{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:03:21Z","timestamp":1790474601756,"version":"4.1.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T00:00:00Z","timestamp":1485302400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T00:00:00Z","timestamp":1485302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Parathyroid Hormone-Like Hormone (PTHLH) is an autocrine\/paracrine ligand that is up-regulated in head and neck squamous cell carcinoma (HNSCC). However, the cellular function and regulatory mechanism in HNSCC remains obscure. We investigated the clinical significance of PTHLH in HNSCC patients, and verified the role of RUNX2\/PTHLH axis, which is stimulated HNSCC cell growth. In patients, PTHLH is a poor prognosis marker. PTHLH expression lead to increasing the cell proliferation potential through an autocrine\/paracrine role and elevating blood calcium level in Nod-SCID mice. In public HNSCC microarray cohorts, PTHLH is found to be co-expressed with RUNX2. Physiologically, PTHLH is regulated by RUNX2 and also acting as key calcium regulator. However, elevations of calcium concentration also increased the RUNX2 expression. PTHLH, calcium, and RUNX2 form a positive feedback loop in HNSCC. Furthermore, ectopic RUNX2 expression also increased PTHLH expression and promoted proliferation potential through PTHLH expression. Using cDNA microarray analysis, we found PTHLH also stimulated expression of cell cycle regulators, namely CCNA2, CCNE2, and CDC25A in HNSCC cells, and these genes are also up-regulated in HNSCC patients. In summary, our results reveal that PTHLH expression is a poor prognosis marker in HNSCC patients, and RUNX2-PTHLH axis contributes to HNSCC tumor growth.<\/jats:p>","DOI":"10.1038\/srep41131","type":"journal-article","created":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T10:41:03Z","timestamp":1485340863000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation"],"prefix":"10.1038","volume":"7","author":[{"given":"Wei-Min","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yi","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan-Yu","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenn-Ren","family":"Hsiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Long","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang-Yang","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Shing","family":"Shieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hsiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shine-Gwo","family":"Shiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,25]]},"reference":[{"key":"BFsrep41131_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646\u2013674, doi: 10.1016\/j.cell.2011.02.013 (2011).","journal-title":"Cell"},{"key":"BFsrep41131_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21332","volume":"66","author":"RL Siegel","year":"2016","unstructured":"Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J Clin 66, 7\u201330, doi: 10.3322\/caac.21332 (2016).","journal-title":"CA Cancer J Clin"},{"key":"BFsrep41131_CR3","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3322\/caac.21262","volume":"65","author":"LA Torre","year":"2015","unstructured":"Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J Clin 65, 87\u2013108, doi: 10.3322\/caac.21262 (2015).","journal-title":"CA Cancer J Clin"},{"key":"BFsrep41131_CR4","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1158\/1055-9965.EPI-08-0347","volume":"18","author":"M Hashibe","year":"2009","unstructured":"Hashibe, M. et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 18, 541\u2013550, doi: 10.1158\/1055-9965.EPI-08-0347 (2009).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"BFsrep41131_CR5","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1007\/s10552-010-9570-1","volume":"21","author":"CP Wen","year":"2010","unstructured":"Wen, C. P. et al. Cancer risks from betel quid chewing beyond oral cancer: a multiple-site carcinogen when acting with smoking. Cancer Causes Control 21, 1427\u20131435, doi: 10.1007\/s10552-010-9570-1 (2010).","journal-title":"Cancer Causes Control"},{"key":"BFsrep41131_CR6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrc2982","volume":"11","author":"CR Leemans","year":"2011","unstructured":"Leemans, C. R., Braakhuis, B. J. & Brakenhoff, R. H. The molecular biology of head and neck cancer. Nat Rev Cancer 11, 9\u201322, doi: 10.1038\/nrc2982 (2011).