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MN/CA9 gene expression as a potential tumor marker for renal cell carcinoma

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Abstract

MN/CA9 is a cell surface glycoprotein and a tumor-associated antigen. It plays a crucial role in the regulation of cell proliferation and oncogenesis. There is no ideal tumor marker currently available for renal cell carcinoma (RCC) with sufficient sensitivity and specificity. Therefore, we studied MN/CA9 gene expression in the tumor tissue, apparently normal kidney tissue, preoperative blood, and urine samples of patients with RCC. We included thirty cases of renal tumors (26 RCC and 4 benign tumors) in the study. We applied an RT-PCR assay for MN/CA9 gene expression to 26 RCC kidney tumor samples and four benign kidney tumor tissue samples. We also evaluated MN/CA9 gene expression in preoperative blood and urine samples of 15 of these cases. Additionally, thirty-five grossly normal renal tissue samples, including 21 from kidneys with RCC, were also evaluated for gene expression. The RT-PCR analysis revealed that twenty-one out of 26 RCC tissue samples showed MN/CA9 gene expression compared to three out of 35 non-malignant renal tissue samples (p < 0.05). Two out of four benign renal tissue samples also expressed this gene. We also observed MN/CA9 gene expression in nine out of 15 blood samples and four out of 15 urine samples. All patients with urinary MN/CA9 gene expression showed expression in blood and tumor tissue samples. We found a correlation in terms of MN/CA9 expression between blood and tumor tissue samples of RCC patients as those who exhibit MN/CA9 expression in blood were also positive at the tumor tissue levels. The difference in MN/CA9 gene expression in tumor tissue, blood, and urine samples in relation to the stage of the disease, nuclear grade, and histological cell-type was not statistically significant. However, all the three patients who had metastatic RCC had MN/CA9 gene expression in their blood. The existence of a tumor-associated antigen such as MN/CA9 may present a possible target for molecular diagnosis and management of RCC.

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All data generated and analyzed during our study are included in the published article.

Abbreviations

CA9:

Carbonic anhydrase 9

DEPC:

Diethyl pyrocarbonate

DNA:

Deoxyribose nucleic acid

dNTP:

Deoxynucleoside triphosphate

RCC:

Renal cell carcinoma

RNA:

Ribonucleic acid

RT-PCR:

Reverse transcriptase polymerase chain reaction

References

  1. Belldegrun A, deKernion J, Walsh PC, Retik AB, Vaughan ED (eds) (1998) Renal tumors in Campbell's Urology, 7th edn, vol 3. WB Saunders Company, pp 2292–2293

  2. Tannenbaum M (1971) Ultrastructural pathology of human renal cell tumors. Pathol Ann 6:249–277

    CAS  Google Scholar 

  3. Robson CJ, Churchill BM, Anderson W (1969) The results of radical nephrectomy for renal cell carcinoma. J Urol 101:297–301

    Article  CAS  Google Scholar 

  4. Murakami Y, Kanda K, Tsuji M, Kanayama H, Kagawa S (1999) MN/CA9 gene expression as a potential biomarker in renal cell carcinoma. BJU Int 83:743–747

    Article  CAS  Google Scholar 

  5. Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B, Venugopal A, Balakrishnan L, Marimuthu A, Banerjee S, Somanathan DS, Sebastian A, Rani S, Ray S, Harrys Kishore CJ, Kanth S, Ahmed M, Kashyap MK, Mohmood R, Ramachandra YL, Krishna V, Rahiman BA, Mohan S, Ranganathan P, Ramabadran S, Chaerkady R (2009) Human Protein Reference Database–2009 update. Nucl Acids Res 37:D767–D772

    Article  CAS  Google Scholar 

  6. Igarashi T, Murakami S, Isaka S, Okano T, Shimazak IJ, Matsuzaki O (1991) Serum immunosuppressive acidic protein as a tumor marker for renal carcinoma. Eur Urol 19:332–335

    Article  CAS  Google Scholar 

  7. Yu CC, Chen K, Chen M, Huang J, Lin A, Lee Y, Chang L (1991) Serum iron as a tumor marker in renal cell carcinoma. Eur Urol 19:54–58

