Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma
Abstract
Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is biologically distinct from HPV-negative HNSCC. Outside of HPV-status, few tumor-intrinsic variables have been identified that correlate to improved survival. As part of exploratory analysis into the trace elemental composition of oropharyngeal squamous cell carcinoma (OPSCC), we performed elemental quanitification by X-ray fluorescence microscopy (XFM) on a small cohort (n = 32) of patients with HPV-positive and -negative OPSCC and identified in HPV-positive cases increased zinc (Zn) concentrations in tumor tissue relative to normal tissue. Subsequent immunohistochemistry of six Zn-binding proteins-zinc-alpha 2-glycoprotein (AZGP1), Lipocalin-1, Albumin, S100A7, S100A8 and S100A9-revealed that only AZGP1 expression significantly correlated to HPV-status (p < 0.001) and was also increased in tumor relative to normal tissue from HPV-positive OPSCC tumor samples. AZGP1 protein expression in our cohort significantly correlated to a prolonged recurrence-free survival (p = 0.029), similar to HNSCC cases from the TCGA (n = 499), where highest AZGP1 mRNA levels correlated to improved overall survival (p = 0.023). By showing for the first time that HPV-positive OPSCC patients have increased intratumoral Zn levels and AZGP1 expression, we identify possible positive prognostic biomarkers in HNSCC as well as possible mechanisms of increased sensitivity to chemoradiationmore »
- Authors:
-
- Northwestern Univ., Evanston, IL (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH), National Cancer Institute; USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1601427
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Poropatich, Kate, Paunesku, Tatjana, Zander, Alia, Wray, Brian, Schipma, Matthew, Dalal, Prarthana, Agulnik, Mark, Chen, Si, Lai, Barry, Antipova, Olga, Maxey, Evan, Brown, Koshonna, Wanzer, Michael Beau, Gursel, Demirkan, Fan, Hanli, Rademaker, Alfred, Woloschak, Gayle E., and Mittal, Bharat B. Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma. United States: N. p., 2019.
Web. doi:10.1038/s41598-019-53268-1.
Poropatich, Kate, Paunesku, Tatjana, Zander, Alia, Wray, Brian, Schipma, Matthew, Dalal, Prarthana, Agulnik, Mark, Chen, Si, Lai, Barry, Antipova, Olga, Maxey, Evan, Brown, Koshonna, Wanzer, Michael Beau, Gursel, Demirkan, Fan, Hanli, Rademaker, Alfred, Woloschak, Gayle E., & Mittal, Bharat B. Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma. United States. https://doi.org/10.1038/s41598-019-53268-1
Poropatich, Kate, Paunesku, Tatjana, Zander, Alia, Wray, Brian, Schipma, Matthew, Dalal, Prarthana, Agulnik, Mark, Chen, Si, Lai, Barry, Antipova, Olga, Maxey, Evan, Brown, Koshonna, Wanzer, Michael Beau, Gursel, Demirkan, Fan, Hanli, Rademaker, Alfred, Woloschak, Gayle E., and Mittal, Bharat B. Mon .
"Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma". United States. https://doi.org/10.1038/s41598-019-53268-1. https://www.osti.gov/servlets/purl/1601427.
