Tumor Biology

, Volume 36, Issue 2, pp 1251–1259 | Cite as

KCNJ1 inhibits tumor proliferation and metastasis and is a prognostic factor in clear cell renal cell carcinoma

  • Zhongqiang Guo
  • Jin Liu
  • Lian Zhang
  • Boxing Su
  • Yunchao Xing
  • Qun He
  • Weimin Ci
  • Xuesong Li
  • Liqun Zhou
Research Article
  • 270 Downloads

Abstract

Potassium inwardly rectifying channel, subfamily J, member 1 (KCNJ1), as an ATP-dependent potassium channel, plays an essential role in potassium balance. KCNJ1 variation is associated with multiple diseases, such as antenatal Bartter syndrome and diabetes. However, the role of KCNJ1 in clear cell renal cell carcinoma (ccRCC) is still unknown. Here, we studied the expression and function of KCNJ1 in ccRCC. The expression of KCNJ1 was evaluated in ccRCC tissues and cell lines by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry analysis. The relationship between KCNJ1 expression and clinicopathological characteristics was analyzed. p3xFLAG-CMV-14 vector containing KCNJ1 was constructed and used for transfecting ccRCC cell lines 786-O and Caki-2. The effects of KCNJ1 on cell proliferation, invasion, and apoptosis were detected in ccRCC cell lines using cell proliferation assay, transwell assay, and flow cytometry, respectively. We found that KCNJ1 was low-expressed in ccRCC tissues samples and cell lines, and its expression level was significantly associated with tumor pathology grade (P = 0.002) and clinical stage (P = 0.023). Furthermore, the KCNJ1 expression was a prognostic factor of ccRCC patient’s survival (P = 0.033). The re-expression of KCNJ1 in 786-O and Caki-2 significantly inhibited cancer cell growth and invasion and promoted cancer cell apoptosis. Moreover, knockdown of KCNJ1 in HK-2 cells promoted cell proliferation. Collectively, these data highlight that KCNJ1, low-expressed in ccRCC and associated with poor prognosis, plays an important role in ccRCC cell growth and metastasis.

Keywords

KCNJ1 Clear cell renal cell carcinoma Prognostic factor Proliferation Invasion Apoptosis 

Notes

Acknowledgments

This project was supported by grants from the National Natural Science Foundation of China (No. 81372746).

