Abstract
FAT atypical cadherin 1 (FAT1) regulates cell-cell adhesion and extracellular matrix architecture, while acting as tumor suppressor or oncogene, context-dependently. Despite implication of FAT1 in several malignancies, its role in oral squamous cell carcinoma (OSCC) remains unclear. Herein, we document the driver-oncogene role of FAT1, and its mediation of cell-death evasion, proliferation, oncogenicity, and chemoresistance in OSCC. In-silica analyses indicate FAT1 mutations are frequent and drive head-neck SCC, with enhanced expression defining high-risk population and poor prognosis. We demonstrated aberrant FAT1 mRNA and protein expression in OSCC compared with non-cancer tissues, whereas loss-of-FAT1-function attenuates human primary SAS and metastatic HSC-3 OSCC cell viability, without affecting normal primary human gingival fibroblast cells. shFAT1 suppressed PCNA and upregulated BAX/BCL2 ratio in SAS and HSC-3 cells. Moreover, compared with wild-type cells, shFAT1 concomitantly impaired HSC-3 cell migration, invasion, and clonogenicity. Interestingly, while over-expressed FAT1 characterized cisplatin-resistance (CispR), shFAT1 synchronously re-sensitized CispR cells to cisplatin, enhanced glutathione (GSH)/GSH synthetase (GSS)-mediated oxidative stress and deregulated LRP5/WNT2 signaling. Concisely, FAT1 is an actionable driver-oncogene in OSCC and targeting FAT1 in patients with erstwhile cisplatin-resistant OSCC is therapeutically promising.
Highlights
Oral cancer, comprising cancers of the oral cavity (International Statistical Classification of Diseases and Related Health Problems, ICD-10: C00-06) and oropharyngeal regions (ICD-10: C09-10), is one of Cancers 2019, 11, 1883; doi:10.3390/cancers11121883 www.mdpi.com/journal/cancersCancers 2019, 11, 1883 the most prevalent malignancies in the world, with an annual incidence of 447, 751 cases [1], and with a predicted 67.1% rise in the disease-specific mortality by 2035 (n = 242, 886) compared with 2012(n = 145, 353), oral cancer remains a principal cause of cancer-related mortality globally [1,2]
Against the background of this ambivalent context-dependent role of FAT atypical cadherin 1 (FAT1) in malignancies and its under-explored role in oral squamous cell carcinoma (OSCC), the present study investigated the probable implication of FAT1 in the oncogenicity, metastatic and therapy-resistance phenotypes of OSCC cells and the poor prognosis of patients with OSCC
Our results indicate that shFAT1 transfection markedly suppressed the proliferation cum viability of SAS (62.5%, p < 0.05) or HSC-3 (58.1%, p < 0.05)
Summary
The oral squamous cell carcinoma (OSCC) histological type constitutes more than 90% of all oral cancer, and is highly invasive, most often insensitive to chemo- and/or radiation therapy, and associated with high incidence of recurrence, and poor survival rates [1,2]. The standard of care remains surgery for patients with early (I and II)—or advanced (III and IV)—stage tumors, and definitive chemoradiotherapy for patients with advanced-stage tumors, where chemotherapy consists of cisplatin (CDDP), docetaxel, and 5-flurouracil, especially for patients with advanced-stage malignancies [5,6], this is often associated with increased risk of severe therapy-related toxicities and adverse effects, including neutropenia and osteoradionecrosis, increasing incidence of therapy failure and disease relapse, and low median survival rates for patients with. Recent work by Mascitti et al, very well encapsulates the epidemiological implication and prognostic ramifications of this dearth of therapeutically-relevant actionable targets and prognostigators, and further begs the case for same [9]
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