2D-DIGE; Parathyroid carcinoma; biomarkers; case report; parathyroid adenoma; proteomics; Adenoma/diagnosis; Adenoma/pathology; Humans; Male; Middle Aged; Parathyroid Neoplasms/diagnosis; Parathyroid Neoplasms/pathology; Proteomics/methods; Adenoma; Parathyroid Neoplasms; Biochemistry; Molecular Biology; Genetics; Cancer Research
Abstract :
[en] BACKGROUND/AIM: The lack of specific parathyroid carcinoma (PC) biomarkers in clinical practice points out the importance of analyzing the proteomic signature of this cancer. We performed a comparative proteomic analysis of PC and parathyroid adenoma (PA) co-existing in the same patient.
PATIENTS AND METHODS: PC and PA were taken from a 63-year-old patient. Using two-dimensional differential gel electrophoresis (2D-DIGE) coupled to mass spectrometry we examined the differences between PC and PA proteins. For validation, additional PC and PA samples were obtained from 10 patients. Western blot analysis was used to validate the difference of expression observed with 2D-DIGE analysis. Bioinfomatic analysis was performed using QIAGEN's Ingenuity Pathways Analysis (IPA) to determine the predominant canonical pathways and interaction networks involved.
RESULTS: Thirty-three differentially expressed proteins were identified in PC compared to PA. Among these, ubiquitin C-terminal hydrolase-L1 (UCH-L1) was highly overexpressed in PC. The result was confirmed by Western Blot analysis in additional PC samples.
CONCLUSION: Our comparative proteomic analysis of co-existing neoplasms allowed detecting specific and peculiar differences between PC and PA overcoming population biological variability.
Disciplines :
Oncology
Author, co-author :
Ciregia, Federica ; Université de Liège - ULiège > GIGA > GIGA I3 - Rheumatology ; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Cetani, Filomena; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Pardi, Elena; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Soggiu, Alessio; Surgical and Dental Sciences-One Health Unit, Department of Biomedical, University of Milano, Milan, Italy
Piras, Cristian; Department of Health Sciences, Campus Universitario "S. Venuta", University "Magna Græcia" of Catanzaro, Catanzaro, Italy
Zallocco, Lorenzo; Department of Pharmacy, University of Pisa, Pisa, Italy
Borsari, Simona; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Ronci, Maurizio; Department of Pharmacy, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
Caruso, Vanni; School of Pharmacy & Pharmacology - College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
Marcocci, Claudio; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Mazzoni, Maria Rosa; Department of Pharmacy, University of Pisa, Pisa, Italy
Lucacchini, Antonio; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Giusti, Laura; School of Pharmacy, University of Camerino, Camerino, Italy laura.giusti@unicam.it
Cetani F, Marcocci C, Torregrossa L and Pardi E: Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer 26(7): R441-R464, 2019. PMID: 31085770. DOI: 10.1530/ERC-19-0135
Cardoso L, Stevenson M and Thakker RV: Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat 38(12): 1621-1648, 2017. PMID: 28881068. DOI: 10.1002/humu.23337
Cetani F, Pardi E and Marcocci C: Update on parathyroid carcinoma. J Endocrinol Invest 39(6): 595-606, 2016. PMID: 27001435. DOI: 10.1007/s40618-016-0447-3
Brewer K, Costa-Guda J and Arnold A: Molecular genetic insights into sporadic primary hyperparathyroidism. Endocr Relat Cancer 26(2): R53-R72, 2019. PMID: 30475215. DOI: 10.1530/ERC-18-0304
