Nano-biomechanical Validation of Epithelial–Mesenchymal Transition in Oral Squamous Cell Carcinomas

Abstract

The effective cure for oral squamous cell carcinoma (OSCC) patients is challenging due late diagnosis and fatal metastasis. The standard diagnosis for OSCC often depends on the subjective interpretation of conventional histopathology. Additionally, there is no standard way for OSCC prognosis. Over the past decade, nano-mechanical stiffness has been considered as a quantitative measure for cancer diagnosis. Nevertheless, its application to OSCC diagnosis and prognosis is still in a primitive stage. In this study, we investigated whether the OSCC progression can be predicted by nano-mechanical properties in combination with biochemical properties, especially the epithelial-mesenchymal transition (EMT). Atomic force microscopy-based nano-mechanical measurements of three different OSCC cell lines-SCC-4, SCC-9, and SCC-15-were conducted together with biochemical analyses. The gradual upregulation of Snail2, N-cadherin, and vimentin and the simultaneous downregulation of E-cadherin were observed, and the degree of upregulation and downregulation was stronger in the order of the cell lines mentioned above. The strength of enhancement in migration was in the same order as well. Consistently, nano-mechanical stiffness was gradually decreased as the EMT progresses. These results suggest that the nano-mechanical assay could serve as a quantitative tool to predict the OSCC progression in the context of the EMT. Furthermore, we found that the upregulated vimentin, a major filamentous component of the cytoskeleton, may contribute to mechanical softening, which can be discerned from the role of actin filaments in mechanical stiffness. In conclusion, our combinational study proposes a novel way to elucidate the mechanism of OSCC progression and its therapeutic targets.Key words nano-mechanics; epithelial-mesenchymal transition; atomic force microscopy; oral cancer Oral squamous cell carcinoma (OSCC) is the most common neoplasm of the head and neck squamous cell carcinoma (HNSCC), which represents approximately 6% of all types of cancer. Also about half a million new cases are diagnosed every year.1) It is a highly invasive malignant tumor characterized by a high rate of metastasis to the cervical lymph nodes.2) Diagnosis and management of OSCC have improved by combining therapies such as radical surgery, radiotherapy and neo-adjuvant chemotherapy, but the overall 5-year survival rate is still below 50% because of late diagnosis and high rate of recurrence.3,4) Thus, it is highly desirable to understand the underlying mechanism governing metastatic dissemination of OSCC for the development of anticancer therapeutics.The progression of OSCC is largely dependent on the epithelial-mesenchymal transition (EMT). 5,6) Recent studies have reported that the EMT has been strongly associated with cancer cell stemness 7,8) and chemoresistance to anti-cancer drugs, [9][10][11][12] indicating that targeting EMT could be a good strategy to overcome cancer metastasis. Notably, transforming growth factor-β1 (TGF-β1) has been known to be a prima...

[Retracted] Comprehensive and Integrated Analysis Identifies ZEB1 as a Key Novel Gene in Oral Squamous Cell Carcinoma

“…ZEB1 is abnormally expressed in various human cancers and is best known for activating EMT in cancer cells to facilitate tumor development [ 28 ]. In recent years, a growing body of evidence has shown that EMT is involved in the pathogenesis of OSCC [ 29 , 30 ]. As a crucial transcription factor of EMT regulation, we speculated that ZEB1 might play a critical role in the pathogenesis of OSCC.…”

M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF

“…Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer in the world, with ~600,000 cases each year. The 5-year survival rate is generally <50% (1,2). HNSCC is divided into two types, human papilloma virus (HPV)-positive and HPV-negative, which is dependent on whether HNSCC is caused by HPV (3).…”

Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast

“…Confined environment can modulate the behavior of mesenchymal or EMT cells by inducing a mesenchymal to amoeboid transition in low adhesion conditions, allowing cancer cells to adapt their migration mode to their environment. Interestingly, studies aiming at measuring the mechanical properties of oral squamous cell carcinoma as they undergo EMT have demonstrated a general softening of cells as the EMT progresses (Park et al 2016). This, along with other similarly reported data, suggests that in environments with high mechanical constraints (like the stiff ECM of confined space), cells modulate their inner mechanical properties to become softer by undergoing an EMT process.…”