Sen Hou’s research while affiliated with Peking University People's Hospital and other places

Background Recent years, immunotherapy has emerged as a pivotal approach in cancer treatment. However, the response of gastric cancer to immunotherapy exhibits significant heterogeneity. Therefore, the early identification of gastric cancer patients who are likely to benefit from immunotherapy and the discovery of novel therapeutic targets are of critical importance. Materials and methods We collected data from European Nucleotide Archive (ENA) and Gene Expression Omnibus (GEO) databases. In project PRJEB25780, we performed WGCNA analysis and Lasso regression and chose CXCR2P1 for the subsequent analysis. Then, we compared the expression difference of CXCR2P1 among different groups. Kaplan-Meier curve was used to analyze the prognostic value of CXCR2P1, which was validated by project IMvigor210 and GEO datasets. ESTIMATE and CIBERSORT algorithm were used to evaluate the reshaping effect of CXCR2P1 to immune microenvironment of tumor. Differentially expressed genes (DEG) analysis, enrichGO analysis, Gene Set Enrichment Analysis (GSEA) and co-expression analysis were used to explore the cell biological function and signaling pathway involved in CXCR2P1. Results WGCNA identified CXCR2P1 as a hub gene significantly associated with immune response to PD-1 inhibitors in gastric cancer. CXCR2P1 expression was elevated in responders and correlated with better prognosis. Functional analysis revealed its role in reshaping the tumor immune microenvironment by promoting immune cell infiltration, including M1 macrophages, activated CD4+ T cells, and follicular helper T cells. CXCR2P1 enhanced antigen presentation via the MHC-II complex, influenced key immune pathways, such as Toll-like receptor signaling and T-cell activation, which led to the up-regulation of expression of PD-L1. GSEA showed CXCR2P1 were correlated with microRNAs. Through DEG analysis and expression analysis, MIR215 was identified as a potential direct target of CXCR2P1. Conclusion High expression of CXCR2P1 is correlated with better response to PD-1 inhibitor. It reshapes the immune microenvironment by increasing immune infiltration and changing the fraction of immune cells. In tumor immune microenvironment, CXCR2P1 can promote inflammation, enhance antigen presentation and activate the PD-1/PD-L1-related signaling pathway, which might be achieved by CXCR2P1-MIR215 axis.

Background An increasing body of evidence indicates that dysregulation of liquid-liquid phase separation (LLPS) in cellular processes is implicated in the development of diverse tumors. Nevertheless, the association between LLPS and the prognosis, as well as the tumor immune microenvironment, in individuals with colon cancer remains poorly understood. Methods We conducted a comprehensive evaluation of the LLPS cluster in 1010 colon cancer samples from the TCGA and GEO databases, utilizing the expression profiles of LLPS-related prognostic differentially expressed genes (DEGs). Subsequently, a LLPS-related gene signature was constructed to calculate the LLPS-related risk score (LRRS) for each individual patient. Results Two LLPS subtypes were identified. Substantial variations were observed between the two LLPS subtypes in terms of prognosis, pathway activity, clinicopathological characteristics, and immune characteristics. Patients with high LRRS exhibited worse prognosis and poorer response to immunotherapy. LRRS was found to be correlated with the clinicopathological characteristics, genomic alterations, and the potential response to immune checkpoint inhibitors therapy of colon cancer patients. Additionally, the biological function of a key gene POU4F1 was verified in vitro. Conclusions This study highlights the crucial role of LLPS in colon cancer, LRRS can be used to predict the prognosis of colon cancer patients and aid in the identification of more effective immunotherapy strategies.

Background: Despite breakthroughs in treatment, ovarian cancer (OC) remains one of the most lethal gynecological malignancies, with an increasing age-standardized mortality rate. This underscores an urgent need for novel biomarkers and therapeutic targets. Although growth factor receptor-bound protein 7 (GRB7) is implicated in cell signaling and tumorigenesis, its expression pattern and clinical implications in OC remain poorly characterized. Methods: To systematically investigate GRB7’s expression in OC, our study utilized extensive datasets from TCGA, GTEx, CCLE, and GEO. The prognostic significance of GRB7 was evaluated by means of Kaplan–Meier and Cox regression analyses. Using a correlation analysis and gene set enrichment analysis, relationships between GRB7’s expression and gene networks, immune cell infiltration and immunotherapy response were investigated. In vitro experiments were conducted to confirm GRB7’s function in the biology of OC. Results: Compared to normal tissues, OC tissues exhibited a substantial upregulation of GRB7. Reduced overall survival, disease-specific survival, and disease-free interval were all connected with high GRB7 mRNA levels. The network study demonstrated that GRB7 is involved in pathways relevant to the course of OC and has a positive connection with several key driver genes. Notably, GRB7’s expression was linked to the infiltration of M2 macrophage and altered response to immunotherapy. Data from single-cell RNA sequencing data across multiple cancer types indicated GRB7’s predominant expression in malignant cells. Moreover, OC cells with GRB7 deletion showed decreased proliferation and migration, as well as increased susceptibility to T cell-mediated cytotoxicity. Conclusion: With respect to OC, our results validated GRB7 as a viable prognostic biomarker and a promising therapeutic target, providing information about its function in tumorigenesis and immune modulation. GRB7’s preferential expression in malignant cells highlights its significance in the biology of cancer and bolsters the possibility that it could be useful in enhancing the effectiveness of immunotherapy.