@article{osti_1601427,
title = {Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma},
author = {Poropatich, Kate and Paunesku, Tatjana and Zander, Alia and Wray, Brian and Schipma, Matthew and Dalal, Prarthana and Agulnik, Mark and Chen, Si and Lai, Barry and Antipova, Olga and Maxey, Evan and Brown, Koshonna and Wanzer, Michael Beau and Gursel, Demirkan and Fan, Hanli and Rademaker, Alfred and Woloschak, Gayle E. and Mittal, Bharat B.},
abstractNote = {Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is biologically distinct from HPV-negative HNSCC. Outside of HPV-status, few tumor-intrinsic variables have been identified that correlate to improved survival. As part of exploratory analysis into the trace elemental composition of oropharyngeal squamous cell carcinoma (OPSCC), we performed elemental quanitification by X-ray fluorescence microscopy (XFM) on a small cohort (n = 32) of patients with HPV-positive and -negative OPSCC and identified in HPV-positive cases increased zinc (Zn) concentrations in tumor tissue relative to normal tissue. Subsequent immunohistochemistry of six Zn-binding proteins-zinc-alpha 2-glycoprotein (AZGP1), Lipocalin-1, Albumin, S100A7, S100A8 and S100A9-revealed that only AZGP1 expression significantly correlated to HPV-status (p < 0.001) and was also increased in tumor relative to normal tissue from HPV-positive OPSCC tumor samples. AZGP1 protein expression in our cohort significantly correlated to a prolonged recurrence-free survival (p = 0.029), similar to HNSCC cases from the TCGA (n = 499), where highest AZGP1 mRNA levels correlated to improved overall survival (p = 0.023). By showing for the first time that HPV-positive OPSCC patients have increased intratumoral Zn levels and AZGP1 expression, we identify possible positive prognostic biomarkers in HNSCC as well as possible mechanisms of increased sensitivity to chemoradiation in HPV-positive OPSCC.},
doi = {10.1038/s41598-019-53268-1},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United States},
year = {2019},
month = {11}
}
Works referenced in this record:
Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial
journal, May 2005
- Tímár, József; Ladányi, Andrea; Forster-Horváth, Csaba
- Journal of Clinical Oncology, Vol. 23, Issue 15
Reduction of AZGP1 predicts poor prognosis in esophageal squamous cell carcinoma patients in Northern China
journal, December 2016
- Tang, Hong; Wu, Yufeng; Qin, Yanru
- OncoTargets and Therapy, Vol. Volume 10
Quantifying X-Ray Fluorescence Data Using MAPS
journal, January 2018
- Nietzold, Tara; West, Bradley M.; Stuckelberger, Michael
- Journal of Visualized Experiments, Issue 132
Zinc transporters and the cellular trafficking of zinc
journal, July 2006
- Eide, David J.
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1763, Issue 7
Papillomavirus E6 proteins
journal, February 2009
- Howie, Heather L.; Katzenellenbogen, Rachel A.; Galloway, Denise A.
- Virology, Vol. 384, Issue 2
Cancer of the prostate: Early diagnosis by zinc and hormone analysis?
journal, June 1979
- Habib, F. K.; Mason, M. K.; Smith, P. H.
- British Journal of Cancer, Vol. 39, Issue 6
Zinc Downregulates HIF-1α and Inhibits Its Activity in Tumor Cells In Vitro and In Vivo
journal, December 2010
- Nardinocchi, Lavinia; Pantisano, Valentina; Puca, Rosa
- PLoS ONE, Vol. 5, Issue 12
HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers
journal, September 2017
- Koneva, Lada A.; Zhang, Yanxiao; Virani, Shama
- Molecular Cancer Research, Vol. 16, Issue 1
TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma: A Subset of HPV + Head and Neck Cancer
journal, March 2017
- Hajek, Michael; Sewell, Andrew; Kaech, Susan
- Cancer, Vol. 123, Issue 10
The many “faces” of copper in medicine and treatment
journal, April 2014
- Hordyjewska, Anna; Popiołek, Łukasz; Kocot, Joanna
- BioMetals, Vol. 27, Issue 4
Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites
journal, October 2016
- Tomaić, Vjekoslav
- Cancers, Vol. 8, Issue 10
Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy
journal, March 2014
- Arriaga, Juan M.; Greco, Angela; Mordoh, José
- Molecular Cancer Therapeutics, Vol. 13, Issue 5
RNA-Seq Analysis of Differentiated Keratinocytes Reveals a Massive Response to Late Events during Human Papillomavirus 16 Infection, Including Loss of Epithelial Barrier Function
journal, October 2017
- Klymenko, T.; Gu, Q.; Herbert, I.
- Journal of Virology, Vol. 91, Issue 24
IGSF4 Methylation as an Independent Marker of Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma
journal, March 2015
- Chen, Kang Mei; Stephen, Josena K.; Havard, Shaleta
- JAMA Otolaryngology–Head & Neck Surgery, Vol. 141, Issue 3
Low AZGP1 expression predicts for recurrence in margin-positive, localized prostate cancer
journal, March 2011
- Yip, Po Yee; Kench, James G.; Rasiah, Krishan K.
- The Prostate, Vol. 71, Issue 15
AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling
journal, June 2010
- Kong, B.; Michalski, C. W.; Hong, X.
- Oncogene, Vol. 29, Issue 37
Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures
journal, April 2016
- Zhang, Y.; Koneva, L. A.; Virani, S.
- Clinical Cancer Research, Vol. 22, Issue 18
Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy
journal, January 2019
- Koenigs, Maria B.; Lefranc-Torres, Armida; Bonilla-Velez, Juliana
- JNCI: Journal of the National Cancer Institute, Vol. 111, Issue 9
Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells
journal, December 2011
- Arora, H. C.; Jensen, M. P.; Yuan, Y.
