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Dysregulated mitogen-activated protein kinase pathway mediated cell cycle disruption in sporadic parathyroid tumors

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Abstract

Objectives

The study was designed to evaluate expression profiling of mitogen-activated protein kinase (MAPK) signalling pathway genes in sporadic parathyroid adenoma.

Methods

Expression of MAPK signalling pathway genes including activated transcription factors and cell cycle regulatory genes was analysed by real-time PCR- based array in parathyroid adenoma (N = 20) and normal parathyroid tissue (N = 4).

Results

MAPK signalling pathway as studied by PCR array revealed that a total of 22 genes were differentially expressed (≥ twofold change, p ≤ 0.05) in parathyroid adenoma. Up-regulated genes were ARAF, MAPK12, CREBBP, MYC, HSPB1, HRAS, CDK4, CCND1, and E2F1, and down-regulated genes were MAP4K1, DLK1, MAP3K4, MAPK10, MAPK8, ATF2, SMAD4, MEF2C, LAMTOR3, FOS, CDKN2A CDKN2B, and RB1. The present study revealed that ERK1/2 signalling pathway with up-regulation of HRAS, ARAF, and MEK1 genes and up-regulation of positive regulators of cell cycle (CCND1, CDK4, and E2F1) and down-regulation negative regulators of cell cycle (CDKN2A, CDKN2B, and RB1) made highly dysregulated MAPK signalling pathway in parathyroid adenoma. Expression of CDK4 was positively associated with plasma PTH level (r = 0.60, p = 0.04) and tumor weight (r = 0.80, p = 0.02) of the adenoma patients, respectively. Expression of CDKN2A was correlated negatively with PTH level (r = − 0.52, p = 0.04) of the adenoma patients.

Conclusion

The current study revealed that ERK pathway and associated cell cycle regulator genes are dysregulated in sporadic parathyroid adenoma.

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References

  1. Carling T (2001) Molecular pathology of parathyroid tumors. Trends Endocrinol Metab 12:53–58

    Article  CAS  Google Scholar 

  2. Imanishi Y, Hosokawa Y, Yoshimoto K, Schipani E, Mallya S, Papanikolaou A et al (2001) Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 107:1093–1102

    Article  CAS  Google Scholar 

  3. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707

    Article  CAS  Google Scholar 

  4. Arya AK, Bhadada SK, Singh P, Sachdeva N, Saikia UN, Dahiya D et al (2017) Promoter hypermethylation inactivates CDKN2A, CDKN2B and RASSF1A genes in sporadic parathyroid adenomas. Sci Rep 7:3123

    Article  Google Scholar 

  5. Kifor O, MacLeod RJ, Diaz R, Bai M, Yamaguchi T, Yao T et al (2001) Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. Am J Physiol Renal Physiol 280:F291–F302

    Article  CAS  Google Scholar 

  6. Corbetta S, Lania A, Filopanti M, Vicentini L, Ballare E, Spada A (2002) Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells. J Clin Endocrinol Metab 87:2201–2205

    Article  CAS  Google Scholar 

  7. See V, Rajala NK, Spiller DG, White MR (2004) Calcium-dependent regulation of the cell cycle via a novel MAPK–NF-kappaB pathway in Swiss 3T3 cells. J Cell Biol 166:661–672

    Article  CAS  Google Scholar 

  8. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25:402–408

    Article  CAS  Google Scholar 

  9. Arya AK, Bhadada SK, Singh P, Dahiya D, Kaur G, Sharma S et al (2019) Quantitative proteomics analysis of sporadic parathyroid adenoma tissue samples. J Endocrinol Invest 42:577–590

    Article  CAS  Google Scholar 

  10. Colicelli J (2004) Human RAS superfamily proteins and related GTPases. Sci STKE 250:RE13

    Google Scholar 

  11. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  CAS  Google Scholar 

  12. Varshney S, Bhadada SK, Saikia UN, Sachdeva N, Behera A, Arya AK et al (2013) Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians. Eur J Endocrinol 169:109–116

