Interleukin–23 (IL–23) is a conventional proinflammatory cytokine that plays a role in tumor progression by inducing inflammation in the tumor microenvironment. However, the role of IL–23 in thyroid cancer migration and invasion remains unclear. In the present study, we observed that the treatment with IL–23, induced migration and invasion in human thyroid cancer cells. Additional data demonstrate that SOCS4 negatively regulates IL-23-mediated migration and invasion. On investigating the mechanisms involved in IL–23 mediated migration and invasion, we observed that miR–25 promotes the migration and invasion of thyroid cancer cells by directly binding to the 3′-UTR of SOCS4 that leads to the inhibition of SOCS4. In addition, we also demonstrated that IL–23 increases miR–25 expression levels, and overexpressed miR–25 is involved in IL-23-associated SOCS4 inhibition and cell migration and invasion. Together, our data suggest that IL–23 induces migration and invasion in thyroid cancer cells by mediating the miR–25/SOCS4 signaling pathway.

Interleukin-22 (IL-22) is an inflammatory cytokine mainly produced by activated Th17 and Th22 cells. The data presented here demonstrate that IL-22 induced the migration and invasion of papillary thyroid cancer (PTC) cells. MicroRNA expression analysis and functional studies indicated that IL-22-mediated migration and invasion is positively regulated by miR-595. Further mechanistic studies revealed that sex-determining region Y-box 17 (Sox17) is directly targeted by miR-595. We then demonstrated that IL-22 regulated migration and invasion of PTC cells via inhibiting Sox17 expression. Interestingly, in PTC cell lines and PTC tissues, expression of IL-22 and miR-595 was upregulated and Sox17 downregulated compared with normal thyroid, and their expression levels were closely correlated. Taken together, this present study suggests that IL-22 stimulation enhances the migration and invasion of PTC cells by regulating miR-595 and its target Sox17.

Leucine-rich-α-2-glycoprotein 1 (LRG1) is considered as a potential biomarker as it is aberrantly expressed in various malignancies. However, there is limited information regarding its role in head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to explore the expression pattern of LRG1 in HNSCC and its clinicopathological significance. We first analyzed LRG1 gene expression in HNSCC by investigating data obtained from the Gene Expression Omnibus (GEO) database. The results showed that LRG1 was downregulated in HNSCC tissues and its expression level was negatively related to tumor T and N stages and degree of malignancy. Then, we further tested a tissue microassay and clinical samples, respectively, by immunohistochemical staining and western blotting. Consistently, the results revealed that LRG1 expression was decreased in tumor tissues regardless of the grade of the tumor. Moreover, the protein level of LRG1 showed slight differences among four T stages or three N stages. In addition, there were no significant associations between LRG1 protein expression and other clinicopathological parameters such as gender, age, tumor location and clinical staging. These findings imply that downregulation of the expression of LRG1 is correlated with tumorigenesis but not with the development of HNSCC, indicating the potential clinical value of LRG1 in the early diagnosis of HNSCC.

We investigated the role of amino acid metabolism (AAM) in head and neck squamous cell carcinoma (HNSCC) tissues to explore its prognostic value and potential therapeutic strategies. A risk score based on four AAM-related genes (AMG) was constructed that could predict the prognosis of HNSCC. These four genes were up-regulated in HNSCC tissues and might act as oncogenes. Internal validation in The Cancer Genome Atlas (TCGA) by bootstrapping showed that patients with high-risk scores had a poorer prognosis than patients with low-risk scores, and this was confirmed in the Gene Expression Omnibus (GEO) cohort. There were also differences between the high-risk and low-risk groups in clinical information and different anatomical sites such as age, sex, TNM stage, grade stage, surgery or no surgery, chemotherapy, radiotherapy, no radiotherapy, neck lymph node dissection or not, and neck lymphovascular invasion, larynx, overlapping lesion of lip, and oral cavity and pharynx tonsil of overall survival (OS). Immune-related characteristics, tumor microenvironment (TME) characteristics, and immunotherapy response were significantly different between high- and low-risk groups. The four AMGs were also found to be associated with the expression of markers of various immune cell subpopulations. Therefore, our comprehensive approach revealed the characterization of AAM in HNSCC to predict prognosis and guide clinical therapy.

Background: The immune responses play significant roles in the onset, progression, and outcome of oral squamous cell carcinoma (OSCC). CD4 + regulatory T cells (Tregs) significantly impact tumor immunity. However, their role in OSCC development remains elusive. Methods: In a carcinogen-induced mouse OSCC model, interleukin-23 receptor (IL-23R) expression on Tregs and Treg function were determined by flow cytometry. IL-23R overexpression in Tregs was achieved by lentiviral infection, followed by evaluation of the expression of Forkhead box P3 (Foxp3), T-bet, retineic-acid-receptor-related orphan nuclear receptor gamma t, and cytokines by flow cytometry. Adoptive transfer assays were applied to analyze the function of IL-23R − overexpressing Tregs in vivo. The cellular sources of IL-23 were also determined by flow cytometry. Results: IL-23R − Tregs and IL-23R + Tregs were found in the tongues but not spleens of OSCC-bearing mice. IL-23R + Tregs expressed lower Foxp3 but higher T-bet than IL-23R − Tregs. IL-23R − Tregs produced abundant IL-10 and transforming growth factor (TGF)-β, while IL-23R + Tregs produced lower IL-10 and TGF-β but remarkably higher interferon (IFN)-γ. Furthermore, IL-23R + Tregs possessed more phosphorylated signal transducer and activator of transcription (STAT3) and STAT4 than IL-23R − Tregs. IL-23R + Tregs were less immunosuppressive than IL-23R − Tregs, as evidenced by weaker inhibition of activated conventional T cells. IL-23R overexpression in splenic Tregs remarkably reduced the expression of IL-10 and TGF-β but increased IFN-γ expression when Tregs were adoptively transferred into OSCC-bearing mice. In the OSCC microenvironment, macrophages, dendritic cells, and malignant OSCC cells produced IL-23 which might modulate the function of IL-23R + Tregs. Conclusions: This study unveils Treg heterogeneity, thus deepening the understanding of Treg biology and tumor immunity in OSCC.