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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]

Background: MLL2 (mixed-lineage leukemia 2) is recognized as an essential role in regulating histone 3 lysine 4 tri-methylation (H3K4me3) in mammalian cells. It is frequently mutated to promote developmental diseases and tumor initiation. However, the expression pattern of MLL2 and its clinical significance for patients with early-stage oral squamous cell carcinoma (OSCC) remain totally unknown.Methods: Eighty-five samples of primary early-stage OSCC were enrolled in this retrospective study, and immunohistochemistry (IHC) was performed to detect the spatial pattern of MLL2. The diagnostic and prognostic value of MLL2 were assessed.Results: MLL2 was widely expressed in tumor cells (TCs), fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs), both in tumor center and invasive tumor front, and showed no distributive heterogeneity. Moreover, regardless of cell types and microlocalization, patients with high expressed MLL2 had increased depth invasion of tumor (DOI). Besides, upregulation of MLL2TC and MLL2TIL in tumor center were both associated with poor differentiation, but showed no correlation with tumor growth with comparable Ki-67 levels. Prognostic analysis indicated that early-stage OSCC patients with enhanced MLL2TIL in invasive tumor front were susceptible to occur postoperative metastasis and recurrence. Indeed, patients with higher expressed MLL2TIL showed shorter overall survival (OS) and disease-free survival (DFS), and MLL2TIL in invasive tumor front was an independent risk factor of DFS.Conclusion: TIL-derived MLL2 in invasive tumor front was an independent prognostic factor of DFS for early-stage OSCC patients. [ABSTRACT FROM AUTHOR]

KiSS-1, first identified as an anti-metastasis gene in melanoma, encodes C-terminally amidated peptide products, including kisspeptin-145, kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10. These products are endogenous ligands coupled to G protein-coupled receptor 54 (GPR54)/hOT7T175/AXOR12. To date, the regulatory activities of the KiSS-1/GPR54 system, such as puberty initiation, antitumor metastasis, fertility in adulthood, hypothalamic-pituitary-gonadal axis (HPG axis) feedback, and trophoblast invasion, have been investigated intensively. Accumulating evidence has demonstrated that KiSS-1 played a key role in reproduction and served as a promising biomarker relative to the diagnosis, identification of therapeutic targets and prognosis in various carcinomas, while few studies have systematically summarized its subjective factors and concluded the functions of KiSS-1/GPR54 signaling in physiology homeostasis and cancer biology. In this review, we retrospectively summarized the regulators of the KiSS-1/GPR54 system in different animal models and reviewed its functions according to physiological homeostasis regulations and above all, cancer biology, which provided us with a profound understanding of applying the KiSS-1/GPR54 system into medical applications., Competing Interests: The authors declare no competing financial interests., (© 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.)