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep41131_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00018-010-0465-9","volume":"68","author":"JP Vilardaga","year":"2011","unstructured":"Vilardaga, J. P., Romero, G., Friedman, P. A. & Gardella, T. J. Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell Mol Life Sci 68, 1\u201313, doi: 10.1007\/s00018-010-0465-9 (2011).","journal-title":"Cell Mol Life Sci"},{"key":"BFsrep41131_CR8","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1002\/jbmr.1617","volume":"27","author":"LK McCauley","year":"2012","unstructured":"McCauley, L. K. & Martin, T. J. Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27, 1231\u20131239, doi: 10.1002\/jbmr.1617 (2012).","journal-title":"J Bone Miner Res"},{"key":"BFsrep41131_CR9","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1158\/1541-7786.MCR-08-0568","volume":"7","author":"V Bhatia","year":"2009","unstructured":"Bhatia, V., Mula, R. V., Weigel, N. L. & Falzon, M. Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase\/Akt signaling. Mol Cancer Res 7, 1119\u20131131, doi: 10.1158\/1541-7786.MCR-08-0568 (2009).","journal-title":"Mol Cancer Res"},{"key":"BFsrep41131_CR10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.canlet.2010.06.009","volume":"298","author":"RV Mula","year":"2010","unstructured":"Mula, R. V., Bhatia, V. & Falzon, M. PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1. Cancer Lett 298, 119\u2013127, doi: 10.1016\/j.canlet.2010.06.009 (2010).","journal-title":"Cancer Lett"},{"key":"BFsrep41131_CR11","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1158\/1055-9965.EPI-07-2924","volume":"17","author":"M Rizk-Rabin","year":"2008","unstructured":"Rizk-Rabin, M. et al. Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine\/paracrine effects on the growth and signaling pathways in H295R cells. Cancer Epidemiol Biomarkers Prev 17, 2275\u20132285, doi: 10.1158\/1055-9965.EPI-07-2924 (2008).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"BFsrep41131_CR12","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13046-014-0100-y","volume":"33","author":"Z Lv","year":"2014","unstructured":"Lv, Z. et al. Parathyroid hormone-related protein serves as a prognostic indicator in oral squamous cell carcinoma. J Exp Clin Cancer Res 33, 100, doi: 10.1186\/s13046-014-0100-y (2014).","journal-title":"J Exp Clin Cancer Res"},{"key":"BFsrep41131_CR13","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1146\/annurev.cellbio.042308.113308","volume":"25","author":"G Karsenty","year":"2009","unstructured":"Karsenty, G., Kronenberg, H. M. & Settembre, C. Genetic control of bone formation. Annu Rev Cell Dev Biol 25, 629\u2013648, doi: 10.1146\/annurev.cellbio.042308.113308 (2009).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"BFsrep41131_CR14","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.1002\/jbmr.2287","volume":"29","author":"H Chen","year":"2014","unstructured":"Chen, H. et al. Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation. J Bone Miner Res 29, 2653\u20132665, doi: 10.1002\/jbmr.2287 (2014).","journal-title":"J Bone Miner Res"},{"key":"BFsrep41131_CR15","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrc3877","volume":"15","author":"Y Ito","year":"2015","unstructured":"Ito, Y., Bae, S. C. & Chuang, L. S. The RUNX family: developmental regulators in cancer. Nat Rev Cancer 15, 81\u201395, doi: 10.1038\/nrc3877 (2015).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep41131_CR16","doi-asserted-by":"publisher","first-page":"7795","DOI":"10.1158\/0008-5472.CAN-08-1078","volume":"68","author":"J Pratap","year":"2008","unstructured":"Pratap, J. et al. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res 68, 7795\u20137802, doi: 10.1158\/0008-5472.CAN-08-1078 (2008).","journal-title":"Cancer Res"},{"key":"BFsrep41131_CR17","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1101\/gad.1174704","volume":"18","author":"CA Yoshida","year":"2004","unstructured":"Yoshida, C. A. et al. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18, 952\u2013963, doi: 10.1101\/gad.1174704 (2004).","journal-title":"Genes Dev"},{"key":"BFsrep41131_CR18","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.bone.2010.05.035","volume":"48","author":"J Pratap","year":"2011","unstructured":"Pratap, J., Lian, J. B. & Stein, G. S. Metastatic bone disease: role of transcription factors and future targets. Bone 48, 30\u201336, doi: 10.1016\/j.bone.2010.05.035 (2011).","journal-title":"Bone"},{"key":"BFsrep41131_CR19","doi-asserted-by":"publisher","first-page":"739","DOI":"10.3892\/or.2015.4430","volume":"35","author":"JC Zong","year":"2016","unstructured":"Zong, J. C. et al. Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2\/PTHrP\/RANKL pathway in mice. Oncol Rep 35, 739\u2013748, doi: 10.3892\/or.2015.4430 (2016).","journal-title":"Oncol Rep"},{"key":"BFsrep41131_CR20","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/onc.2013.98","volume":"33","author":"JJ Sheu","year":"2014","unstructured":"Sheu, J. J. et al. LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene 33, 1375\u20131384, doi: 10.1038\/onc.2013.98 (2014).","journal-title":"Oncogene"},{"key":"BFsrep41131_CR21","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/S0901-5027(05)80494-1","volume":"24","author":"K Rikimaru","year":"1995","unstructured":"Rikimaru, K., Matsumoto, F., Hayashi, E., Bando, H. & Nagayama, M. Evaluation of serum concentration of parathyroid hormone-related protein and its implication in hypercalcemia in squamous cell carcinoma of the head and neck. Int J Oral Maxillofac Surg 24, 365\u2013368 (1995).","journal-title":"Int J Oral Maxillofac Surg"},{"key":"BFsrep41131_CR22","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.molmed.2009.03.001","volume":"15","author":"KK Papachroni","year":"2009","unstructured":"Papachroni, K. K., Karatzas, D. N., Papavassiliou, K. A., Basdra, E. K. & Papavassiliou, A. G. Mechanotransduction in osteoblast regulation and bone disease. Trends Mol Med 15, 208\u2013216, doi: 10.1016\/j.molmed.2009.03.001 (2009).","journal-title":"Trends Mol Med"},{"key":"BFsrep41131_CR23","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/j.1600-0765.2007.01037.x","volume":"44","author":"S Tabuchi","year":"2009","unstructured":"Tabuchi, S. et al. Runt-related gene 2 is involved in the inhibition of matrix metalloproteinase-13 expression by roxithromycin in human gingival epithelial cell cultures. J Periodontal Res 44, 283\u2013288, doi: 10.1111\/j.1600-0765.2007.01037.x (2009).","journal-title":"J Periodontal Res"},{"key":"BFsrep41131_CR24","doi-asserted-by":"publisher","first-page":"D955","DOI":"10.1093\/nar\/gks1111","volume":"41","author":"W Yang","year":"2013","unstructured":"Yang, W. et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 41, D955\u2013961, doi: 10.1093\/nar\/gks1111 (2013).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep41131_CR25","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1359\/jbmr.2001.16.12.2173","volume":"16","author":"C Luparello","year":"2001","unstructured":"Luparello, C. et al. Midregion parathyroid hormone-related protein inhibits growth and invasion in vitro and tumorigenesis in vivo of human breast cancer cells. J Bone Miner Res 16, 2173\u20132181, doi: 10.1359\/jbmr.2001.16.12.2173 (2001).","journal-title":"J Bone Miner Res"},{"key":"BFsrep41131_CR26","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s10555-006-9033-z","volume":"25","author":"J Liao","year":"2006","unstructured":"Liao, J. & McCauley, L. K. Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP). Cancer Metastasis Rev 25, 559\u2013571, doi: 10.1007\/s10555-006-9033-z (2006).","journal-title":"Cancer Metastasis Rev"},{"key":"BFsrep41131_CR27","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1152\/physrev.1996.76.1.127","volume":"76","author":"WM Philbrick","year":"1996","unstructured":"Philbrick, W. M. et al. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76, 127\u2013173 (1996).","journal-title":"Physiol Rev"},{"key":"BFsrep41131_CR28","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1007\/s10555-006-9032-0","volume":"25","author":"J Pratap","year":"2006","unstructured":"Pratap, J. et al. Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev 25, 589\u2013600, doi: 10.1007\/s10555-006-9032-0 (2006).","journal-title":"Cancer Metastasis Rev"},{"key":"BFsrep41131_CR29","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrc3829","volume":"14","author":"JM Argiles","year":"2014","unstructured":"Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 14, 754\u2013762, doi: 10.1038\/nrc3829 (2014).