Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro ^–/– female mice with doxorubicin (DOX) because Ptpro ^–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro ^–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro ^–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.

Background: Protein tyrosine phosphatase non-receptor type 1 (PTPN1), a member of the protein tyrosine phosphatase superfamily, has been identified as an oncogene and therapeutic target in various cancers. However, its precise role in determining the prognosis of human cancer and immunological responses remains elusive. This study investigated the relationship between PTPN1 expression and clinical outcomes, immune infiltration, and drug sensitivity in human cancers, which will improve understanding regarding its prognostic value and immunological role in pan-cancer.Methods: The PTPN1 expression profile was obtained from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia databases. Kaplan-Meier, univariate Cox regression, and time-dependent receiver operating characteristic curve analyses were utilized to clarify the relationship between PTPN1 expression and the prognosis of pan-cancer patients. The relationships between PTPN1 expression and the presence of tumor-infiltrated immune cells were analyzed using Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data and Tumor Immune Estimation Resource. The cell counting kit-8 (CCK-8) assay was performed to examine the effects of PTPN1 level on the sensitivity of breast cancer cells to paclitaxel. Immunohistochemistry and immunoblotting were used to investigate the relationship between PTPN1 expression, immune cell infiltration, and immune checkpoint gene expression in human breast cancer tissues and a mouse xenograft model.Results: The pan-cancer analysis revealed that PTPN1 was frequently up-regulated in various cancers. High PTPN1 expression was associated with poor prognosis in most cancers. Furthermore, PTPN1 expression correlated highly with the presence of tumor-infiltrating immune cells and the expression of immune checkpoint pathway marker genes in different cancers. Furthermore, PTPN1 significantly predicted the prognosis for patients undergoing immunotherapy. The results of the CCK-8 viability assay revealed that PTPN1 knockdown increased the sensitivity of MDA-MB-231 and MCF-7 cells to paclitaxel. Finally, our results demonstrated that PTPN1 was associated with immune infiltration and immune checkpoint gene expression in breast cancer.Conclusion: PTPN1 was overexpressed in multiple cancer types and correlated with the clinical outcome and tumor immunity, suggesting it could be a valuable potential prognostic and immunological biomarker for pan-cancer.

Breast cancer is a prevalent and deadly disease affecting women worldwide. Recent studies have shown that γ-glutamyl cyclotransferase (GGCT), an enzyme involved in glutathione metabolism, is consistently upregulated in various cancers. However, its specific role in breast cancer remains poorly understood. This study aimed to investigate the functional role of GGCT in breast cancer. Bioinformatics, immunohistochemistry and immunoblotting analysis revealed that GGCT is significantly upregulated in breast cancer tissues, and its high expression is associated with poor survival outcomes. The knockdown of GGCT significantly suppressed MCF-7 and SKBR-3 cell activities. Cell proliferation decreased by 29.4–45.9%, and colony formation reduced by 51.5–56.6%. Migratory ability diminished by 36.8–49.1%, while invasion capability declined by 35.2–55.0%. Moreover, GGCT silencing reduced epithelial-mesenchymal transition (EMT) and inhibited the PI3K/AKT/mTOR signaling pathway. Notably, E-cadherin expression significantly increased in MCF-7 and SKBR-3-shGGCT cells, with changes ranging from 2.1-fold to 5.4-fold. Conversely, N-cadherin expression decreased by 54.2–84.2% in both cell lines. Vimentin expression also decreased significantly, with reductions of 58.8–83.0%. Further analyses indicated that p-AKT expression in MCF-7 and SKBR-3-shGGCT cells decreased by 51.4–84.8%. Additionally, p-mTOR expression was reduced by 71.2–87.2% in both cell lines, compared to shCtrl. Our data highlights the crucial role of GGCT in regulating EMT and the progression of breast cancer. The findings suggest that GGCT not only serves as a valuable prognostic marker but also represents a potential target for therapeutic interventions in breast cancer patients.