Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms of oral cancer worldwide. Although great efforts have been made in the past decades, the 5‐year survival rate of OSCC patients is no more than 60% due to tumor metastasis and subsequent recurrence. The metastasis from the primary site is due to a complex process known as epithelial‐to‐mesenchymal transition (EMT). During the EMT, epithelial cells gradually acquire the structural and functional characteristics of mesenchymal cells, leading to the upregulation of cell migration and the promotion of tumor cell dissemination. Therefore, EMT attracted broad attention due to its close relationship with cancer invasion and metastasis. Therefore, in the present review, an extensive description of the current research on OSCC and the role of EMT in this cancer type is provided, including diverse EMT markers, regulatory networks and crucial EMT‐inducing transcription factors in OSCC. Moreover, a brief summary was made regarding the current application of EMT‐correlated indexes in the prognostic analysis of OSCC patients, and the potential therapeutic approaches against OSCC and difficulties in the development of an effective anti‐EMT treatment are discussed. Our aim is to provide novel insights to develop new strategies to combat OSCC by targeting EMT.

Background R-spondins (Rspo) and leucine-rich repeat-containing G-protein-coupled receptors (LGR) play important roles in development, stem cells survival, and tumorigenicity by activating Wnt signaling pathway. Whether R-spondins-LGR signaling affects the progression of squamous cell carcinoma (SCC) remain unknown. This study aims to uncover the role of R-spodin2/LGR4 in tongue SCC (TSCC). Methods The expression of Rspo2 in TSCC specimens and its correlation with TSCC clinical outcome were evaluated. Levels of Rspo2 or LGR4 were altered by pharmacological and genetic approaches, and the effects on TSCC progression were assessed. Findings Aberrantly high levels of Rspo2 were detected in TSCC specimens. Its levels were closely related with lymph node metastasis, clinical stage and survival rate in patients with tongue SCC. Exogenous Rspo2 or overexpression of Rspo2 promoted growth, migration and invasion, epithelial-mesenchymal transition (EMT) and stem-like properties in SCC both in vivo and in vitro. Silence of Rspo2 abolished these phenotypes. LGR4 was functionally upregulated by Rspo2 in TSCC. Overexpression of Rspo2 increased, whereas Rspo2 silencing decreased the expression of LGR4, leading to subsequent phosphorylation of LRP6 and nuclear translocation of β-catenin in TSCC cell lines. This nuclear translocation of β-catenin was associated with a significant alteration in TCF-1, a downstream nuclear transcription factor of β-catenin, as well as its target genes: CD44, CyclinD1 and c-Myc. Interpretation Rspo2-LGR4 system regulates growth, migration and invasion, EMT and stem-like properties of TSCC via Wnt/β-catenin signaling pathway.

Background Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC. Methods Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial‐mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays. Results We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E‐cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC. Conclusions CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.

BackgroundAlanine‐serine‐cysteine transporter 2 (ASCT2), a major glutamine transporter, is essential for cell growth and tumor development in a variety of cancers. However, the clinicopathological significance and pathological role of ASCT2 in OSCC (oral squamous cell carcinoma) lesions remain unclear.MethodsSections from 89 OSCC patients and 10 paracancerous tissue controls were stained by immunohistochemistry (IHC) to detect the expression of ASCT2, glutaminase, and Ki‐67. Survival analysis was carried out to determine the predictive value of ASCT2 expression using the log‐rank test. Moreover, the critical role of ASCT2 in tumor growth was determined by a series of in vitro and in vivo assays. Cell Counting Kit‐8 (CCK8), Western Blotting (WB), Reactive Oxygen Species (ROS), and Glutathione (GSH) detection were applied to explore the molecular mechanism of ASCT2 involvement in tumor development.ResultsIn OSCC lesions, ASCT2 expression was significantly increased and associated with cell proliferation index (Ki‐67) and GLS expression. Moreover, survival analysis showed that OSCC patients with high ASCT2 expression had lower overall survival (P = 0.0365). In OSCC cell lines, the high level of ASCT2 was inherent and related to the glutamine addiction of tumor cells. In vitro and in vivo functional experiments revealed that targeted silencing of ASCT2 can effectively inhibit OSCC cell proliferation and tumor growth. Mechanistically, targeting ASCT2 knockdown reduced glutamine uptake and intracellular GSH levels, which contribute to the accumulation of ROS and induce apoptosis in OSCC cells.ConclusionASCT2 is a significant factor for predicting overall survival in patients with OSCC, and targeting ASCT2 to inhibit glutamine metabolism may be a promising strategy for OSCC treatment.

For head and neck squamous cell carcinoma (HNSCC), the local invasion and distant metastasis represent the predominant causes of mortality. Targeted inhibition of chemokines and their receptors is an ongoing antitumor strategy established on the crucial roles of chemokines in cancer invasion and metastasis. Herein, we showed that C-C motif chemokine ligand 2 (CCL2)- C-C motif chemokine receptor 4 (CCR4) signaling, but not the CCL2- C-C motif chemokine receptor 2 (CCR2) axis, induces the formation of the vav guanine nucleotide exchange factor 2 (Vav2)- Rac family small GTPase 1 (Rac1) complex to activate the phosphorylation of myosin light chain (MLC), which is involved in the regulation of cell motility and cancer metastasis. We identified that targeting CCR4 could effectively interrupt the activation of HNSCC invasion and metastasis induced by CCL2 without the promoting cancer relapse observed during the subsequent withdrawal period. All current findings suggested that CCL2-CCR4-Vav2-Rac1-p-MLC signaling plays an essential role in cell migration and cancer metastasis of HNSCC, and CCR4 may serve as a new potential molecular target for HNSCC therapy.

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Gene mutations play an important role in head and neck squamous cell carcinoma (HNSCC) by not only promoting the occurrence and progression of HNSCC but also affecting sensitivity to treatment and prognosis. KRAS is one of the most frequently mutated oncogenes, which has been reported to have a mutation rate from 1.7% to 12.7% and may lead to poor prognosis in HNSCC, but its role remains unclear. Here, we found that the KRAS mutation can promote HNSCC generation through synergism with 4‐Nitroquinoline‐1‐Oxide(4NQO). Mechanistically, KRAS mutations can significantly upregulate Runx1 to promote oral epithelial cell proliferation and migration and inhibit apoptosis. Runx1 inhibitor Ro 5‐3335 can effectively inhibit KRAS‐mutated HNSCC progression both in vitro and in vivo. These findings suggest that the KRAS mutation plays an important role in HNSCC and that Runx1 may be a novel therapeutic target for KRAS‐mutated HNSCC.