Costa-Guda J and Arnold A: Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol Cell Endocrinol 386(1-2): 46-54, 2014. PMID: 24035866. DOI: 10.1016/j.mce.2013.09.005
Cetani F, Pardi E, Giovannetti A, Cerrai P, Borsari S, Vignali E, Picone A, Cianferotti L, Miccoli P, Pinchera A and Marcocci C: Six novel MEN1 gene mutations in sporadic parathyroid tumors. Hum Mutat 16(5): 445, 2000. PMID: 11058905. DOI: 10.1002/1098-1004(200011)16:5<445::AID-HUMU12>3.0.CO;2-6
Newey PJ, Nesbit MA, Rimmer AJ, Attar M, Head RT, Christie PT, Gorvin CM, Stechman M, Gregory L, Mihai R, Sadler G, McVean G, Buck D and Thakker RV: Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J Clin Endocrinol Metab 97(10): E1995-E2005, 2012. PMID: 22855342. DOI: 10.1210/jc.2012-2303
Cetani F, Pardi E and Marcocci C: Parathyroid carcinoma: a clinical and genetic perspective. Minerva Endocrinol 43(2): 144-155, 2018. PMID: 28949121. DOI: 10.23736/S0391-1977.17.02737-7
Giusti L, Cetani F, Ciregia F, Da Valle Y, Donadio E, Giannaccini G, Banti C, Pardi E, Saponaro F, Basolo F, Berti P, Miccoli P, Pinchera A, Marcocci C and Lucacchini A: A proteomic approach to study parathyroid glands. Mol Biosyst 7(3): 687-699, 2011. PMID: 21180715. DOI: 10.1039/c0mb00191k
Arya AK and Sachdeva N: Changes in plasma intact parathyroid hormone levels following 24-hour incubation at room temperature as determined by Roche electrochemiluminescence PTH immunoassay. Clin Lab 60(4): 689-692, 2014. PMID: 24779307. DOI: 10.7754/clin.lab.2013.130419
Arya AK, Bhadada SK, Mukherjee S, Singh P, Rana SS, Dahiya D, Sood A, Saikia UN, Prakash M, Bhasin DK, Behera A, Walia R and Bhansali A: Frequency & predictors of pancreatitis in symptomatic primary hyperparathyroidism. Indian J Med Res 148(6): 721-727, 2018. PMID: 30778006. DOI: 10.4103/ijmr.IJMR_353_16
Akpinar G, Kasap M, Canturk NZ, Zulfigarova M, Islek EE, Guler SA, Simsek T and Canturk Z: Proteomics analysis of tissue samples reveals changes in mitochondrial protein levels in parathyroid hyperplasia over adenoma. Cancer Genomics Proteomics 14(3): 197-211, 2017. PMID: 28446534. DOI: 10.21873/cgp.20031
Giusti L, Cetani F, Ciregia F, Da Valle Y, Donadio E, Giannaccini G, Banti C, Pardi E, Saponaro F, Basolo F, Berti P, Miccoli P, Pinchera A, Marcocci C and Lucacchini A: A proteomic approach to study parathyroid glands. Mol Biosyst 7(3): 687-699, 2011. PMID: 21180715. DOI: 10.1039/c0mb00191k
Ciregia F, Giusti L, Da Valle Y, Donadio E, Consensi A, Giacomelli C, Sernissi F, Scarpellini P, Maggi F, Lucacchini A and Bazzichi L: A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med 11: 243, 2013. PMID: 24088505. DOI: 10.1186/1479-5876-11-243
Erickson LA and Mete O: Immunohistochemistry in diagnostic parathyroid pathology. Endocr Pathol 29(2): 113-129, 2018. PMID: 29626276. DOI: 10.1007/s12022-018-9527-6
Fang Y and Shen X: Ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications. Cancer Metastasis Rev 36(4): 669-682, 2017. PMID: 29080080. DOI: 10.1007/s10555-017-9702-0
Hibi K, Liu Q, Beaudry GA, Madden SL, Westra WH, Wehage SL, Yang SC, Heitmiller RF, Bertelsen AH, Sidransky D and Jen J: Serial analysis of gene expression in non-small cell lung cancer. Cancer Res 58(24): 5690-5694, 1998. PMID: 9865724.
Yamazaki T, Hibi K, Takase T, Tezel E, Nakayama H, Kasai Y, Ito K, Akiyama S, Nagasaka T and Nakao A: PGP9.5 as a marker for invasive colorectal cancer. Clin Cancer Res 8(1): 192-195, 2002. PMID: 11801558.