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep41131_CR30","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1067\/mhn.2000.110726","volume":"123","author":"RS Sellers","year":"2000","unstructured":"Sellers, R. S. et al. Head and neck squamous cell carcinoma: measurement of plasma parathyroid hormone-related protein and serum and urine calcium concentrations. Otolaryngol Head Neck Surg 123, 558\u2013562, doi: 10.1067\/mhn.2000.110726 (2000).","journal-title":"Otolaryngol Head Neck Surg"},{"key":"BFsrep41131_CR31","doi-asserted-by":"crossref","unstructured":"Chang, W. M. et al. Dysregulation of Runx2\/Activin A axis upon miR376c downregulation promotes lymph node metastasis in head and neck squamous cell carcinoma. Cancer Res, doi: 10.1158\/0008-5472.CAN-16-1188 (2016).","DOI":"10.1158\/0008-5472.CAN-16-1188"},{"key":"BFsrep41131_CR32","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1042\/BJ20030046","volume":"372","author":"RK Lindemann","year":"2003","unstructured":"Lindemann, R. K., Braig, M., Hauser, C. A., Nordheim, A. & Dittmer, J. Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells. Biochem J 372, 787\u2013797, doi: 10.1042\/BJ20030046 (2003).","journal-title":"Biochem J"},{"key":"BFsrep41131_CR33","doi-asserted-by":"publisher","first-page":"499","DOI":"10.3109\/10428199809050909","volume":"29","author":"F Firkin","year":"1998","unstructured":"Firkin, F., Schneider, H. & Grill, V. Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Leuk Lymphoma 29, 499\u2013506, doi: 10.3109\/10428199809050909 (1998).","journal-title":"Leuk Lymphoma"},{"key":"BFsrep41131_CR34","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/sj.bjc.6600115","volume":"86","author":"AA Bryden","year":"2002","unstructured":"Bryden, A. A., Hoyland, J. A., Freemont, A. J., Clarke, N. W. & George, N. J. Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. Br J Cancer 86, 322\u2013325, doi: 10.1038\/sj.bjc.6600115 (2002).","journal-title":"Br J Cancer"},{"key":"BFsrep41131_CR35","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1097\/01.mlg.0000161333.67977.93","volume":"115","author":"LJ Kornberg","year":"2005","unstructured":"Kornberg, L. J. et al. Gene expression profiling in squamous cell carcinoma of the oral cavity shows abnormalities in several signaling pathways. Laryngoscope 115, 690\u2013698, doi: 10.1097\/01.mlg.0000161333.67977.93 (2005).","journal-title":"Laryngoscope"},{"key":"BFsrep41131_CR36","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.bbrc.2008.01.121","volume":"368","author":"T Yamada","year":"2008","unstructured":"Yamada, T. et al. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling. Biochem Biophys Res Commun 368, 575\u2013581, doi: 10.1016\/j.bbrc.2008.01.121 (2008).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep41131_CR37","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1177\/0194599813486876","volume":"149","author":"S Trivedi","year":"2013","unstructured":"Trivedi, S., Mattos, J., Gooding, W., Godfrey, T. E. & Ferris, R. L. Correlation of tumor marker expression with nodal disease burden in metastatic head and neck cancer. Otolaryngol Head Neck Surg 149, 261\u2013268, doi: 10.1177\/0194599813486876 (2013).","journal-title":"Otolaryngol Head Neck Surg"},{"key":"BFsrep41131_CR38","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1210\/endo.143.2.8645","volume":"143","author":"VA Tovar Sepulveda","year":"2002","unstructured":"Tovar Sepulveda, V. A., Shen, X. & Falzon, M. Intracrine PTHrP protects against serum starvation-induced apoptosis and regulates the cell cycle in MCF-7 breast cancer cells. Endocrinology 143, 596\u2013606, doi: 10.1210\/endo.143.2.8645 (2002).","journal-title":"Endocrinology"},{"key":"BFsrep41131_CR39","doi-asserted-by":"publisher","first-page":"e19975","DOI":"10.1371\/journal.pone.0019975","volume":"6","author":"IW Mak","year":"2011","unstructured":"Mak, I. W., Cowan, R. W., Turcotte, R. E., Singh, G. & Ghert, M. PTHrP induces autocrine\/paracrine proliferation of bone tumor cells through inhibition of apoptosis. PLoS One 6, e19975, doi: 10.1371\/journal.pone.0019975 (2011).","journal-title":"PLoS