    Article  CAS  Google Scholar 

  8. Partin AW, Criley SR, Steiner MS, Hsieh K, Simons JW, Lumadue J, Carter HB, Marshall FF (1995) Serum ferritin as a clinical marker for renal cell carcinoma: influence of tumor volume. Urology 45:211–217

    Article  CAS  Google Scholar 

  9. Zhu YY, Takashi M, Miyake K, Kato K (1991) An immunochemical and immunohistochemical study of aldolase isoenzymes in renal cell carcinoma. J Urol 146:469–472

    Article  CAS  Google Scholar 

  10. Takashi M, Haimoto H, Tanaka J, Murase T, Kato K (1989) Evaluation of gamma enolase as a tumor marker for renal cell carcinoma. J Urol 141:830–834

    Article  CAS  Google Scholar 

  11. Takashi M, Zhu Y, Hasegawa S, Kato K (1992) Serum creatinine kinase B subunit in patients with renal cell carcinoma. Urol Int 48:144–148

    Article  CAS  Google Scholar 

  12. Kuroda N, Naruse K, Miyazaki E, Hayashi Y, Yoshikawa C, Ashida S, Moriki T, Yamasak iY, Numoto S, Yamamoto Y, Yamasaki I, Hiroi M, Shuin T, Enzan H (2000) Vinculin: its possible use as a marker of normal collecting ducts and renal neoplasms with collecting duct system phenotype. Mod Pathol 13:1109–1114

    Article  CAS  Google Scholar 

  13. Ljungberg B, Rasmuson T, Grankvist K (1992) Erythropoietin in renal cell carcinoma: evaluation of its usefulness as a tumor marker. Eur Urol 21:160–163

    Article  CAS  Google Scholar 

  14. Der C, Stanbridge EJ (1981) A tumor-specific membrane phosphoprotein marker in human cell hybrids. Cell 26:429–438

    Article  CAS  Google Scholar 

  15. Zhao Z, Liao G, Li Y, Zhou S, Zou H, Fernando S (2014) Prognostic value of carbonic anhydrase 9 immiuno histochemical expression in renal cell carcinoma: a meta analysis of the Literature. PLoS ONE 1–6.

  16. Opavský R, Pastoreková S, Zelník V, Gibadulinová A, Stanbridge EJ, Závada J, Kettmann R, Pastorek J (1996) Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33:480–487

    Article  Google Scholar 

  17. Pastorek J, Pastoreková S, Callebaut I, Mornon JP, Zelník V, Opavský R, Zat’ovicová M, Liao S, Portetelle D, Stanbridge, Jea E (1994) Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9:2877–2888

    CAS  PubMed  Google Scholar 

  18. Gomella LG, Raj GU, Moreno JG (1997) Reverse transcriptase-polymerase chain reaction for prostate-specific antigen in the management of prostate cancer. J Urol 158:336–337

    Google Scholar 

  19. Nakagawa Y, Uemura H, Shimizu K, Cho M, Yoshikawa M, Hirao Y, Yoshikawa K (2001) The role of MN/CA IX antigen in carcinogenesis and metastasis of renal cell carcinoma. Hinyokika Kiyo 47:809–814

    CAS  PubMed  Google Scholar 

  20. Klein A, Zemer R, Buchumensky V, Klaper R, Nissenkorn I (1998) Expression of cytokeratin 20 in urinary cytology of patients with bladder carcinoma. Cancer 82:349–354

    Article  CAS  Google Scholar 

  21. Soeth E, Vogel I, Röder C, Juhl H, Marxsen J, Krüger U, Henne-Bruns D, Kremer B, Kalthoff H (1997) A comparative analysis of bone marrow and venous blood isolates from disseminated tumor cells using reverse transcription PCR. Cancer Res 57:3106–3110

    CAS  PubMed  Google Scholar 

  22. Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, Horvath S, Leibovich BC, Chopra S, Liao SY, Stanbridge EJ, Lerman MI, Palotie A, Figlin RA, Belldegrun AS (2003) Carbonic anhydrase is an independent predictor of survival in advanced prognosis and therapy. Clin Cancer Res 9:802–811