Background Immunotherapy brings new hope to patients with advanced gastric cancer. However, liver metastases can reduce the efficacy of immunotherapy in patients. Tumor-associated macrophages (TAMs) may be the cause of this reduction in efficacy. SPP1 + TAMs are considered to have immunosuppressive properties. We aimed to investigate the involvement of SPP1 + TAMs in the metastasis of gastric cancer. Methods The single-cell transcriptome was combined with batched BULK datasets for analysis. Animal models were used to verify the analysis results. Results We reveal the interaction of SPP1 + TAMs with CD8 + exhausted T cells in metastatic cancer. Among these interactions, GDF15-TGFBR2 may play a key immunosuppressive role. We constructed an LR score to quantify interactions based on ligands and receptors. The LR score is highly correlated with various immune features and clinical molecular subtypes. The LR score may also guide the prediction of the efficacy of immunotherapy and prognosis. Conclusions The crosstalk between SPP1 + TAMs and CD8 + exhausted T cells plays a key immunosuppressive role in the gastric metastatic cancer microenvironment. Graphical Abstract

Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.

Background Pylorus-preserving gastrectomy (PPG) is a function-preserving surgery for the treatment of early gastric cancer (EGC) in the middle third of the stomach. According to the literature reports, PPG decreases the incidence of dumping syndrome, bile reflux, gallstone formation, and nutritional deficit compared with conventional distal gastrectomy (CDG). However, the debates about PPG have been dominated by the incomplete lymphadenectomy and oncological safety. We carried out a systematic review and meta-analysis to evaluate the pathological and oncological outcomes of PPG. Methods The protocol was registered in PROSPERO under number CRD42022304677. Databases including PubMed, Embase, Web of Science, and the Cochrane Register of Controlled Trials were searched before February 21, 2022. The outcomes included the pooled odds ratios (ORs) for dichotomous variables and weighted mean differences (WMDs) for continuous variables. For all outcomes, 95% confidence intervals (CIs) were calculated. Meta-analysis was performed using STATA software (Stata 14, Stata Corporation, Texas) and Review Manager 5.4. Results A total of 4500 patients from 16 studies were included. Compared with the CDG group, the PPG group had fewer lymph nodes harvested (WMD= −3.09; 95% CI −4.75 to −1.43; P < 0.001). Differences in the number of resected lymph nodes were observed at stations No. 5, No. 6, No. 9, and No. 11p. There were no differences in lymph node metastasis at each station. Shorter proximal resection margins (WMD = −0.554; 95% CI −0.999 to −0.108; P = 0.015) and distal resection margins (WMD = −1.569; 95% CI −3.132 to −0.007; P = 0.049) were observed in the PPG group. There were no significant differences in pathological T1a stage (OR = 0.99; 95% CI 0.80 to 1.23; P = 0.88), T1b stage (OR = 1.01; 95% CI 0.81 to 1.26; P = 0.88), N0 stage (OR = 0.97; 95% CI 0.63 to 1.48; P = 0.88), tumor size (WMD = −0.10; 95% CI −0.25 to 0.05; P = 0.187), differentiated carcinoma (OR = 1.04; 95% CI 0.74 to 1.47; P = 0.812) or signet ring cell carcinoma (OR = 1.22; 95% CI 0.90 to 1.64; P = 0.198). No significant differences were observed between the groups in terms of overall survival (HR = 0.63; 95% CI 0.24 to 1.67; P = 0.852) or recurrence-free survival (HR = 0.29; 95% CI 0.03 to 2.67; P = 0.900). Conclusions The meta-analysis of existing evidence demonstrated that the survival outcomes of PPG may be comparable to those of CDG. However, fewer lymph nodes at stations in No. 5, No. 6, No. 9, and No. 11p were harvested with PPG. We also found shorter proximal resection margins and distal resection margins for PPG, meaning more remnant stomachs would be preserved in PPG.

Faced with the high heterogeneity and poor prognosis of colorectal cancer (CRC), this study sought to find new predictive prognostic strategies to improve the situation. Cuproptosis is a novel cell death mechanism that relies on copper regulation. However, the role of cuproptosis-related gene (CRG) in CRC remains to be elucidated. In this study, we comprehensively assessed the CRG landscape in CRC based on The Cancer Genome Atlas (TCGA). We identified differential expression and genetic alterations of CRG in CRC. CRG is highly correlated with initiation, progression, prognosis, and immune infiltration of CRC. We construct a risk score signature containing 3 CRGs based on LASSO. We explored the correlation of CRG-Score with clinicopathological features of CRC. Age, stage, and CRG-Score were integrated to construct a nomogram. The nomogram has robust predictive performance. We also understand the correlation of CRG-Score with CRC immune landscape. CRG-Score can effectively predict the immune landscape of CRC patients. Low-risk CRC patients have greater immunogenicity and higher immune checkpoint expression. Low-risk CRC patients may be better candidates for immunotherapy. At the same time, we also predicted more sensitive drugs in the high-risk CRC patients. In conclusion, the CRG risk score signature is a strong prognostic marker and may help provide new insights into the treatment of individuals with CRC.