Abstract. The prognosis of oral squamous cell carcinoma (OSCC) patients is affected by tumor recurrence and metastasis, and cancer stem cells are hypothesized to be involved in these processes. Thus, the aim of the present study was to determine whether the expression levels of five stem cell-related transcription factors, sex determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc), Krüppel-like factor 4 (KLF4) and brachyury, are associated with metastasis and survival in OSCC. Immunohistochemistry was performed to analyze the expression of these proteins in biopsy specimens obtained from 108 OSCC patients. The results revealed that the expression of SOX2, Oct4, KLF4 and brachyury were significantly associated with lymph node metastasis (P=0.002, P=0.031, P=0.003 and P=0.007, respectively). In addition, the expression of KLF4 and brachyury were significantly associated with distant metastasis (P=0.014 and P=0.012, respectively). Furthermore, multivariate analysis revealed that SOX2 and KLF4 are predictive factors for lymph node metastasis [odds ratios (ORs), 4.526 and 4.851, respectively], and KLF4 is also a predictive factor for distant metastasis (OR, 9.607). In addition, OSCC patients with low co-expression of SOX2, KLF4 and brachyury exhibited a significantly lower disease-specific survival rate (78.6 vs. 100%; P=0.025; χ 2 =5.033) and disease-free survival rate (60.7 vs. 90.9%; P=0.015; χ 2 =5.897) when compared with OSCC patients with high co-expression of these factors. The results indicate that SOX2, KLF4 and brachyury serve important roles in tumor progression, and these transcription factors may thus represent clinically useful prognostic markers for OSCC.
These results suggest that unique T-cell populations bearing V beta 2, V beta 6, or V beta 19 gene products tend to expand in OLP lesions as a consequence of in situ stimulation with a restricted epitope of either a nominal antigen on the MHC molecule for the majority of the V beta families, even if only in minor populations, or of a common superantigen for the minority of the V beta families.
Chronic GVHD (cGVHD) after allogeneic hematopoietic SCT (HSCT) is characterized by an infiltration of T cells into target organs including the oral mucosa and salivary glands. This study was designed to clarify the molecular mechanism of the local accumulation of pathogenic T cells in cGVHD. The expression of cytokines, chemokines and chemokine receptors in the buccal mucosa (BM), labial salivary glands (LSG) and PBMC from 16 patients with cGVHD after allogeneic HSCT was examined. The mRNA expression of T helper 1 (Th1) and Th2 cytokines, and several chemokines and chemokine receptors was significantly increased in the BM and LSG from cGVHD patients, in comparison with both those in the BM and LSG from controls, respectively, and also with those in the PBMC from cGVHD patients. Furthermore, the mRNA expression of Th2 cytokines, macrophage-derived chemokine and CC chemokine receptor 4 was closely associated with a strong T-cell infiltration in the BM and LSG from cGVHD patients. These results suggest that cGVHD might be initiated and/or maintained by Th1/Th0 cells and thereafter progresses in association with Th2 cell accumulation via the interaction of particular chemokine and chemokine receptors.
Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.
We recently described that the SART-1 690 -698 peptide could induce HLA-A24-restricted cytotoxic T lymphocytes (CTLs), which recognize the SART-1 259 ؉ tumor cells from peripheral blood mononuclear cells (PBMCs) of HLA-A24 ؉ cancer patients. In our study, in 5 of 14 HLA-A24 ؉ patients with oral squamous cell carcinomas (SCCs), CTLs could be induced with the SART-1 690 -698 peptide from the PBMCs. In 2 of the patients from whom the highest CTL activities were induced, the T-cell receptor (TCR) V repertoire expressed by the SART-1 690 -698 -specific CTLs was found to be restricted and multiple V families were predominantly expressed in each patient. Although the predominant V families were different between the 2 patients, V7 was highly and commonly predominant. The same predominant V families were also detected in the tumor-infiltrating lymphocytes (TILs) from each patient, and each V family contained one or more unique T-cell clonotypes. The unique T-cell clonotypes were found to be common between the TILs and SART-1 690 -698 -specific CTLs from each patient, and especially 2 T-cell clonotypes with V7 were identical even in the 2 patients. Key words: cytotoxic T lymphocytes; HLA-A24; squamous cell carcinoma; T-cell receptor; tumor antigenMany antigenic peptides recognized by HLA class I-restricted cytotoxic T lymphocytes (CTLs) against melanomas have been identified in the past 10 years. 1-5 Some of them are presently being investigated in clinical trial as cancer vaccines and have led to major tumor regression in some patients with melanomas. 6 -8 These tumor-rejection peptides are thus expected to be a new tool for specific immunotherapy to melanomas. In squamous cell carcinomas (SCCs), one of the major cancers in humans, tumorinfiltrating lymphocytes (TILs) are quite commonly observed 9 and specific immunotherapy with the tumor-rejection antigens is thus also expected as a new treatment modality for patients with SCCs. 10 We recently identified a SART-1 gene encoding both the 43 kD of SART-1 259 antigen and the 125 kD of SART-1 800 antigen. 11,12 The SART-1 259 antigen is preferentially expressed in the cytosol of a majority of SCCs and some adenocarcinomas, but not in other types of cancers or any normal cells except for those of the testis, while the SART-1 800 antigen is expressed in the nucleus of all proliferating cells. Therefore, the SART-1 259 antigen is expected to be a source of tumor-rejection peptides recognized by T cells, while the SART-1 800 antigen is not. More recently, we also identified several nonapeptides from the SART-1 259 antigen that are capable of inducing HLA-A26-or A24-restricted and tumor-specific CTLs from peripheral blood mononuclear cells (PBMCs) of patients with esophageal, lung, breast, brain, gynecologic and renal cancers, 12-17 and some of the nonapeptides have already been used in clinical trials for specific immunotherapy of HLA-A26 ϩ or -A24 ϩ patients with SCCs and adenocarcinomas as a cancer vaccine. 18 These antigenic peptides complexed with HLA molecules ...
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