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Published in: Osteoporosis International 7/2019

01-07-2019 | Hyperparathyroidism | Original Article

Genome-wide analysis of differentially expressed lncRNA in sporadic parathyroid tumors

Authors: T. Jiang, B. J. Wei, D. X. Zhang, L. Li, G. L. Qiao, X. A. Yao, Z. W. Chen, X. Liu, X. Y. Du

Published in: Osteoporosis International | Issue 7/2019

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Abstract

Summary

Diagnosis of parathyroid carcinoma on histological examination is challenging. Thousands of differentially expressed lncRNAs were identified on the microarray data between parathyroid cancer and adenoma samples. Four lncRNAs were significantly dysregulated in further validation. The “lncRNA score” calculated from these lncRNAs differentiated parathyroid carcinomas from adenomas. LncRNAs serve as biomarkers for parathyroid cancer diagnosis.

Introduction

Diagnosis of parathyroid carcinoma (PC) on histological examination is challenging. LncRNA profile study was conducted to find diagnostic biomarkers for PC.

Methods

LncRNA arrays containing 91,007 lncRNAs as well as 29,857 mRNAs were used to assess parathyroid specimen (5 carcinomas and 6 adenomas). Bioinformatics analyses were also conducted to compare the microarray results between parathyroid carcinomas and adenomas (PAs). Differentially expressed lncRNAs of 11 PCs and 31 PAs were validated by real-time quantitative PCR.

Results

On the microarray data between PC and PA samples (fold change ≥ 2, P < 0.05), 1809 differentially expressed lncRNAs and 1349 mRNAs also were identified. All carcinomas were clustered in the same group by clustering analysis using dysregulated lncRNAs or mRNAs. Four lncRNAs (LINC00959, lnc-FLT3-2:2, lnc-FEZF2-9:2, and lnc-RP11-1035H13.3.1-2:1) identified were significantly dysregulated in further RT-PCR validation. The global “lncRNA score” calculated from the lncRNAs above also differentiated parathyroid carcinomas from adenomas.

