Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis (type III). It is a multifaceted phenomenon governed by the activation of genes associated with cell migration, extracellular matrix degradation, DNA repair, and angiogenesis. The cancer cells employ EMT to acquire the ability to migrate, resist therapeutic agents and escape immunity. One of the key biomarkers of EMT is vimentin, a type III intermediate filament that is normally expressed in mesenchymal cells but is upregulated during cancer metastasis. This review highlights the pivotal role of vimentin in the key events during EMT and explains its role as a downstream as well as an upstream regulator in this highly complex process. This review also highlights the areas that require further research in exploring the role of vimentin in EMT. As a cytoskeletal protein, vimentin filaments support mechanical integrity of the migratory machinery, generation of directional force, focal adhesion modulation and extracellular attachment. As a viscoelastic scaffold, it gives stress-bearing ability and flexible support to the cell and its organelles. However, during EMT it modulates genes for EMT inducers such as Snail, Slug, Twist and ZEB1/2, as well as the key epigenetic factors. In addition, it suppresses cellular differentiation and upregulates their pluripotent potential by inducing genes associated with self-renewability, thus increasing the stemness of cancer stem cells, facilitating the tumour spread and making them more resistant to treatments. Several missense and frameshift mutations reported in vimentin in human cancers may also contribute towards the metastatic spread. Therefore, we propose that vimentin should be a therapeutic target using molecular technologies that will curb cancer growth and spread with reduced mortality and morbidity.

Oral cancer is a sub-category of head and neck cancers that primarily initiates in the oral cavity. The primary treatment option for oral cancer remains surgery but it is associated with massive disfigurement, inability to carry out normal oral functions, psycho-social stress and exhaustive rehabilitation. Other treatment options such as chemotherapy and radiotherapy have their own limitations in terms of toxicity, intolerance and therapeutic resistance. Immunological treatments to enhance the body's ability to recognize cancer tissue as a foreign entity are also being used but they are new and underdeveloped. Although substantial progress has been made in the treatment of oral cancer, its complex heterogeneous nature still needs to be explored, to elucidate the molecular basis for developing resistance to therapeutic agents and how to overcome it, with the aim of improving the chances of patients' survival and their quality of life. This review provides an overview of up-to-date information on the complex role of the major molecules and associated signaling, epigenetic changes, DNA damage repair systems, cancer stem cells and micro RNAs in the development of therapeutic resistance and treatment failure in oral cancer. We have also summarized the current strategies being developed to overcome these therapeutic challenges. This review will help not only researchers but also oral oncologists in the management of the disease and in developing new therapeutic modalities.

In advanced metastatic cancers with reduced patient survival and poor prognosis, expression of vimentin, a type III intermediate filament protein is frequently observed. Vimentin appears to suppress epithelial characteristics and augments cell migration but the molecular basis for these changes is not well understood. Here, we have ectopically expressed vimentin in MCF-7 and investigated its genomic and functional implications. Vimentin changed the cell shape by decreasing major axis, major axis angle and increased cell migration, without affecting proliferation. Vimentin downregulated major keratin genes KRT8, KRT18 and KRT19. Transcriptome-coupled GO and KEGG analyses revealed that vimentin-affected genes were linked to either cell–cell/cell-ECM or cell cycle/proliferation specific pathways. Using shRNA mediated knockdown of vimentin in two cell types; MCF-7FV (ectopically expressing) and MDA-MB-231 (endogenously expressing), we identified a vimentin-specific signature consisting of 13 protein encoding genes (CDH5, AXL, PTPRM, TGFBI, CDH10, NES, E2F1, FOXM1, CDC45, FSD1, BCL2, KIF26A and WISP2) and two long non-coding RNAs, LINC00052 and C15ORF9-AS1. CDH5, an endothelial cadherin, which mediates cell–cell junctions, was the most downregulated protein encoding gene. Interestingly, downregulation of CDH5 by shRNA significantly increased cell migration confirming our RNA-Seq data. Furthermore, presence of vimentin altered the lamin expression in MCF-7. Collectively, we demonstrate, for the first time, that vimentin in breast cancer cells could change nuclear architecture by affecting lamin expression, which downregulates genes maintaining cell–cell junctions resulting in increased cell migration.

