FAP overexpression induce Epithelial-Mesenchymal Transition (EMT) in oral squamous cell carcinoma by down-regulating DPP9 gene

Abstract

17FAP acts as a tumor promoter via epithelial-mesenchymal transition (EMT) in 18 human oral squamous cell carcinoma (OSCC). The present study was designed to 19 investigate the interaction proteins with FAP and explore the precise mechanism 20 of FAP promoting EMT in OSCC. IP-MS analysis confirmed that DPP9 was an 21 interacting protein of FAP. DPP9 was down-regulated in OSCC tissue samples 22 compared with MNT using immunohistochemistry and quantitative-PCR detection. 23Lower DPP9 was correlated with unfavorable overall survival of patients with OSCC. 24Repressing DPP9 accelerates the proliferation of OSCC cells in vitro and in vivo. 25 Mechanistically, overexpression of FAP downregulate the expression of the DPP9 26 and the effect of FAP on OSCC proliferation, migration, invasion and EMT could be 27 reversed by up-regulated DPP9. Our study suggests that FAP could induce EMT 28 and promote carcinogenesis in oral squamous cell carcinoma by down-regulating 29 DPP9 gene. That will hint different dimension on therapy for patients with OSCC.30 31 Keyword 32 OSCC, FAP, DPP9, EMT, Oral cancer 33 34 Abbreviations 35 FAP: fibroblast activation protein 36 OSCC: Oral squamous cell carcinoma 37 IP: Immunoprecipitation 38 MS: Mass spectrometry 39 qPCR: Quantitative real-time PCR 40 EMT: Epithelial-mesenchymal transition 41 42 43 Introduction 44 Cancer of the oral cavity is one of the most common malignancies and an important 45 cause of morbidity and death(1). OSCC accounts for more than 90% of all oral 46 cancers with the main factors of consumption of tobacco and/or alcohol and chewing 47 areca. In spite of major advances in diagnosis and treatment, the prognosis of OSCC 48 is poor due to invasion, metastasis, and recurrence. Although the oral cavity is easily 49 examined, yet up to 60% of OSCC cases are undiagnosed in the clinical stage. At 50 histopathological level, OSCC is characterized squamous differentiation, nuclear 51 pleomorphisms, invasive growth and metastasis(2). The biomarkers(3) for early 52 diagnosis of OSCC is therefore key to improving patient prognosis and survival rates. 53 FAP is a member of the dipeptidyl peptidase (DPP) family with around 50% homology 54 with DPP4(4). FAP is expressed during development, and in the context of cancer, it is 55 highly expressed and can be a marker of cancer-associated fibroblasts(CAFs), and 56 itself has been demonstrated to have pro-tumorigenic activity(5). Structurally, FAP 57 consists of a 6 amino acid cytoplasmic tail, a single 20 amino acid transmembrane 58 domain, and a 734 amino acid extracellular domain(4) and FAP have both post-59 proline exopeptidase activity and gelatinase activity (6). FAP plays its role in cancer 60 promotion both by enzymatic effects and non-enzymatic effects. Its dual enzymatic 61 activity gives it a range of putative substrates, and many different types of substrates 62 had been reported (7). Although many studies (7) suggested that FAP can enhance 63 various carcinogenesis process, it is still not clear whether that is based on its ...

Dipeptidyl-Aminopeptidases 8 and 9 Regulate Autophagy and Tamoxifen Response in Breast Cancer Cells

“…DPP8 and DPP9 are reported to affect proliferation as well as cell death in several ways. The knockdown of DPP9 in oral squamous cell carcinoma cells increased cell growth via FAP-α [ 45 ], whereas the overexpression of DPP9 in Huh-7 and HepG2 cells reduced proliferation and increased apoptosis independent of its enzymatic activity by interacting with HRAS [ 46 ]. In contrast, DPP9 deficiency in non-small-cell lung cancer cells [ 17 ], as well as DPP8 deficiency in cervical cancer cells, reduced proliferation [ 26 ].…”