    CAS  PubMed  Google Scholar 

  23. Li G, Cuilleron M, Cottier M, Gentil-Perret A, Lambert C, Genin C, Tostain J, Etienne S (2006) The use of MN/CA9 gene expression in identifying malignant solid renal tumors. Eur Urol 49:401–405

    Article  CAS  Google Scholar 

  24. Mulders P, Bleumer I, Oosterwijk E (2003) Tumor antigens and markers in renal cell carcinoma. Uro Clin N Am 30:455–456

    Article  Google Scholar 

  25. McKiernan JM, Buttyan R, Bander NH, de la Taille A, Stifelman MD, Emanuel ER, Bagiella E, Rubin MA, Katz AE, Olsson CA, Sawczuk IS (1999) The detection of renal carcinoma cells in the peripheral blood with an enhanced reverse transcriptase-polymerase chain reaction assay for MN/CA9. Cancer 86:492–497

    Article  CAS  Google Scholar 

  26. Takacova M, Bartosova M, Skvarkova L, Zatovicova M, Vidlickova I, Csaderova L, Barathova M, Breza JJ, Bujdak P, Pastorek J, Breza JS, Pastorekova S (2012) Carbonic anhydrase IX is a clinically significant tissue and serum biomarker associated with renal cell carcinoma. Oncol Lett 5:191–197. https://doi.org/10.3892/ol.2012.1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Uemura H, Nakagawa Y, Yoshida K, Saga S, Yoshikawa K, Hirao Y, Oosterwijk E (1999) MN/CA9/G250 as a potential target for immunotherapy of renal cell carcinoma. J Cancer 81:741–746

    Article  CAS  Google Scholar 

  28. de la Taille A, Katz A, Cao Y, McKiernan J, Buttyan R, Burchardt M, Burchardt T, Hayek O, Olsson CA, Chopin DK, Sawczuk IS (2000) Blood-based RT-PCR assays of MN/CA9 or PSMA: clinical application in renal cancer patients. Urology 56:393–398

    Article  Google Scholar 

  29. Courcier J, de la Taille A, Nourieh M, Leguerney I, Lassau N, Ingels A (2020) Carbonic anhydrase IX in renal cell carcinoma, implications for disease management. Int J Mol Sci 21:7146

    Article  CAS  Google Scholar 

  30. Gray RE, Harris GT (2019) Renal cell carcinoma: diagnosis and management. Am Fam Physician 99:179–184

    PubMed  Google Scholar 

  31. Feldstein MS, Rhodes DJ, Parker AS, Orford RR, Castle EP (2009) The haphazard approach to the early detection of asymptomatic renal cancer: results from a contemporary executive health programme. BJU Int 104:53–56. https://doi.org/10.1111/j.1464-410X.2008.08315.x

    Article  PubMed  Google Scholar 

  32. Li G, Feng G, Gentil-Perret A, Genin C, Tostain J (2008) Serum Carbonic anhydrase 9 level is associated with post operative recurrence of conventional renal cell carcinoma. J Urol 180:510–514

    Article  CAS  Google Scholar 

  33. Xu J, Zhu S, Xu L, Liu X, Ding W, Wang Q, Chen Y, Deng H (2020) CA9 silencing promotes mitochondrial biogenesis, increases putrescine toxicity and decreases cell motility to suppress ccRCC progression. Int J Mol Sci 21:5939. https://doi.org/10.3390/ijms21165939

    Article  PubMed Central  Google Scholar 

  34. Iikuni S, Watanabe H, Shimizu Y, Nakamoto Y, Ono M (2020) IPET imaging and pharmacological therapy targeting carbonic anhydrase-IX high-expressing tumors using US2 platform based on bivalent ureidosulfonamide. PLoS ONE 15:e0243327. https://doi.org/10.1371/journal.pone.0243327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen M, Hu J, Wang L, Li Y, Zhu C, Chen C, Shi M, Ju Z, Cao X, Zhang Z (2020) Targeted and redox-responsive drug delivery systems based on carbonic anhydrase IX-decorated mesoporous silica nanoparticles for cancer therapy. Sci Rep 10:14447. https://doi.org/10.1038/s41598-020-71071-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rini BI, Campbell SC (2015) Urinary biomarkers for the detection and management of localized renal cell carcinoma. JAMA Oncol 1:212–213. https://doi.org/10.1001/jamaoncol.2015.0262