Conflicts of interest

None

References

  1. 1.
    Vasudev NS, Selby PJ, Banks RE. Renal cancer biomarkers: the promise of personalized care. BMC Med. 2012;10:112.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49:798–805.CrossRefPubMedGoogle Scholar
  4. 4.
    Patil S, Manola J, Elson P, Negrier S, Escudier B, Eisen T, et al. Improvement in overall survival of patients with advanced renal cell carcinoma: prognostic factor trend analysis from an international data set of clinical trials. J Urol. 2012;188:2095–100.CrossRefPubMedGoogle Scholar
  5. 5.
    He GC, Wang HR, Huang SK, Huang CL. Intersectin links WNK kinases to endocytosis of ROMK1. J Clin Investig. 2007;117:1078–87.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity and regulation of renal potassium channels. Physiol Rev. 2005;85:319–71.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Foster DB, Ho AS, Rucker J, Garlid AO, Chen L, Sidor A, et al. Mitochondrial ROMK channel is a molecular component of mitoK(ATP). Circ Res. 2012;111:446–54.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    O’Connell AD, Leng Q, Dong K, MacGregor GG, Giebisch G, Hebert SC. Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK). Proc Natl Acad Sci U S A. 2005;102:9954–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yue P, Lin DH, Pan CY, Leng Q, Giebisch G, Lifton RP, et al. Src family protein tyrosine kinase (PTK) modulates the effect of SGK1 and WNK4 on ROMK channels. Proc Natl Acad Sci U S A. 2009;106:15061–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lin D, Sterling H, Lerea KM, Giebisch G, Wang WH. Protein kinase c (PKC)-induced phosphorylation of ROMK1 is essential for the surface expression of ROMK1 channels. J Biol Chem. 2002;277:44278–84.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yoo D, Kim BY, Campo C, Nance L, King A, Maouyo D, et al. Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase a. J Biol Chem. 2003;278:23066–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Srivastava S, Li D, Edwards N, Hynes AM, Wood K, Al-Hamed M, et al. Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter’s syndrome and a functional analysis of their pathogenicity. Physiol Rep. 2013;1:e00160.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Huang L, Luiken GPM, van Riemsdijk IC, Petrij F, Zandbergen AAM, Dees A. Nephrocalcinosis as adult presentation of Bartter syndrome type II. Neth J Med. 2014;72:91–3.PubMedGoogle Scholar
  14. 14.
    Cho JT, Guay-Woodford LM. Heterozygous mutations of the gene for Kir 1.1 (ROMK) in antenatal Bartter syndrome presenting with transient hyperkalemia, evolving to a benign course. J Korean Med Sci. 2003;18:65–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fretzayas A, Gole E, Attilakos A, Daskalaki A, Nicolaidou P, Papadopoulou A. Expanding the spectrum of genetic mutations in antenatal Bartter syndrome type II. Pediatr Int. 2013;55:371–3.CrossRefPubMedGoogle Scholar
  16. 16.
    Karnes JH, McDonough CW, Gong Y, Vo TT, Langaee TY, Chapman AB, et al. Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment. Pharmacogenomic J. 2013;13:430–6.CrossRefGoogle Scholar
  17. 17.
    Zhou X, Zhang Z, Shin MK, Horwitz SB, Levorse JM, Zhu L, et al. Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure. Hypertension. 2013;62:288–94.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhu X, Liang J, Shrubsole MJ, Ness RM, Cai Q, Long J, Chen Z, Li G, Wiese D, Zhang B, Smalley WE, Edwards TL, Giovannucci E, Zheng W, Dai Q. Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study. J Nutr. 2014; [Epub ahead of print] doi: 10.3945/jn.114.196709.
  19. 19.
    Valletti A, Gigante M, Palumbo O, Carella M, Divella C, Sbisa E, et al. Genome-wide analysis of differentially expressed genes and splicing isoforms in clear cell renal cell carcinoma. PLoS One. 2013;8:e78452.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wahafu W, He ZS, Zhang XY, Zhang CJ, Yao K, Hao H, et al. The nucleosome binding protein nsbp1 is highly expressed in human bladder cancer and promotes the proliferation and invasion of bladder cancer cells. Tumour Biol. 2011;32:931–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Gamba G, Friedman PA. Thick ascending limb: The Na(+):K (+):2Cl (−) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflug Arch Eur J Phys. 2009;458:61–76.CrossRefGoogle Scholar
  22. 22.
    Sahmoun AE, Singh BB. Does a higher ratio of serum calcium to magnesium increase the risk for postmenopausal breast cancer? Med Hypotheses. 2010;75:315–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cheng MH, Chiu HF, Tsai SS, Chen CC, Yang CY. Calcium and magnesium in drinking-water and risk of death from lung cancer in women. Magnes Res. 2012;25:112–9.PubMedGoogle Scholar
  24. 24.
    Dai Q, Motley SS, Smith Jr JA, Concepcion R, Barocas D, Byerly S, et al. Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer. PLoS One. 2011;6:e18237.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Zhongqiang Guo
    • 1
    • 2
    • 3
  • Jin Liu
    • 1
    • 2
    • 3
  • Lian Zhang
    • 1
    • 2
    • 3
  • Boxing Su
    • 1
    • 2
    • 3
  • Yunchao Xing
    • 1
    • 2
    • 3
  • Qun He
    • 1
    • 2
    • 3
  • Weimin Ci
    • 4
  • Xuesong Li
    • 1
    • 2
    • 3
  • Liqun Zhou
    • 1
    • 2
    • 3
  1. 1.Department of UrologyPeking University First HospitalBeijingChina
  2. 2.The Institute of UrologyPeking UniversityBeijingChina
  3. 3.National Urological Cancer CenterBeijingChina
  4. 4.Beijing Institute of GenomicsChinese Academy of SciencesBeijingChina

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