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The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-derived cancer-associated fibroblasts (CAFsWPOI4-5), characterized by high oxytocin receptor expression (OXTRHigh), contribute to local-regional metastasis. OXTRHigh CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3+ tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTRHigh CAFs. Therefore, targeting ERK5 signaling in OXTRHigh CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5. Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis. [ABSTRACT FROM AUTHOR]

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC. [ABSTRACT FROM AUTHOR]

Background: Local resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties. However, the mechanism and the effects underlying the transition of NFs to CAFs in oral squamous cell carcinoma (OSCC) remain unclear. Methods: Five pairs of matching primary NFs and CAFs derived from OSCC patients were sent for RNA sequencing. Epiregulin (EREG) expression was analyzed by IHC in fibroblasts from OSCC patients. The role of EREG in the NF-CAF transition and the consequential effects on OSCC progression were examined by upregulation/downregulation of EREG in NFs/CAFs both in vitro and in vivo. Results: Here, we identified epiregulin (EREG) as the most remarkably upregulated gene in CAFs. High EREG expression in CAFs correlated with higher T stage, deeper invasion and inferior worst pattern of invasion (WPOI) in OSCC patients and predicted shorter overall survival. Overexpression of EREG in NFs activated the CAF phenotype. Mechanistically, the JAK2/STAT3 pathway was enhanced by EREG in parallel with increased IL-6 expression, which could be inhibited by the JAK2 inhibitor AG490. Recombinant IL-6 upregulated the JAK2/STAT3/EREG pathway in a feedback loop. Moreover, EREG-induced CAF activation promoted the epithelial-mesenchymal transition (EMT) necessary for migration and invasion, which was dependent on JAK2/STAT3 signaling and IL-6. In vivo, EREG expression in stroma fibroblasts promoted tumor growth with high stromal α-SMA, phospho-JAK2/STAT3, and IL-6 expression and upregulated EMT in HSC3 cells. Conclusions: EREG is essential for the NF-CAF transformation needed to induce EMT of tumor cells in a JAK2-STAT3- and IL-6-dependent manner in OSCC. [ABSTRACT FROM AUTHOR]

Background: Monocytes, which subdivided into three functional subsets (classical, intermediate, and nonclassical), play important roles in the progression of cancer. The subset composition is altered in several pathologic conditions including cancers. However, the composition and function of circulating monocyte subsets in patients with oral squamous cell carcinoma (OSCC) are still obscure.Methods: The frequencies of monocyte subsets in peripheral blood of patients with OSCC and healthy donors are determined by flow cytometry, and their diagnostic values for OSCC were evaluated. The associations between levels of monocyte subsets and clinicopathological features of patients with OSCC were analyzed using cross-tabulation with the chi-square test.Results: We demonstrated that the frequency of CD14++ CD16+ intermediate monocytes was remarkably increased (P < 0.0001) in OSCC patients compared with healthy controls (7.33% ± 2.56% of total monocytes, n = 68 versus 4.78% ± 1.50% of total monocytes, n = 57). A trend of decrease in CD14++ CD16- classical subset was observed between these two groups (P = 0.0508), whereas no significant difference was detected in CD14+ CD16++ nonclassical subset (P > 0.05). The receiver operating characteristic (ROC) curve analysis indicated that the frequency of intermediate monocytes (AUC = 0.810, P < 0.0001) could be a potential diagnostic biomarker to discriminate patients with OSCC from healthy subjects. Moreover, this parameter was significantly correlated to the worst pattern of invasion (WPOI, P < 0.05) of OSCC tissues.Conclusions: Detection of monocyte subsets in peripheral blood sheds a light on utilizing the frequency of intermediate monocytes as a potential diagnostic biomarker for OSCC. [ABSTRACT FROM AUTHOR]

Previous studies showed that lectin galactoside-binding soluble 3 binding protein (LGALS3BP) is an important participant in tumor progression. However, its prognostic value and functional mechanism in oral squamous cell carcinoma (OSCC) are still unclear. In this study, we analyzed LGALS3BP expression in OSCC tissues via Oncomine databases and immunohistochemical staining. LGALS3BP was significantly up-regulated in OSCC tumor tissues. IHC analysis showed that LGALS3BP was predominantly expressed in tumor cells and correlated with poor clinical characteristics. In addition, high LGALS3BP expression predicted poor clinical outcomes and multivariate analysis revealed that LGALS3BP expression was as an independent prognostic factor for OS, DFS and RFS (p <.0001, p =.002, p =.002). Mechanically, LGALS3BP regulated OSCC proliferation and migration via PI3K/AKT pathways, which was abrogated by PI3K inhibitor LY294002 in a dose-dependent manner. Our results suggested that LGALS3BP could be served as a novel independent prognostic factor as well as a potential therapeutic target for OSCC treatment. Unlabelled Image • LGALS3BP is overexpressed in OSCC and correlated with poor clinical characteristics. • LGALS3BP is an independent prognostic factor for OS, DFS and RFS. • LGALS3BP promoted OSCC cell proliferation and migration via PI3K/AKT pathways. [ABSTRACT FROM AUTHOR]