One"},{"key":"BFsrep41131_CR40","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/S0360-3016(03)00736-3","volume":"57","author":"K Saarilahti","year":"2003","unstructured":"Saarilahti, K. et al. Cyclin A and Ki-67 expression as predictors for locoregional recurrence and outcome in laryngeal cancer patients treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 57, 986\u2013995 (2003).","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"BFsrep41131_CR41","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/S1357-2725(01)00137-6","volume":"34","author":"M Payton","year":"2002","unstructured":"Payton, M. & Coats, S. Cyclin E2, the cycle continues. Int J Biochem Cell Biol 34, 315\u2013320 (2002).","journal-title":"Int J Biochem Cell Biol"},{"key":"BFsrep41131_CR42","doi-asserted-by":"publisher","first-page":"631","DOI":"10.2174\/187152012800617678","volume":"12","author":"T Shen","year":"2012","unstructured":"Shen, T. & Huang, S. The role of Cdc25A in the regulation of cell proliferation and apoptosis. Anticancer Agents Med Chem 12, 631\u2013639 (2012).","journal-title":"Anticancer Agents Med Chem"},{"key":"BFsrep41131_CR43","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1161\/CIRCGENETICS.115.001145","volume":"8","author":"S Guauque-Olarte","year":"2015","unstructured":"Guauque-Olarte, S. et al. Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease. Circ Cardiovasc Genet 8, 812\u2013822, doi: 10.1161\/CIRCGENETICS.115.001145 (2015).","journal-title":"Circ Cardiovasc Genet"},{"key":"BFsrep41131_CR44","doi-asserted-by":"publisher","first-page":"E1267","DOI":"10.1152\/ajpendo.2001.281.6.E1267","volume":"281","author":"JL Sanders","year":"2001","unstructured":"Sanders, J. L., Chattopadhyay, N., Kifor, O., Yamaguchi, T. & Brown, E. M. Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. Am J Physiol Endocrinol Metab 281, E1267\u20131274 (2001).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep41131_CR45","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1056\/NEJM200001203420306","volume":"342","author":"GJ Strewler","year":"2000","unstructured":"Strewler, G. J. The physiology of parathyroid hormone-related protein. N Engl J Med 342, 177\u2013185, doi: 10.1056\/NEJM200001203420306 (2000).","journal-title":"N Engl J Med"},{"key":"BFsrep41131_CR46","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1146\/annurev.med.45.1.189","volume":"45","author":"JJ Wysolmerski","year":"1994","unstructured":"Wysolmerski, J. J. & Broadus, A. E. Hypercalcemia of malignancy: the central role of parathyroid hormone-related protein. Annu Rev Med 45, 189\u2013200, doi: 10.1146\/annurev.med.45.1.189 (1994).","journal-title":"Annu Rev Med"},{"key":"BFsrep41131_CR47","first-page":"13","volume":"87","author":"FL Greene","year":"2002","unstructured":"Greene, F. L. The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg 87, 13\u201315 (2002).","journal-title":"Bull Am Coll Surg"},{"key":"BFsrep41131_CR48","doi-asserted-by":"publisher","first-page":"D1253","DOI":"10.1093\/nar\/gkt1060","volume":"42","author":"CY Seiler","year":"2014","unstructured":"Seiler, C. Y. et al. DNASU plasmid and PSI:Biology-Materials repositories: resources to accelerate biological research. Nucleic Acids Res 42, D1253\u20131260, doi: 10.1093\/nar\/gkt1060 (2014).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep41131_CR49","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1038\/sj.leu.2401236","volume":"12","author":"WA Hudson","year":"1998","unstructured":"Hudson, W. A., Li, Q., Le, C. & Kersey, J. H. Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects. Leukemia 12, 2029\u20132033 (1998).","journal-title":"Leukemia"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep41131.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41131","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41131.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T00:27:36Z","timestamp":1671841656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep41131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,25]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,3,13]]}},"alternative-id":["BFsrep41131"],"URL":"https:\/\/doi.org\/10.1038\/srep41131","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,25]]},"assertion":[{"value":"22 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41131"}}