Leiblich A, Cross SS, Catto JW, Pesce G, Hamdy FC and Rehman I: Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A. Prostate 67(16): 1761-1769, 2007. PMID: 17929277. DOI: 10.1002/pros.20654
Xiang T, Li L, Yin X, Yuan C, Tan C, Su X, Xiong L, Putti TC, Oberst M, Kelly K, Ren G and Tao Q: The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer. PLoS One 7(1): e29783, 2012. PMID: 22279545. DOI: 10.1371/journal. pone.0029783
Zhao Y, Lei Y, He SW, Li YQ, Wang YQ, Hong XH, Liang YL, Li JY, Chen Y, Luo WJ, Zhang PP, Yang XJ, He QM, Ma J, Liu N and Tang LL: Hypermethylation of UCHL1 promotes metastasis of nasopharyngeal carcinoma by suppressing degradation of cortactin (CTTN). Cells 9(3): 559, 2020. PMID: 32120844. DOI: 10.3390/cells9030559
Liu S, González-Prieto R, Zhang M, Geurink PP, Kooij R, Iyengar PV, van Dinther M, Bos E, Zhang X, Le Dévédec SE, van de Water B, Koning RI, Zhu HJ, Mesker WE, Vertegaal ACO, Ovaa H, Zhang L, Martens JWM and Ten Dijke P: Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis. Clin Cancer Res 26(6): 1460-1473, 2020. PMID: 31857432. DOI: 10.1158/1078-0432.CCR-19-1373
Haven CJ, Howell VM, Eilers PH, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievit J, Tan MH, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ and Teh BT: Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype. Cancer Res 64(20): 7405-7411, 2004. PMID: 15492263. DOI: 10.1158/0008-5472.CAN-04-2063
Adam MA, Untch BR and Olson JA Jr: Parathyroid carcinoma: current understanding and new insights into gene expression and intraoperative parathyroid hormone kinetics. Oncologist 15(1): 61-72, 2010. PMID: 20051478. DOI: 10.1634/theoncologist.2009-0185
Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O and Marsh DJ: Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. J Clin Endocrinol Metab 94(2): 434-441, 2009. PMID: 19017757. DOI: 10.1210/jc.2008-1740
Kruijff S, Sidhu SB, Sywak MS, Gill AJ and Delbridge LW: Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol 21(2): 426-433, 2014. PMID: 24081804. DOI: 10.1245/s10434-013-3288-8
Truran PP, Johnson SJ, Bliss RD, Lennard TW and Aspinall SR: 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): 2845-2854, 2014. PMID: 25002250. DOI: 10.1007/s00268-014-2700-2
Kumari N, Chaudhary N, Pradhan R, Agarwal A and Krishnani N: Role of histological criteria and immunohistochemical markers in predicting risk of malignancy in parathyroid neoplasms. Endocr Pathol 27(2): 87-96, 2016. PMID: 26984237. DOI: 10.1007/s12022-016-9426-7
Agarwal A, Pradhan R, Kumari N, Krishnani N, Shukla P, Gupta SK, Chand G, Mishra A, Agarwal G, Verma AK and Mishra SK: Molecular characteristics of large parathyroid adenomas. World J Surg 40(3): 607-614, 2016. PMID: 26669787. DOI: 10.1007/ s00268-015-3380-2
Sharma MC: Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers. Int J Cancer 144(9): 2074-2081, 2019. PMID: 30125343. DOI: 10.1002/ijc.31817
Hu Y, Zhang X, Cui M, Wang M, Su Z, Liao Q and Zhao Y: Circular RNA profile of parathyroid neoplasms: analysis of co-expression networks of circular RNAs and mRNAs. RNA Biol 16(9): 1228-1236, 2019. PMID: 31213128. DOI: 10.1080/ 15476286.2019.1622962
Jaiswal JK and Nylandsted J: S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells. Cell Cycle 14(4): 502-509, 2015. PMID: 25565331. DOI: 10.1080/15384101.2014.995495
Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Kallunki T, Jäättelä M and Nylandsted J: S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun 5: 3795, 2014. PMID: 24806074. DOI: 10.1038/ncomms4795
Pennington KL, Chan TY, Torres MP and Andersen JL: The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein-protein interactions. Oncogene 37(42): 5587-5604, 2018. PMID: 29915393. DOI: 10.1038/s41388-018-0348-3
Ciregia F, Giusti L, Molinaro A, Niccolai F, Mazzoni MR, Rago T, Tonacchera M, Vitti P, Giannaccini G and Lucacchini A: Proteomic analysis of fine-needle aspiration in differential diagnosis of thyroid nodules. Transl Res 176: 81-94, 2016. PMID: 27172385. DOI: 10.1016/j.trsl.2016.04.004
Magnoni R, Palmfeldt J, Hansen J, Christensen JH, Corydon TJ and Bross P: The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function. Free Radic Res 48(2): 168-179, 2014. PMID: 24151936. DOI: 10.3109/10715762.2013.858147
Yun CW, Kim HJ, Lim JH and Lee SH: Heat shock proteins: Agents of cancer development and therapeutic targets in anticancer therapy. Cells 9(1): 60, 2019. PMID: 31878360. DOI: 10.3390/cells9010060
Guo J, Li X, Zhang W, Chen Y, Zhu S, Chen L, Xu R, Lv Y, Wu D, Guo M, Liu X, Lu W and Deng H: HSP60-regulated mitochondrial proteostasis and protein translation promote tumor growth of ovarian cancer. Sci Rep 9(1): 12628, 2019. PMID: 31477750. DOI: 10.1038/s41598-019-48992-7
Zhang J, Zhou X, Chang H, Huang X, Guo X, Du X, Tian S, Wang L, Lyv Y, Yuan P and Xing J: Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma. Oncotarget 7(42): 68976-68989, 2016. PMID: 27677587. DOI: 10.18632/oncotarget.12185
Park WS, Chung KW, Young MS, Kim SK, Lee YJ and Lee EK: Differential protein expression of lymph node metastases of papillary thyroid carcinoma harboring the BRAF mutation. Anticancer Res 33(10): 4357-4364, 2013. PMID: 24123003.
