title: Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma.
abstract: Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic.
authors.affiliation: a Department of Oncology , Johns Hopkins Medical Institutions , Baltimore , MD USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Cheng
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ozawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Jason D
authors.initials: JD
authors.lastname: Howard
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez
authors.forename: Michael
authors.initials: M
authors.lastname: Considine
authors.forename: Manjusha
authors.initials: M
authors.lastname: Thakar
authors.forename: Ruchira
authors.initials: R
authors.lastname: Ranaweera
authors.forename: Gabriel
authors.initials: G
authors.lastname: Krigsfeld
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D027383:Papillomaviridae; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D000068818:Cetuximab
keywords: CDKN2A, cyclin-dependent kinase Inhibitor 2A; CTX, cetuximab; EGFR, epidermal growth factor receptor; EMT, epithelial-to-msenchymal transition; FDR, false delivery rate; HB-EGF, heparin-binding EGF-like growth factor; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; KD, knocked-down; RPPA, reverse phase protein arrays; RSEM, RNA-Seq by Expectation Maximization; SMAD4; SMAD4, mothers against decapentaplegic homolog 4; TCGA, The Cancer Genome Atlas; cetuximab; epithelial-to-mesenchymal transition; head and neck squamous cell carcinoma; mIR, microRNA; qRT-PCR, quantitative real-time polymerase chain reaction; shRNA, small hairpin RNA