Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways.
Oropharyngeal carcinoma (OPC) can be classified into two equally prevalent subtypes depending on the presence of human papillomavirus (HPV). Patients with HPV-positive (HPV+) OPC represent a unique cohort with a distinct tumor biology and clinical behavior compared to HPV-negative (HPV-) OPC. Genetic studies have demonstrated chromosomal and gene expression changes associated with distinct subclasses of OPC; however, the proteomic consequences of HPV infection are not known. We analyzed sets of ten HPV+ and ten HPV- OPCs and ten normal adult oral epithelia using a standardized global proteomic analysis platform. This analysis yielded a total of 2,653 confidently identified proteins from which we chose 31 proteins on the basis of expression differences between HPV+, HPV- and normal epithelium for targeted protein quantitation. Analysis of differentially expressed proteins by HPV status revealed enrichment of proteins involved in epithelial cell development, keratinization and extracellular matrix organization in HPV- OPC, whereas enrichment of proteins in DNA initiation and replication and cell cycle control was found for HPV+ OPC. Enrichment analysis for transcription factor targets identified transcription factors E2F1 and E2F4 to be highly expressed in HPV+ OPC. We also found high expression of argininosuccinate synthase 1 in HPV+ OPC, suggesting that HPV+ OPC is more dependent on conditionally essential amino acid, arginine, and this was confirmed on a OPC-specific tissue microarray. These identified proteomic changes reveal novel driving molecular pathways for HPV+ and HPV- OPCs that may be pertinent in therapeutic strategies and outcomes of OPC.
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. r.slebos@vanderbilt.edu
Robbert J C
RJ
Slebos
Nico
N
Jehmlich
Brandee
B
Brown
Zhirong
Z
Yin
Christine H
CH
Chung
Wendell G
WG
Yarbrough
Daniel C
DC
Liebler
D001124:Argininosuccinate Synthase / Q000096:biosynthesis; D002454:Cell Differentiation; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D050704:E2F4 Transcription Factor / Q000096:biosynthesis; D005109:Extracellular Matrix; D020869:Gene Expression Profiling; D006801:Humans; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000821:virology; D040901:Proteomics
D004279:DNA, Viral; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D001124:Argininosuccinate Synthase