title: MIEN1 promotes oral cancer progression and implicates poor overall survival.
abstract: Oral squamous cell carcinoma is a highly malignant tumor with the potential to invade local and distant sites and promote lymph node metastasis. Major players underlying the molecular mechanisms behind tumor progression are yet to be fully explored. Migration and invasion enhancer 1 (MIEN1), a novel protein overexpressed in various cancers, facilitates cell migration and invasion. In the present study we investigated the expression and role of MIEN1 in oral cancer progression using an in vitro model, patient derived oral tissues and existing TCGA data. Expression analysis using immortalized normal and cancer cells demonstrated increased expression of MIEN1 in cancer. Assays performed after MIEN1 knockdown in OSC-2 cells showed decreased migration, invasion and filopodia formation; while MIEN1 overexpression in DOK cells increased these characteristics and also up-regulated some Akt/NF-κB effectors, thereby suggesting an important role for MIEN1 in oral cancer progression. Immunohistochemical staining and analyses of oral tissue specimens, collected from patients over multiple visits, revealed significantly more staining in severe dysplasia and squamous cell carcinoma compared to mildly dysplastic or hyperplastic tissues. Finally, this was corroborated with the TCGA dataset, where MIEN1 expression was not only higher in intermediate and high grade cancer with significantly lower survival but also correlated with smoking. In summary, we demonstrate that MIEN1 expression not only positively correlates with oral cancer progression but also seems to be a critical molecular determinant in migration and invasion of oral cancer cells, thereby, playing a possible role in their metastatic dissemination.
authors.affiliation: a Department of Molecular and Medical Genetics ; Institute for Cancer Research and Texas Center for Health Disparities; University of North Texas Health Science Center ; Fort Worth , TX USA.
authors.forename: Smrithi
authors.initials: S
authors.lastname: Rajendiran
authors.forename: Marilyne
authors.initials: M
authors.lastname: Kpetemey
authors.forename: Sayantan
authors.initials: S
authors.lastname: Maji
authors.forename: Lee D
authors.initials: LD
authors.lastname: Gibbs
authors.forename: Subhamoy
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mantsch
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hare
authors.forename: Jamboor K
authors.initials: JK
authors.lastname: Vishwanatha
mesh_terms: D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C517054:MIEN1 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: CRS, current reformed smoker; CS, current smoker; GFP, green fluorescent protein; HNSCC, head and neck squamous cell carcinoma; MIEN1; MIEN1, migration and invasion enhancer 1; MMP-9, matrix metallopeptidase 9; NF-κB; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OSCC, oral squamous cell carcinoma; TCGA HNSCC database; TCGA, the cancer genome atlas; VEGF, vascular endothelial growth factor; filopodia; invasion; longitudinal study; migration; oral cancer; siRNA, small interfering RNA; survival; uPA, urokinase plasminogen activator