Conclusions

LncRNA profiling shows distinct differentially expressed lncRNAs in parathyroid neoplasm. They may play a key role in parathyroid cancer and serve as potential biomarkers to distinguish parathyroid cancers from parathyroid adenomas.
Appendix
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Literature
1.
go back to reference DeLellis RA, Mazzaglia P, Mangray S (2008) Primary hyperparathyroidism: a current perspective. Arch Pathol Lab Med 132(8):1251–1262PubMed DeLellis RA, Mazzaglia P, Mangray S (2008) Primary hyperparathyroidism: a current perspective. Arch Pathol Lab Med 132(8):1251–1262PubMed
2.
go back to reference Schulte KM, Talat N (2012) Diagnosis and management of parathyroid cancer. Nat Rev Endocrinol. 8(10):612–622CrossRefPubMed Schulte KM, Talat N (2012) Diagnosis and management of parathyroid cancer. Nat Rev Endocrinol. 8(10):612–622CrossRefPubMed
3.
go back to reference Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT (2003) HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 40(9):657–663CrossRefPubMedPubMedCentral Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT (2003) HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 40(9):657–663CrossRefPubMedPubMedCentral
4.
go back to reference Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A (2003) Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349(18):1722–1729CrossRefPubMed Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A (2003) Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349(18):1722–1729CrossRefPubMed
5.
go back to reference Haven CJ, van Puijenbroek M, Tan MH, Teh BT, Fleuren GJ, van Wezel T, Morreau H (2007) Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clin Endocrinol 67(3):370–376CrossRef Haven CJ, van Puijenbroek M, Tan MH, Teh BT, Fleuren GJ, van Wezel T, Morreau H (2007) Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clin Endocrinol 67(3):370–376CrossRef
6.
go back to reference Yu W, McPherson JR, Stevenson M et al (2015) Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J Clin Endocrinol Metab 100(2):E360–E364CrossRefPubMed Yu W, McPherson JR, Stevenson M et al (2015) Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J Clin Endocrinol Metab 100(2):E360–E364CrossRefPubMed
8.
go back to reference Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 458(7235):223–227CrossRefPubMedPubMedCentral Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 458(7235):223–227CrossRefPubMedPubMedCentral
9.
go back to reference Silva A, Bullock M, Calin G (2015) The clinical relevance of long non-coding RNAs in Cancer. Cancers (Basel) 7(4):2169–2182CrossRef Silva A, Bullock M, Calin G (2015) The clinical relevance of long non-coding RNAs in Cancer. Cancers (Basel) 7(4):2169–2182CrossRef
11.
go back to reference Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29CrossRefPubMedPubMedCentral Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29CrossRefPubMedPubMedCentral
12.
go back to reference Corbetta S, Vaira V, Guarnieri V, Scillitani A, Eller-Vainicher C, Ferrero S, Vicentini L, Chiodini I, Bisceglia M, Beck-Peccoz P, Bosari S, Spada A (2010) Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr Relat Cancer 17(1):135–146CrossRefPubMed Corbetta S, Vaira V, Guarnieri V, Scillitani A, Eller-Vainicher C, Ferrero S, Vicentini L, Chiodini I, Bisceglia M, Beck-Peccoz P, Bosari S, Spada A (2010) Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr Relat Cancer 17(1):135–146CrossRefPubMed
14.
go back to reference Kebebew E, Arici C, Duh QY, Clark OH (2001) Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg 136(8):878–885CrossRefPubMed Kebebew E, Arici C, Duh QY, Clark OH (2001) Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg 136(8):878–885CrossRefPubMed
15.
go back to reference Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG, Borsari S, Lemmi M, Berti P, Miccoli P, Pinchera A, Marcocci C (2007) Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma. Eur J Endocrinol 156(5):547–554CrossRefPubMed Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG, Borsari S, Lemmi M, Berti P, Miccoli P, Pinchera A, Marcocci C (2007) Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma. Eur J Endocrinol 156(5):547–554CrossRefPubMed
16.
go back to reference Fernandez-Ranvier GG, Khanafshar E, Tacha D, Wong M, Kebebew E, Duh QY, Clark OH (2009) Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer. 115(2):334–344CrossRefPubMed Fernandez-Ranvier GG, Khanafshar E, Tacha D, Wong M, Kebebew E, Duh QY, Clark OH (2009) Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer. 115(2):334–344CrossRefPubMed
17.
go back to reference Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O, Marsh DJ (2009) Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94(2):434–441CrossRefPubMed Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O, Marsh DJ (2009) Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94(2):434–441CrossRefPubMed
18.
go back to reference Truran PP, Johnson SJ, Bliss RD, Lennard TW, Aspinall SR (2014) Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer. World J Surg 38(11):2845–2854CrossRefPubMed Truran PP, Johnson SJ, Bliss RD, Lennard TW, Aspinall SR (2014) Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer. World J Surg 38(11):2845–2854CrossRefPubMed
19.