In advanced metastatic cancers with reduced patient survival and poor prognosis, expression of vimentin, a type III intermediate filament protein is frequently observed. Vimentin appears to suppress epithelial characteristics and augments cell migration but the molecular basis for these changes are not well understood. Here we have ectopically expressed vimentin in MCF-7 and investigated its genomic and functional implications. Vimentin changed the cell shape, by decreasing major axis and major axis angle, and increased cell migration, without affecting proliferation. Vimentin downregulated major keratin genes KRT8, KRT18 and KRT19. Transcriptome-coupled GO and KEGG analyses revealed that vimentin-affected genes were linked to either cell-cell/cell-ECM or cell cycle/proliferation specific pathways. Using shRNA mediated knockdown of vimentin in two breast cancer cell types; MCF-7FV (ectopically expressing) and MDA-MB-231 (endogenously expressing), we identified a vimentin-specific signature consisting of 13 protein encoding genes (CDH5, AXL, PTPRM, TGFBI, CDH10, FOXM1, BCL2, NES, E2F1, FOXM1, CDC45, FSD1, BCL2, KIF26A and WISP2) and two long non-coding RNAs, LINC00052 and C15ORF9-AS1. CDH5, an endothelial cadherin, which mediates cell-cell junctions was the most downregulated protein encoding gene. Interestingly, downregulation of CDH5 by shRNA significantly increased cell migration confirming our RNA-Seq data. Furthermore, vimentin reduced MCF-7 nuclear area perhaps through altered lamin expression. Collectively, we demonstrate, for the first time, that vimentin in cancer cells changes nuclear architecture by affecting lamin expression, which downregulates genes maintaining cell-cell junctions resulting in increased cell migration.

Background Vimentin is a type III intermediate filament (IF) protein, whose expression correlates with advanced metastatic cancer, reduced patient survival and poor prognosis across many cancers. During EMT-induced metastasis when vimentin begins to express, the epithelial characteristics are lost, and cell motility is augmented. The molecular bases for these changes are not well defined. Methods Ectopic expression of vimentin was carried in MCF-7 using spinfection of retroviruses. shRNA was used to knockdown vimentin in vimentin overexpressing MCF-7 and MDM-MB-231 cells, which express vimentin endogenously. The transcriptome profiling was carried out by RNA-Seq and validated by qPCR. Protein expression was measured by western blotting. Effect of vimentin on MCF-7 was determined by cell proliferation, migration and adhesion assays. Results Vimentin expression elicited a change in cell shape by significantly decreasing major axis, major axis angle and increasing cell migration, with no change in cell proliferation. Vimentin suppresses expression of major keratin genes KRT18, KRT19 and KRT8. Transcriptome-coupled GO and KEGG analyses revealed that vimentin-affected genes were linked to either cell-cell/cell-ECM or cell cycle/proliferation specific pathways. Using shRNA mediated downregulation of vimentin in two cell types; MCF-7FV (ectopically expressing vimentin) and MDA-MB-231 (endogenously expressing vimentin), we identified 13 vimentin-responsive protein encoding genes common in both approaches and two long non-coding RNAs, LINC00052 and C15ORF9-AS1. Eight of these gene products CDH5, AXL, PTPRM, TGFBI, CDH10, FOXM1, BCL2 and NES were associated with cell-cell and cell-ECM interactions, E2F1, FOXM1 and CDC45 were in the cell proliferation group and the rest FSD1, BCL2, KIF26A and WISP2 were outside the two groups. Interestingly, downregulation of CDH5 significantly increased MCF-7 cell migration. Furthermore, vimentin expression in MCF-7 reduced nuclear area, altered expression of lamins, which was mostly reversed after its downregulation. Conclusion Collectively, we demonstrate, for the first time, that vimentin expression in cancer cells downregulates genes maintaining cell-cell junctions resulting in increased cell migration. Furthermore, this is the first report linking vimentin expression with LINC00052, which is dysregulated in many cancers.