Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma

  • 14 Accesses



We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients.


KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed.


The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels.


KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

  2. 2.

    Chen H, Zhou L, Yang Y, Yang L, Chen L. Clinical effect of radiotherapy combined with chemotherapy for non-surgical treatment of the esophageal squamous cell carcinoma. Med Sci Monit. 2018;24:4183–91.

  3. 3.

    Matsuda S, Takeuchi H, Kawakubo H, Ando N, Kitagawa Y. Current advancement in multidisciplinary treatment for resectable cStage II/III esophageal squamous cell carcinoma in Japan. Ann Thorac Cardiovasc Surg. 2016;22(5):275–83.

  4. 4.

    Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017;390(10110):2383–96.

  5. 5.

    Wang C, Wang J, Chen Z, Gao Y, He J. Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review. Chin. J. Cancer. 2017;36(1):65.

  6. 6.

    Kumakura Y, Yokobori T, Yoshida T, et al. Elucidation of the anatomical mechanism of nodal skip metastasis in superficial thoracic esophageal squamous cell carcinoma. Ann Surg Oncol. 2018;25(5):1221–8.

  7. 7.

    Wang Q, Ma C, Kemmner W. Wdr66 is a novel marker for risk stratification and involved in epithelial-mesenchymal transition of esophageal squamous cell carcinoma. BMC Cancer. 2013;13:137.

  8. 8.

    Xiao Z, Jia Y, Jiang W, Wang Z, Zhang Z, Gao Y. FOXM1: A potential indicator to predict lymphatic metastatic recurrence in stage IIA esophageal squamous cell carcinoma. Thorac Cancer. 2018;9(8):997–1004.

  9. 9.

    Uemura N, Kondo T. Current status of predictive biomarkers for neoadjuvant therapy in esophageal cancer. World J. Gastrointest. Pathophysiol. 2014;5(3):322–34.

  10. 10.

    Comes N, Serrano-Albarras A, Capera J, et al. Involvement of potassium channels in the progression of cancer to a more malignant phenotype. Biochim Biophys Acta. 2015;1848(10 Pt B):2477–92.

  11. 11.

    Kosuga T, Shiozaki A, Kudou M, et al. Blockade of potassium ion transports enhances hypotonicity-induced cytocidal effects in gastric cancer. Oncotarget. 2017;8(60):101394–405.

  12. 12.

    Lastraioli E, Iorio J, Arcangeli A. Ion channel expression as promising cancer biomarker. Biochim Biophys Acta. 2015;1848(10 Pt B):2685–702.

  13. 13.

    Liu Y, Wang H, Ni B, et al. Loss of KCNJ15 expression promotes malignant phenotypes and correlates with poor prognosis in renal carcinoma. Cancer Manag Res. 2019;11:1211–20.

  14. 14.

    Okamoto K, Iwasaki N, Nishimura C, et al. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus. Am J Hum Genet. 2010;86(1):54–64.

  15. 15.

    Gosset P, Ghezala GA, Korn B, et al. A new inward rectifier potassium channel gene (KCNJ15) localized on chromosome 21 in the Down syndrome chromosome region 1 (DCR1). Genomics. 1997;44(2):237–41.

  16. 16.

    Tanaka H, Shimada Y, Imamura M, Shibagaki I, Ishizaki K. Multiple types of aberrations in the p16 (INK4a) and the p15(INK4b) genes in 30 esophageal squamous-cell-carcinoma cell lines. Int J Cancer. 1997;70(4):437–42.

  17. 17.

    Umeda S, Kanda M, Koike M, et al. Copine 5 expression predicts prognosis following curative resection of esophageal squamous cell carcinoma. Oncology Reports. 2018;40(6):3772–80.

  18. 18.

    Miwa T, Kanda M, Koike M, et al. Identification of NCCRP1 as an epigenetically regulated tumor suppressor and biomarker for malignant phenotypes of squamous cell carcinoma of the esophagus. Oncol. Lett. 2017;14(4):4822–8.

  19. 19.

    Kanda M, Tanaka C, Kobayashi D, et al. Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer. Int. J. Cancer. 2016;139(10):2290–8.

  20. 20.

    Kanda M, Shimizu D, Tanaka H, et al. Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer. Brit. J. Surg 2018;105(10):1349–58.

  21. 21.

    Kanda M, Tanaka H, Shimizu D, et al. SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells. Oncogene. 2018;37(39):5355–66.

  22. 22.

    Kanda M, Shimizu D, Fujii T, et al. Function and diagnostic value of Anosmin-1 in gastric cancer progression. Int. J. Cancer. 2016;138(3):721–30.

  23. 23.

    Kanda M, Shimizu D, Tanaka H, et al. Significance of SYT8 for the detection, prediction, and treatment of peritoneal metastasis from gastric cancer. Ann. Surg. 2018;267(3):495–503.

  24. 24.

    deHart GW, Jin T, McCloskey DE, Pegg AE, Sheppard D. The alpha9beta1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel. Proc. Natl. Acad. Sci. USA. 2008;105(20):7188–93.

  25. 25.

    Vandenberg CA. Integrins step up the pace of cell migration through polyamines and potassium channels. Proc. Natl. Acad. Sci. USA. 2008;105(20):7109–10.

  26. 26.

    Veeravalli KK, Ponnala S, Chetty C, Tsung AJ, Gujrati M, Rao JS. Integrin alpha9beta1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway. Cell Signal. 2012;24(1):272–81.

  27. 27.

    Gupta SK, Vlahakis NE. Integrin alpha9beta1: unique signaling pathways reveal diverse biological roles. Cell Adh. Migr. 2010;4(2):194–8.

  28. 28.

    Wang XQ, Tang ZX, Yu D, et al. Epithelial but not stromal expression of collagen alpha-1(III) is a diagnostic and prognostic indicator of colorectal carcinoma. Oncotarget. 2016;7(8):8823–38.

  29. 29.

    Tan Y, Peng J, Wei D, Chen P, Zhao Y. Effect of Jagged1 on the proliferation and migration of colon cancer cells. Exp Ther Med. 2012;4(1):89–92.

  30. 30.

    Tian Y, Tian Y, Zhang W, et al. Junctional adhesion molecule-A, an epithelial-mesenchymal transition inducer, correlates with metastasis and poor prognosis in human nasopharyngeal cancer. Carcinogenesis. 2015;36(1):41–8.

  31. 31.

    Nava P, Capaldo CT, Koch S, et al. JAM-A regulates epithelial proliferation through Akt/beta-catenin signalling. EMBO Rep. 2011;12(4):314–20.

  32. 32.

    Chang L, Graham PH, Hao J, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013;4:e875.

  33. 33.

    Xu W, Yang Z, Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9(4):317–24.

  34. 34.

    Banyard J, Bielenberg DR. The role of EMT and MET in cancer dissemination. Connect. Tissue Res. 2015;56(5):403–13.

  35. 35.

    Paduch R. The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol. (Dordr). 2016;39(5):397–410.

Download references

Author information

Correspondence to Mitsuro Kanda MD, PhD, FACS.

Ethics declarations


Shunsuke Nakamura, Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Shinichi Umeda, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Kenji Omae, and Yasuhiro Kodera have no commercial interests to declare. No sources of financial or material support were used in the preparation of this study.

Additional information

Publisher's Note

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

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nakamura, S., Kanda, M., Koike, M. et al. KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol (2020). https://doi.org/10.1245/s10434-019-08189-8

Download citation