- Cancer Research, Vol. 72, Issue 3
DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri
journal, May 2004
- Melsheimer, P.
- Clinical Cancer Research, Vol. 10, Issue 9
Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses
journal, December 2007
- Lazarczyk, Maciej; Pons, Christian; Mendoza, José-Andrès
- The Journal of Experimental Medicine, Vol. 205, Issue 1
Trends in head and neck cancer incidence in Denmark, 1978-2007: Focus on human papillomavirus associated sites
journal, October 2010
- Blomberg, Maria; Nielsen, Ann; Munk, Christian
- International Journal of Cancer, Vol. 129, Issue 3
Zinc and prostatic cancer
journal, January 2009
- Ho, Emily; Song, Yang
- Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 12, Issue 6
Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses
journal, December 2007
- Lazarczyk, Maciej; Pons, Christian; Mendoza, José-Andrès
- The Journal of Cell Biology, Vol. 179, Issue 7
Datura genome reveals duplications of psychoactive alkaloid biosynthetic genes and high mutation rate following tissue culture
journal, March 2021
- Rajewski, Alex; Carter-House, Derreck; Stajich, Jason
- BMC Genomics, Vol. 22, Issue 1
Comprehensive T-cell immunophenotyping and next-generation sequencing of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinomas
journal, October 2017
- Poropatich, Kate; Fontanarosa, Joel; Swaminathan, Suchitra
- The Journal of Pathology, Vol. 243, Issue 3
Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists
journal, May 2018
- Lewis, James S.; Beadle, Beth; Bishop, Justin A.
- Archives of Pathology & Laboratory Medicine, Vol. 142, Issue 5
Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels
journal, January 2013
- Jemal, Ahmedin; Simard, Edgar P.; Dorell, Christina
- JNCI: Journal of the National Cancer Institute, Vol. 105, Issue 3
X-Ray Fluorescence Microscopy for Investigation of Archival Tissues
journal, January 2012
- Paunesku, T.; Wanzer, M. B.; Kirillova, E. N.
- Health Physics, Vol. 103, Issue 2
Zinc-induced oligomerization of zinc α2 glycoprotein reveals multiple fatty acid-binding sites
journal, December 2015
- Zahid, Henna; Miah, Layeque; Lau, Andy M.
- Biochemical Journal, Vol. 473, Issue 1
Copper and Zinc levels in normal and malignant tissues
journal, September 1983
- Margalioth, Ehud J.; Schenker, Joseph G.; Chevion, Mordechai
- Cancer, Vol. 52, Issue 5
Reversible Dysfunction of Wild-Type p53 following Homeodomain-Interacting Protein Kinase-2 Knockdown
journal, May 2008
- Puca, R.; Nardinocchi, L.; Gal, H.
- Cancer Research, Vol. 68, Issue 10
Zinc-α2-glycoprotein expression as a marker of differentiation in human oral tumors
journal, March 1999
- Brysk, Miriam M.; Lei, Gang; Adler-Storthz, Karen
- Cancer Letters, Vol. 137, Issue 1
Reduced AZGP1 expression is an independent predictor of early PSA recurrence and associated with ERG-fusion positive and PTEN deleted prostate cancers: Clinical Relevance of AZGP1 Expression in Prostate Cancer
journal, October 2015
- Burdelski, Christoph; Kleinhans, Sandra; Kluth, Martina
- International Journal of Cancer, Vol. 138, Issue 5
Strong and weak zinc binding sites in human zinc-α2-glycoprotein
journal, November 2013
- Kumar, Aditya Arun; Hati, Debolina; Thaker, Thana'a Mohajer
- FEBS Letters, Vol. 587, Issue 24
Additive effect of the AZGP1, PIP, S100A8 and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma: Four-marker panel predicts breast cancer survival
journal, October 2013
- Parris, Toshima Z.; Kovács, Anikó; Aziz, Luaay
- International Journal of Cancer, Vol. 134, Issue 7
Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs
journal, May 2011
- Puca, Rosa; Nardinocchi, Lavinia; Porru, Manuela
- Cell Cycle, Vol. 10, Issue 10
The TRPV4-AKT axis promotes oral squamous cell carcinoma cell proliferation via CaMKII activation
journal, December 2019
- Fujii, Shinsuke; Tajiri, Yudai; Hasegawa, Kana
- Laboratory Investigation, Vol. 100, Issue 2
AZGP1 inhibits soft tissue sarcoma cells invasion and migration
journal, January 2018
- Liu, Jiayong; Han, Haibo; Fan, Zhengfu
- BMC Cancer, Vol. 18, Issue 1
Overexpression of Metallothionein-II Sensitizes Rodent Cells to Apoptosis Induced by DNA Cross-linking Agent through Inhibition of NF-κB Activation
journal, November 2001
- Papouli, Efterpi; Defais, Martine; Larminat, Florence
- Journal of Biological Chemistry, Vol. 277, Issue 7
Preserving elemental content in adherent mammalian cells for analysis by synchrotron-based x-ray fluorescence microscopy: PRESERVING ELEMENTAL CONTENT
journal, August 2016
- Jin, Qiaoling; Paunesku, Tatjana; Lai, Barry
- Journal of Microscopy, Vol. 265, Issue 1
Interrogation of EGFR-Targeted Uptake of TiO[sub 2] Nanoconjugates by X-ray Fluorescence Microscopy
conference, January 2011
- Yuan, Y.; Paunesku, T.; Arora, H.
