Renhong Huang

Background Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC. Methods In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification. Results We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8 + T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression. Conclusions Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.

Background . Although the neutrophil percentage‐to‐albumin ratio (NPAR) has proven to be a robust systemic inflammation‐based predictor of mortality in a wide range of diseases, the prognostic value of the NPAR in critically ill patients with cardiogenic shock (CS) remains unknown. This study aimed at investigating the association between the admission NPAR and clinical outcomes in CS patients using real‐world data. Methods . Critically ill patients diagnosed with CS in the Medical Information Mart for Intensive Care‐III (MIMIC‐III) database were included in our study. The study endpoints included all‐cause in‐hospital, 30‐day, and 365‐day mortality in CS patients. First, the NPAR was analyzed as a continuous variable using restricted cubic spline Cox regression models. Second, X‐tile analysis was used to calculate the optimal cut‐off values for the NPAR and divide the cohort into three NPAR groups. Moreover, multivariable Cox regression analyses were used to assess the association of the NPAR groups with mortality. Results . A total of 891 patients hospitalized with CS were enrolled in this study. A nonlinear relationship between the NPAR and in‐hospital and 30‐day mortality was observed (all P values for nonlinear trend<0.001). According to the optimal cut‐off values by X‐tile, NPARs were divided into three groups: group I (NPAR < 25.3), group II (25.3 ≤ NPAR < 34.8), and group III (34.8 ≤ NPAR). Multivariable Cox analysis showed that higher NPAR was independently associated with increased risk of in‐hospital mortality (group III vs. group I: hazard ratio [HR] 2.60, 95% confidence interval [CI] 1.72‐3.92, P < 0.001), 30‐day mortality (group III vs. group I: HR 2.42, 95% CI 1.65‐3.54, P < 0.001), and 365‐day mortality (group III vs. group I: HR 6.80, 95% CI 4.10‐11.26, P < 0.001) in patients with CS. Conclusions . Admission NPAR was independently associated with in‐hospital, 30‐day, and 365‐day mortality in critically ill patients with CS.

BACKGROUND: Osteopontin (OPN) is highly expressed in colorectal cancer (CRC) and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy. METHODS: HCT116 cell proliferation, apoptosis, and migration and invasion ability were identified by cell counting k¡t-8 assay, flow cytometry, wound healing assay, and transwell chamber invasion assay, respectively. The ratios of proteins LC3-II/LC3-I, P62, and Atg7 were analyzed by Western-blot. Expressions of Beclin-1, Atg4b, Bnip3, and Vps34, both in transcriptional and translational levels, were analyzed and compared by RT-PCR and Western blot. Immunofluorescence and co-focusing experiments were used to investigate the formation of autophagosomes. RESULTS: The results showed that OPN can promote cell proliferation, migration, and invasion, as well as inhibit cell apoptosis. It was also demonstrated that OPN could inhibit cell autophagy. Further experiments revealed that the inhibitory effect of OPN on autophagy could be reversed by blocking the p38 MAPK pathway in HCT116 cells. CONCLUSION: OPN is involved in HCT116 cell progression and is capable of inhibiting cell autophagy possibly by activating the p38 MAPK signaling pathway, implying that OPN could be a potential novel molecular therapeutic biomarker in patients with CRC.

Metastasis is the main cause of gastric cancer (GC) related death and the underlying mechanisms still remain unclear. Collagen triple helix repeat containing 1 (CTHRC1) protein is known to be involved in tissue remodeling processes and closely associated with carcinogenesis and metastasis in solid tumors, but the functional role of CTHRC1 and its underlying mechanism with tumor metastasis in GC have not been fully illuminated. In the present study, CTHRC1 was highly expressed in tumor tissues and associated with poor prognosis of GC according to TCGA and GEO database. Functional studies revealed that CTHRC1 overexpression in GC significantly increased cell migration and invasion capacity. However, the promoting effects were abolished subsequent to silencing of CXCR4. In addition, CTHRC1 increased CXCR4 expression through upregulating HIF-1α expression, which eventually contributed to the promotion of cell migration and invasion. Inhibiting HIF-1α expression decreased CXCR4 expression and suppressed cell migration and invasion in GC. These results substantiated our hypothesis that HIF-1α/CXCR4 signaling pathway mediated the promoting effect of CTHRC1 on cell migration and invasion in GC.

Abstract Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial–mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4 + T and CD8 + T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.