    Article  PubMed  Google Scholar 

  37. Solano-Iturri JD, Errarte P, Etxezarraga MC, Echevarria E, Angulo J, López JI, Larrinaga G (2020) Altered tissue and plasma levels of fibroblast activation protein-α (FAP) in renal tumours. Cancers (Basel) 12:3393. https://doi.org/10.3390/cancers12113393

    Article  CAS  Google Scholar 

  38. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244. https://doi.org/10.1046/j.1523-1755.2002.00433.x

    Article  CAS  PubMed  Google Scholar 

  39. Hulick P, Zimmer M, Margulis V, Skates D, M. H, D.M. D, D.M. M, T. L, S. S, W. C, C. W, O. I (2009) Blood levels of carbonic anhydrase 9 correlate with clear cell renal cell carcinoma activity. Clin Proteomics 5:37–45. https://doi.org/10.1007/s12014-008-9012-1

    Article  CAS  Google Scholar 

  40. Soyupak B, Erdoğan S, Ergin M, Seydaoğlu G, Kuzgunbay B, Tansuğ Z (2005) CA9 expression as a prognostic factor in renal clear cell carcinoma. Unrol Int 74:68–73. https://doi.org/10.1159/000082713

    Article  CAS  Google Scholar 

  41. Gigante M, Li G, Ferlay C, Perol D, Blanc E, Paul S, Zhao A, Tostain J, Escudier B, Negrier S, Genin C (2012) Prognostic value of serum CA9 in patients with metastatic clear cell renal cell carcinoma under targeted therapy. Anticancer Res 32:5447–5451

    CAS  PubMed  Google Scholar 

  42. Liao SY, Aurelio ON, Jan K, Zavada J, Stanbridge EJ (1997) Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57:2827–2831

    CAS  PubMed  Google Scholar 

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Acknowledgements

Not applicable.

Funding

The study was funded by the intramural grant from the Post-graduate Institute of Medical Education & Research (PGIMER), Chandigarh. MKK is recipient of the TARE fellowship (Grant # TAR/2018/001054) from the Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India.

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Authors and Affiliations

  1. Department of Urology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, 171001, India

    Pamposh Raina & Kailash Chander Barwal

  2. Department of Urology, Postgraduate Institute of Medical Education & Research, Chandigarh, 160012, India

    Pamposh Raina, S. K. Singh, Anil K. Goswami, S. K. Sharma & Kailash Chander Barwal

  3. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh, 160012, India

    Manoj Kumar Kashyap & Madhu Khullar

  4. Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon (Manesar), Gurugram, HR, 122413, India

    Manoj Kumar Kashyap

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  1. Pamposh Raina
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Contributions

PR, SKS, AKG, MK, SKS conceptualized the study. PR, MK, and SKS designed the study. SKS, AKG, MK, and SKS did the study supervision. SKS, AKG, SKS, and MK provided the material to carry out the study. PR, MKK, MK collected the data and analysis was done by PR, SKS, AKG, MKK, MK, SKS, and KCB. Review of literature was collected by PR, and KCB. The manuscript was wrote by PR, SKS, and KCB. The manuscript was critically reviewed and proofread by all the authors. All the authors read, critically evaluated, gave their feedback, and edited the manuscript.

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Correspondence to Kailash Chander Barwal.

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The study was initiated only after the approval from the Institute Committee on Human Ethics and Institutional Biosafety Committee (IBSC) of the Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.

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Raina, P., Singh, S.K., Goswami, A.K. et al. MN/CA9 gene expression as a potential tumor marker for renal cell carcinoma. Mol Cell Biochem 477, 333–343 (2022). https://doi.org/10.1007/s11010-021-04279-y

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