Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

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.

doi:10.1038/s41598-019-53268-1

Title: Elemental Zn and its Binding Protein Zinc-α2-Glycoprotein are Elevated in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

Journal Article · 17 November 2019 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-019-53268-1 · OSTI ID:1601427

Poropatich, Kate ^[1];

^[1]; Zander, Alia ^[1]; Wray, Brian ^[1]; Schipma, Matthew ^[1]; Dalal, Prarthana ^[1]; Agulnik, Mark ^[1]; Chen, Si ^[2]; Lai, Barry ^[1]; Antipova, Olga ^[2]; Maxey, Evan ^[2]; Brown, Koshonna ^[1]; Wanzer, Michael Beau ^[1]; Gursel, Demirkan ^[1]; Fan, Hanli ^[1]; Rademaker, Alfred ^[1]; Woloschak, Gayle E. ^[1]; Mittal, Bharat B. ^[1]

Northwestern Univ., Evanston, IL (United States)
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH), National Cancer Institute; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1601427

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 9; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Love, Michael I.; Huber, Wolfgang; Anders, Simon Genome Biology, Vol. 15, Issue 12 https://doi.org/10.1186/s13059-014-0550-8	journal	December 2014
Zinc Downregulates HIF-1α and Inhibits Its Activity in Tumor Cells In Vitro and In Vivo Nardinocchi, Lavinia; Pantisano, Valentina; Puca, Rosa PLoS ONE, Vol. 5, Issue 12 https://doi.org/10.1371/journal.pone.0015048	journal	December 2010
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Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells Arora, H. C.; Jensen, M. P.; Yuan, Y. Cancer Research, Vol. 72, Issue 3 https://doi.org/10.1158/0008-5472.CAN-11-2890	journal	December 2011
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Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures Zhang, Y.; Koneva, L. A.; Virani, S. Clinical Cancer Research, Vol. 22, Issue 18 https://doi.org/10.1158/1078-0432.CCR-16-0323	journal	April 2016
Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy Arriaga, Juan M.; Greco, Angela; Mordoh, José Molecular Cancer Therapeutics, Vol. 13, Issue 5 https://doi.org/10.1158/1535-7163.MCT-13-0944	journal	March 2014
Zinc 2-Glycoprotein: A Multidisciplinary Protein Hassan, Md. I.; Waheed, A.; Yadav, S. Molecular Cancer Research, Vol. 6, Issue 6 https://doi.org/10.1158/1541-7786.MCR-07-2195	journal	June 2008
HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers Koneva, Lada A.; Zhang, Yanxiao; Virani, Shama Molecular Cancer Research, Vol. 16, Issue 1 https://doi.org/10.1158/1541-7786.MCR-17-0153	journal	September 2017
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AZGP1 inhibits soft tissue sarcoma cells invasion and migration Liu, Jiayong; Han, Haibo; Fan, Zhengfu BMC Cancer, Vol. 18, Issue 1 https://doi.org/10.1186/s12885-017-3962-5	journal	January 2018
Radiosensitization of clioquinol and zinc in human cancer cell lines Lu, Shan; Ke, Yuan; Wu, Chaoyan BMC Cancer, Vol. 18, Issue 1 https://doi.org/10.1186/s12885-018-4264-2	journal	April 2018
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Love, Michael I.; Huber, Wolfgang; Anders, Simon Genome Biology, Vol. 15, Issue 12 https://doi.org/10.1186/s13059-014-0550-8	journal	December 2014
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Decreased Expression of AZGP1 Is Associated with Poor Prognosis in Primary Gastric Cancer Huang, Chun-yu; Zhao, Jing-jing; Lv, Lin PLoS ONE, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pone.0069155	journal	July 2013
Comprehensive genomic characterization of head and neck squamous cell carcinomas Libraries, The University of North Carolina at Chapel Hill University The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/tkv9-c797	text	January 2015
Reduction of AZGP1 predicts poor prognosis in esophageal squamous cell carcinoma patients in Northern China Tang, Hong; Wu, Yufeng; Qin, Yanru OncoTargets and Therapy, Vol. Volume 10 https://doi.org/10.2147/OTT.S113932	journal	December 2016
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Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs Puca, Rosa; Nardinocchi, Lavinia; Porru, Manuela Cell Cycle, Vol. 10, Issue 10 https://doi.org/10.4161/cc.10.10.15642	journal	May 2011
Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists Lewis, James S.; Beadle, Beth; Bishop, Justin A. Archives of Pathology & Laboratory Medicine, Vol. 142, Issue 5 https://doi.org/10.5858/arpa.2017-0286-CP	journal	May 2018

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