Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation

As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy

Prognostic Factors and a Model for Occult Breast Cancer: A Population-Based Cohort Study

Occult breast cancer (OBC) is a special type of breast cancer of an unknown primary origin. Early stage OBC is treated as stage II–III breast cancer. Currently, there are no models for predicting the survival outcomes. Hence, we aimed to evaluate the role of the positive lymph node ratio (PLNR) in OBC and further establish and validate a prognostic nomogram. Patients with stage T0N+M0 breast cancer were enrolled from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox analyses were used to evaluate the effects of prognostic factors on breast-cancer-specific survival (BCSS), and a nomogram was established and validated for OBC. Overall, 843 patients were included, and the 5-year BCSS rate was 92.4%. Patients with a PLNR < 0.54 had better BCSS rates than those with a PLNR ≥ 0.54. The nomogram combined clinicopathological parameters, including the PLNR, pN stage, and estrogen receptor status, and showed a higher accuracy than the TNM staging system in predicting the BCSS. The patients could be stratified into different risk groups based on their prognostic scores. Patients in the low-risk subgroup showed an improved BCSS compared those in the high-risk subgroup. In conclusion, the PLNR is an independent prognostic factor for OBC. The PLNR-based nomogram has a better predictive ability than the TNM staging system and could be of great value for the treatment of OBC and prediction of its prognosis

Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling

The extracellular matrix (ECM) serves as signals that regulate specific cell states in tumor tissues. Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression. In this study, we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status. Experiments were conducted using 3D collagen, fibrinogen, and Matrigel matrices to investigate the role of mechanical force in tumor development. Integrin-cytoskeleton-AIRE and DDR-STAT signals were examined using RNA sequencing and western blotting. Data from 1358 patients and 86 clinical specimens were used for ECM signature-prognosis analysis. Our findings revealed that ECM-derived mechanical force regulated tumor stemness and cell quiescence in breast cancer cells. A mechanical force of ~45 Pa derived from the extracellular substrate activated integrin β1/3 receptors, stimulating stem cell signaling pathways through the cytoskeleton/AIRE axis and promoting tumorigenic potential and stem-like phenotypes. However, excessive mechanical force (450 Pa) could drive stem-like cancer cells into a quiescent state, with the removal of mechanical forces leading to vigorous proliferation in quiescent cancer stem cells. Mechanical force facilitated cell cycle arrest to induce quiescence, dependent on DDR2/STAT1/P27 signaling. Therefore, ECM-derived mechanical force governs breast cancer cell status and proliferative characteristics through stiffness alterations. We further established an ECM signature based on the fibrinogen/fibronectin/vitronectin/elastin axis, which efficiently predicts patient prognosis in breast cancer. Our findings highlight the vital role of ECM-derived mechanical force in governing breast cancer cell stemness/quiescence transition and suggest the novel use of ECM signature in predicting the clinical prognosis of breast cancer

PRR15 deficiency facilitates malignant progression by mediating PI3K/Akt signaling and predicts clinical prognosis in triple-negative rather than non-triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast neoplasms with a higher risk of recurrence and metastasis than non-TNBC. Nevertheless, the factors responsible for the differences in the malignant behavior between TNBC and non-TNBC are not fully explored. Proline rich 15 (PRR15) is a protein involved in the progression of several tumor types, but its mechanisms are still controversial. Therefore, this study aimed to investigate the biological role and clinical applications of PRR15 on TNBC. PRR15 gene was differentially expressed between TNBC and non-TNBC patients, previously described as an oncogenic factor in breast cancer. However, our results showed a decreased expression of PRR15 that portended a favorable prognosis in TNBC rather than non-TNBC. PRR15 knockdown facilitated the proliferation, migration, and invasive ability of TNBC cells in vitro and in vivo, which was abolished by PRR15 restoration, without remarkable effects on non-TNBC. High-throughput drug sensitivity revealed that PI3K/Akt signaling was involved in the aggressive properties of PRR15 silencing, which was confirmed by the PI3K/Akt signaling activation in the tumors of PRR15Low patients, and PI3K inhibitor reversed the metastatic capacity of TNBC in mice. The reduced PRR15 expression in TNBC patients was positively correlated with more aggressive clinicopathological characteristics, enhanced metastasis, and poor disease-free survival. Collectively, PRR15 down-regulation promotes malignant progression through the PI3K/Akt signaling in TNBC rather than in non-TNBC, affects the response of TNBC cells to antitumor agents, and is a promising indicator of disease outcomes in TNBC