SOX2-associated signaling pathways regulate biological phenotypes of cancers.

SOX2 is a transcription factor involved in multiple stages of embryonic development. In related reports, SOX2 was found to be abnormally expressed in tumor tissues and correlated with clinical features such as TNM staging, tumor grade, and prognosis in patients with various cancer types. In most cancer types, SOX2 is a tumor-promoting factor that regulates tumor progression and metastasis primarily by maintaining the stemness of cancer cells. In addition, SOX2 also regulates the proliferation, apoptosis, invasion, migration, ferroptosis and drug resistance of cancer cells. However, SOX2 acts as a tumor suppressor in some cases in certain cancer types, such as gastric and lung cancer. These key regulatory functions of SOX2 involve complex regulatory networks, including protein-protein and protein-nucleic acid interactions through signaling pathways and noncoding RNA interactions, modulating SOX2 expression may be a potential therapeutic strategy for clinical cancer patients. Therefore, we sorted out the phenotypes related to SOX2 in cancer, hoping to provide a basis for further clinical translation.

Evidence of synergy between Thy-1 and CD3/TCR complex in signal delivery to murine thymocytes for cell death.

The potential role of Thy-1 in CD3/TCR complex-mediated signal delivery to murine thymocytes was studied. Ag-mimicking cross-linked anti-CD3 mAb stimulated suspension of thymocytes from adult (6 to 8 wk old) mice for a brisk free cytoplasmic calcium ion ([Ca2+]i) rise, low level of inositol phosphate production, and marginal increase in tyrosine-specific phosphorylation of 110/120-kDa and 40-kDa cellular proteins. Weak but sustained [Ca2+]i rise, low inositol phosphate production, and weak protein tyrosine phosphorylation were also induced by the cross-linked anti-Thy-1 mAb that mimicked the putative natural ligand. The signal delivered via either of these two pathways was however insufficient for definitively promoting cell death and DNA fragmentation in the adult thymocytes. Here we demonstrated that anti-Thy-1 mAb synergized with anti-CD3 mAb for inducing a long-lasting prominent [Ca2+]i rise, definite inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakiphosphate production, and extensive tyrosine-specific phosphorylation of 110/120-, 92-, 75-, and 40-kDa proteins, which resulted in marked promotion of cell death and DNA fragmentation in the adult thymocytes. This unique anti-Thy-1 antibody activity was confirmed to be directed to glycosylphosphatidylinositol-anchored Thy-1, and was distinguished from the known anti-L3T4 activity that augmented the CD3-mediated signal transduction in a different manner. The synergistic actions of anti-CD3 and anti-Thy-1 mAb obligatorily required the cross-linking of the two mAb together. The anti-CD3 and anti-Thy-1 mAb cross-linked together acted on immature thymocytes from newborn (less than 24 h after birth) mice for rather more extensive promotion of protein tyrosine phosphorylation and cell death. In addition, they affected peripheral T lymphocytes for accelerating protein tyrosine phosphorylation but not cell death. These results suggest a novel function of glycosylphosphatidylinositol-anchored Thy-1 as a possible unique intrathymic intensifier of the CD3/TCR complex-delivered signal for negative thymocyte selection.

Characterization of the individual and cross-reactive antigens involved in the anti-tumor immunity induced by use of an H-2K-erbB recombinant gene transfectant.

The specificities of the antisera raised in the CDF1 mice that had been immunized with the P1.HTR tumor cells xenogenized by transfection with recombinant H-2Kb-erbB gene were studied. The antisera cross-reacted with a broad range of tumor cell lines maintained either in vitro or in vivo in an immunofluorescence assay. However, they did not react at all with syngeneic normal tissue cells from thymus, spleen, bone marrow and fetal liver. Even though antigens related to the murine leukemia virus and murine mammary tumor virus (MuMTV) were demonstrated in many of the tumor cell lines tested with specific antibodies, these antigens did not seem to be primarily involved in the anti-P1.HTR antibody activity. The 74 kDa molecule, which was precipitated by the anti-P1.HTR anti-serum from the surface radiolabeled cell extract of P1.HTR tumor and was discriminated from the 70 kDa molecule precipitated by the anti-MuMTV serum, was widely distributed among various tumor cell lines tested, but was absent in normal tissue cells. In contrast to the extensive cross-reaction by the antibody, the cytotoxic T lymphocyte generated in the P1.HTR immune mice were shown to be specific to the P1.HTR tumor, and the 98 kDa molecule was precipitated by the anti-P1.HTR serum from the P1.HTR tumor but not from other tumors tested. It is suggested from these results that the 98 kDa molecule is a candidate for an individual tumor-specific transplantation antigen, and is immunodominant for inducing cytotoxic T lymphocytes to coexisting intrinsic retroviral antigens and other serologically cross-reactive tumor antigens.

Induction of high-grade anti-tumor immunity by use of a recombinant H-2Kb/avian erythroblastosis virus erbB gene transfectant.

The recombinant H-2Kb-erbB gene, encoding for a part of the H-2 class I antigen and the kinase domain of the V-erbB peptide, was successfully introduced into murine mastocytoma P815 variant P1.HTR cells, which resulted in low but significant cell-surface expression of the hybrid gene product. When the chimeric gene transfectant was inoculated into the CDF1 mice, it soon grew but regressed thereafter. The tumorigenicity of this transfectant was lower than the H-2Kb gene transfectant that expressed the H-2Kb antigen at a comparable level. These CDF1 mice that had received the chimeric gene transfectant obtained a high-grade anti-tumor immunity against the challenge of a high dose of parental tumor. Corresponding to these observations, anti-tumor cytotoxic T lymphocytes, which lyse parental P1.HTR cells but not syngeneic L1210 or NS-1 tumor cells, were developed in the peritoneal cavity of mice that had been inoculated with the transfectant and parental tumor. Definite antibody activity binding to parental P1.HTR tumor cells was also demonstrated in the sera of these mice, precipitating 40-kDa, 74-kDa and 98-kDa molecules from the surface of the radiolabeled P1-HTR tumor cells. The results suggested that the chimeric H-2-erB gene transfectant efficiently triggers both cellular and humoral anti-tumor immune responses.

Induction of antitumor immunity in mice by allo-major histocompatibility complex class I gene transfectant with strong antigen expression.

An allo-major histocompatibility complex class I gene (H-2Kb) was transfected to murine mastocytoma P1.HTR (P815 subline) cells, after which several transfectant clones were obtained. Two clones, which expressed a low level of H-2Kb antigen, grew well and killed the syngeneic DBA/2 mice when they were inoculated ip. These mice lived longer than the mice given injections of the parental P1.HTR tumor. However, one clone, which expressed a high level of H-2Kb antigen, was rejected completely by the syngeneic DBA/2 mice and induced a generation of H-2Kb-specific cytotoxic T cells. Interestingly, the mice that had rejected the clone with high H-2Kb expression received strong anti-tumor immunity for rejection of the parental P1.HTR tumor challenged at the high dose.