbrc.2018.12.080. View

13.

Li J, Zhang J, Jiang X, Shi X, Shen J, Feng F . The cystic fibrosis transmembrane conductance regulator as a biomarker in non-small cell lung cancer. Int J Oncol. 2015; 46(5):2107-15. DOI: 10.3892/ijo.2015.2921. View

14.

Tu Z, Chen Q, Zhang J, Jiang X, Xia Y, Chan H . CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis. Oncotarget. 2016; 7(47):76955-76965. PMC: 5363562. DOI: 10.18632/oncotarget.12762. View

15.

Zhang J, Jiang X, Xie C, Cheng H, Dong J, Wang Y . Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta. 2013; 1833(12):2961-2969. DOI: 10.1016/j.bbamcr.2013.07.021. View

16.

Su M, Chang W, Zhang K, Cui M, Wu S, Xu T . Expression and purification of recombinant ATF-mellitin, a new type fusion protein targeting ovarian cancer cells, in P. pastoris. Oncol Rep. 2016; 35(2):1179-85. DOI: 10.3892/or.2015.4448. View

17.

Olson J, Hallahan A . p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med. 2004; 10(3):125-9. DOI: 10.1016/j.molmed.2004.01.007. View

18.

Bulavin D, Fornace Jr A . p38 MAP kinase's emerging role as a tumor suppressor. Adv Cancer Res. 2004; 92:95-118. DOI: 10.1016/S0065-230X(04)92005-2. View

19.

Wen G, Deng S, Song W, Jin H, Xu J, Liu X . Helicobacter pylori infection downregulates duodenal CFTR and SLC26A6 expressions through TGFβ signaling pathway. BMC Microbiol. 2018; 18(1):87. PMC: 6098588. DOI: 10.1186/s12866-018-1230-8. View

20.

Miyazaki H, Shiozaki A, Niisato N, Ohsawa R, Itoi H, Ueda Y . 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. 2007; 366(2):506-12. DOI: 10.1016/j.bbrc.2007.11.144. View