    Article  CAS  Google Scholar 

  13. Cetani F, Pardi E, Viacava P, Pollina GD, Fanelli G, Picone A et al (2004) A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid cancer. Clin Endocrinol 60:99–106

    Article  CAS  Google Scholar 

  14. Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery AL Jr et al (1994) Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 330:757–761

    Article  CAS  Google Scholar 

  15. Matoso A, Zhou Z, Hayama R, Flesken-Nikitin A, Nikitin AY (2008) Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia. Carcinogenesis 29:620–628

    Article  CAS  Google Scholar 

  16. Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN, Thakker RV (1996) Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumours. Clin Endocrinol 45:195–200

    Article  CAS  Google Scholar 

  17. Simpson DJ, Hibberts NA, McNicol AM, Clayton RN, Farrell WE (2000) Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island. Cancer Res 60:1211–1216

    CAS  PubMed  Google Scholar 

  18. Gartel AL, Shchors K (2003) Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp Cell Res 283:17–21

    Article  CAS  Google Scholar 

  19. Aesoy R, Gradin K, Aasrud KS, Hoivik EA, Ruas JL, Poellinger L et al (2014) Regulation of CDKN2B expression by interaction of Arnt with Miz-1–a basis for functional integration between the HIF and Myc gene regulatory pathways. Mol Cancer 13:54

    Article  Google Scholar 

  20. Di Giorgio E, Gagliostro E, Clocchiatti A, Brancolini C (2015) The control operated by the cell cycle machinery on MEF2 stability contributes to the downregulation of CDKN1A and entry into S phase. Mol Cell Biol 35:1633–1647

    Article  Google Scholar 

  21. Koh J, Hogue JA, Roman SA, Scheri RP, Fradin H, Corcoran DL et al (2018) Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT. Endocr Relat Cancer 25:407–420

    Article  CAS  Google Scholar 

  22. Shi Y, Hogue J, Dixit D, Koh J, Olson JA Jr (2014) Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia. Proc Natl Acad Sci USA 111:3092–3097

    Article  CAS  Google Scholar 

  23. Koh J, Hogue JA, Wang Y, DiSalvo M, Allbritton NL, Shi Y et al (2016) Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism. J Cell Mol Med 20:351–359

    Article  CAS  Google Scholar 

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Funding

The study was partially supported by grant from Endocrine Society of India (ESI) Grant no. R201512003. AKA is grateful to University Grants Commission (UGC), New Delhi, India for providing the research fellowship

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Authors and Affiliations

  1. Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    A. K. Arya, P. Singh, N. Sachdeva & S. K. Bhadada

  2. Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    U. N. Saikia

  3. Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    D. Dahiya & A. Behera

  4. Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI, USA

    S. D. Rao

Authors
  1. A. K. Arya
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  2. P. Singh
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  3. U. N. Saikia
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  4. N. Sachdeva
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  5. D. Dahiya
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  6. A. Behera
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  7. S. D. Rao
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  8. S. K. Bhadada
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Contributions

AKA, and SKB planned the study, AKA and PS performed the experiments; UNS performed the histopathological analysis of parathyroid tumors; AKA, SKB, NS, and SDR analysed and interpreted the data; DD, AB, and SKB provided the resource to the study. SDR reviewed the final draft of the entire manuscript and provided critical appraisal. All authors read the manuscript and corrected in its final form.

Corresponding author

Correspondence to S. K. Bhadada.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The research protocol was approved by the Institutional Ethics committee, PGIMER, Chandigarh, India. The study was carried out in accordance with the approved guidelines.

Informed consent

Informed written consent was taken from each subject prior to the recruitment.

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Arya, A.K., Singh, P., Saikia, U.N. et al. Dysregulated mitogen-activated protein kinase pathway mediated cell cycle disruption in sporadic parathyroid tumors. J Endocrinol Invest 43, 247–253 (2020). https://doi.org/10.1007/s40618-019-01098-3

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  • DOI: https://doi.org/10.1007/s40618-019-01098-3

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