- THE 10TH INTERNATIONAL CONFERENCE ON X-RAY MICROSCOPY, AIP Conference Proceedings
Peritumoral cuffing by T-cell tumor-infiltrating lymphocytes distinguishes HPV-related oropharyngeal squamous cell carcinoma from oral cavity squamous cell carcinoma
journal, July 2017
- Poropatich, Kate; Hernandez, David; Fontanarosa, Joel
- Journal of Oral Pathology & Medicine
Radiosensitization of clioquinol and zinc in human cancer cell lines
journal, April 2018
- Lu, Shan; Ke, Yuan; Wu, Chaoyan
- BMC Cancer, Vol. 18, Issue 1
Zinc promotes prostate cancer cell chemosensitivity to paclitaxel by inhibiting epithelial‐mesenchymal transition and inducing apoptosis
journal, January 2019
- Xue, Ya‐Nan; Yu, Bing‐Bing; Liu, Ya‐Nan
- The Prostate, Vol. 79, Issue 6
Concentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study
journal, June 2002
- Geraki, K.; Farquharson, M. J.; Bradley, D. A.
- Physics in Medicine and Biology, Vol. 47, Issue 13
Serum copper is a simple but valuable prognostic marker in B-cell chronic lymphocytic leukemia
journal, October 2014
- Labib, Hany A.; Hassanein, Mona; Etewa, Rasha L.
- International Journal of Hematology, Vol. 100, Issue 6
Transcriptional activation by the papillomavirus E6 zinc finger oncoprotein.
journal, June 1990
- Lamberti, C.; Morrissey, L. C.; Grossman, S. R.
- The EMBO Journal, Vol. 9, Issue 6
Zinc 2-Glycoprotein: A Multidisciplinary Protein
journal, June 2008
- Hassan, Md. I.; Waheed, A.; Yadav, S.
- Molecular Cancer Research, Vol. 6, Issue 6
X-ray fluorescence microscopy reveals large-scale relocalization and extracellular translocation of cellular copper during angiogenesis
journal, February 2007
- Finney, L.; Mandava, S.; Ursos, L.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 7
Decreased Expression of AZGP1 Is Associated with Poor Prognosis in Primary Gastric Cancer
journal, July 2013
- Huang, Chun-yu; Zhao, Jing-jing; Lv, Lin
- PLoS ONE, Vol. 8, Issue 7
Trends in head and neck cancer incidence in relation to smoking prevalence: An emerging epidemic of human papillomavirus-associated cancers?
journal, January 2007
- Sturgis, Erich M.; Cinciripini, Paul M.
- Cancer, Vol. 110, Issue 7
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
journal, December 2014
- Love, Michael I.; Huber, Wolfgang; Anders, Simon
- Genome Biology, Vol. 15, Issue 12
Use of the serum copper/zinc ratio in the differential diagnosis of ovarian malignancy.
journal, January 1986
- Lightman, A.; Brandes, J. M.; Binur, N.
- Clinical Chemistry, Vol. 32, Issue 1
Comprehensive genomic characterization of head and neck squamous cell carcinomas
text, January 2015
- Libraries, The University of North Carolina at Chapel Hill University
- The University of North Carolina at Chapel Hill University Libraries