go back to reference Hu Y, Liao Q, Cao S, Gao X, Zhao Y (2016) Diagnostic performance of parafibromin immunohistochemical staining for sporadic parathyroid carcinoma: a meta-analysis. Endocrine. 54(3):612–619CrossRefPubMed Hu Y, Liao Q, Cao S, Gao X, Zhao Y (2016) Diagnostic performance of parafibromin immunohistochemical staining for sporadic parathyroid carcinoma: a meta-analysis. Endocrine. 54(3):612–619CrossRefPubMed
20.
go back to reference Wei CH, Harari A (2012) Parathyroid carcinoma: update and guidelines for management. Curr Treat Options in Oncol 13(1):11–23CrossRef Wei CH, Harari A (2012) Parathyroid carcinoma: update and guidelines for management. Curr Treat Options in Oncol 13(1):11–23CrossRef
21.
go back to reference Murugan AK, Munirajan AK, Alzahrani AS (2018) Long noncoding RNAs: emerging players in thyroid cancer pathogenesis. Endocr Relat Cancer 25(2):R59–R82 Murugan AK, Munirajan AK, Alzahrani AS (2018) Long noncoding RNAs: emerging players in thyroid cancer pathogenesis. Endocr Relat Cancer 25(2):R59–R82
22.
go back to reference Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, Finelli A, Kulkarni G, Hamilton R, Zlotta A, Ghai S, Fleshner N (2018) Defining a cohort that may not require repeat prostate biopsy based on PCA3 score and magnetic resonance imaging: the dual negative effect. J Urol 199(5):1182–1187 Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, Finelli A, Kulkarni G, Hamilton R, Zlotta A, Ghai S, Fleshner N (2018) Defining a cohort that may not require repeat prostate biopsy based on PCA3 score and magnetic resonance imaging: the dual negative effect. J Urol 199(5):1182–1187
23.
go back to reference Dijkstra S, Mulders PF, Schalken JA (2014) Clinical use of novel urine and blood based prostate cancer biomarkers: a review. Clin Biochem 47(10–11):889–896CrossRefPubMed Dijkstra S, Mulders PF, Schalken JA (2014) Clinical use of novel urine and blood based prostate cancer biomarkers: a review. Clin Biochem 47(10–11):889–896CrossRefPubMed
24.
go back to reference Zhang D, Liu X, Wei B, Qiao G, Jiang T, Chen Z (2017) Plasma lncRNA GAS8-AS1 as a potential biomarker of papillary thyroid carcinoma in Chinese patients. Int J Endocrinol 2017:2645904PubMedPubMedCentral Zhang D, Liu X, Wei B, Qiao G, Jiang T, Chen Z (2017) Plasma lncRNA GAS8-AS1 as a potential biomarker of papillary thyroid carcinoma in Chinese patients. Int J Endocrinol 2017:2645904PubMedPubMedCentral
25.
go back to reference Leelahavanichkul K, Amornphimoltham P, Molinolo AA, Basile JR, Koontongkaew S, Gutkind JS (2014) A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol 8(1):105–118CrossRefPubMed Leelahavanichkul K, Amornphimoltham P, Molinolo AA, Basile JR, Koontongkaew S, Gutkind JS (2014) A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis. Mol Oncol 8(1):105–118CrossRefPubMed
26.
go back to reference Zhang HJ, Tao J, Sheng L, Hu X, Rong RM, Xu M, Zhu TY (2016) Twist2 promotes kidney cancer cell proliferation and invasion by regulating ITGA6 and CD44 expression in the ECM-receptor interaction pathway. Onco Targets Ther 9:1801–1812PubMedPubMedCentral Zhang HJ, Tao J, Sheng L, Hu X, Rong RM, Xu M, Zhu TY (2016) Twist2 promotes kidney cancer cell proliferation and invasion by regulating ITGA6 and CD44 expression in the ECM-receptor interaction pathway. Onco Targets Ther 9:1801–1812PubMedPubMedCentral
27.
go back to reference Hoskin V, Szeto A, Ghaffari A, Greer PA, Côté GP, Elliott BE (2015) Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion. Mol Biol Cell 26(19):3464–3479CrossRefPubMedPubMedCentral Hoskin V, Szeto A, Ghaffari A, Greer PA, Côté GP, Elliott BE (2015) Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion. Mol Biol Cell 26(19):3464–3479CrossRefPubMedPubMedCentral
28.
go back to reference Whibley C, Pharoah PD, Hollstein M (2009) p53 polymorphisms: cancer implications. Nat Rev Cancer 9(2):95–107CrossRefPubMed Whibley C, Pharoah PD, Hollstein M (2009) p53 polymorphisms: cancer implications. Nat Rev Cancer 9(2):95–107CrossRefPubMed
30.
go back to reference Jo JH, Chung TM, Youn H, Yoo JY (2014) Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis. Nat Commun 5:5433CrossRefPubMed Jo JH, Chung TM, Youn H, Yoo JY (2014) Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis. Nat Commun 5:5433CrossRefPubMed
32.
go back to reference Rather MI, Nagashri MN, Swamy SS, Gopinath KS, Kumar A (2013) Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. J Biol Chem 288:608–618CrossRefPubMed Rather MI, Nagashri MN, Swamy SS, Gopinath KS, Kumar A (2013) Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. J Biol Chem 288:608–618CrossRefPubMed
33.
go back to reference Hahn MA, Howell VM, Gill AJ, Clarkson A, Weaire-Buchanan G, Robinson BG, Delbridge L, Gimm O, Schmitt WD, Teh BT, Marsh DJ (2010) CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors. Endocr Relat Cancer 17:273–282CrossRefPubMed Hahn MA, Howell VM, Gill AJ, Clarkson A, Weaire-Buchanan G, Robinson BG, Delbridge L, Gimm O, Schmitt WD, Teh BT, Marsh DJ (2010) CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors. Endocr Relat Cancer 17:273–282CrossRefPubMed
Metadata
Title
Genome-wide analysis of differentially expressed lncRNA in sporadic parathyroid tumors
Authors
T. Jiang
B. J. Wei
D. X. Zhang
L. Li
G. L. Qiao
X. A. Yao
Z. W. Chen
X. Liu
X. Y. Du
Publication date
01-07-2019
Publisher
Springer London
Published in
Osteoporosis International / Issue 7/2019
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-019-04959-y

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