Corrado A, Aceto R, Silvestri R, Dell’Anno I, Ricci B, Miglietta S, Romei C, Giovannoni R, Poliseno L, Evangelista M, Vitiello M, Cipollini M, Garritano S, Giusti L, Zallocco L, Elisei R, Landi S and Gemignani F: Pro64His (rs4644) polymorphism within galectin-3 is a risk factor of differentiated thyroid carcinoma and affects the transcriptome of thyrocytes engineered via CRISPR/Cas9 system. Thyroid 31(7): 1056-1066, 2021. PMID: 33308024. DOI: 10.1089/thy.2020.0366
Wulfkuhle JD, Sgroi DC, Krutzsch H, McLean K, McGarvey K, Knowlton M, Chen S, Shu H, Sahin A, Kurek R, Wallwiener D, Merino MJ, Petricoin EF 3rd, Zhao Y and Steeg PS: Proteomics of human breast ductal carcinoma in situ. Cancer Res 62(22): 6740-6749, 2002. PMID: 12438275.
Tang HY, Beer LA, Tanyi JL, Zhang R, Liu Q and Speicher DW: Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer. J Proteomics 89: 165-178, 2013. PMID: 23792823. DOI: 10.1016/j.jprot.2013.06.016
Wang L, He S, Tu Y, Ji P, Zong J, Zhang J, Feng F, Zhao J, Zhang Y and Gao G: Elevated expression of chloride intracellular channel 1 is correlated with poor prognosis in human gliomas. J Exp Clin Cancer Res 31: 44, 2012. PMID: 22578365. DOI: 10.1186/1756-9966-31-44
Peretti M, Angelini M, Savalli N, Florio T, Yuspa SH and Mazzanti M: Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim Biophys Acta 1848(10 Pt B): 2523-2531, 2015. PMID: 25546839. DOI: 10.1016/j.bbamem.2014.12.012
Wang YY, Chen J, Liu XM, Zhao R and Zhe H: Nrf2-mediated metabolic reprogramming in cancer. Oxid Med Cell Longev 2018: 9304091, 2018. PMID: 29670683. DOI: 10.1155/ 2018/9304091
Kim YS, Gupta Vallur P, Phaëton R, Mythreye K and Hempel N: Insights into the dichotomous regulation of SOD2 in cancer. Antioxidants (Basel) 6(4): 86, 2017. PMID: 29099803. DOI: 10.3390/antiox6040086
Ashtekar A, Huk D, Magner A, La Perle KMD, Boucai L and Kirschner LS: Alterations in Sod2-induced oxidative stress affect endocrine cancer progression. J Clin Endocrinol Metab 103(11): 4135-4145, 2018. PMID: 30165401. DOI: 10.1210/jc.2018-01039
Zhang B, Tornmalm J, Widengren J, Vakifahmetoglu-Norberg H and Norberg E: Characterization of the role of the malate dehydrogenases to lung tumor cell survival. J Cancer 8(11): 2088-2096, 2017. PMID: 28819410. DOI: 10.7150/jca.19373
Wang YP, Zhou W, Wang J, Huang X, Zuo Y, Wang TS, Gao X, Xu YY, Zou SW, Liu YB, Cheng JK and Lei QY: Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Mol Cell 64(4): 673-687, 2016. PMID: 27840030. DOI: 10.1016/j.molcel.2016.09.028
Hanse EA, Ruan C, Kachman M, Wang D, Lowman XH and Kelekar A: Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer. Oncogene 36(27): 3915-3924, 2017. PMID: 28263970. DOI: 10.1038/onc.2017.36