Liyun Zheng’s research while affiliated with Zhejiang Chinese Medical University and other places

Introduction Peritoneal metastasis often predicts advanced progression and a poor prognosis in colorectal cancer (CRC). However, peritoneal metastases are extremely difficult to predict or diagnose by routine diagnostic methods. Material and methods In this study, a microarray containing 30 samples from peritoneal metastasis and their matched CRC primaries obtained during cytoreductive surgery were compared to take a long hard look at all the options on the significant differentially expressed genes. The potential interactions and mechanisms of these expressed genes in promoting peritoneal metastasis were analyzed and studied by multiple bioinformatics analysis. Results The results suggested that the functions of these genes are closely related to immune response and cytokine activity. Additionally, the top 10 core genes’ correction with the leukocyte infiltration and serum cytokine profiles were identified and may be expected to become diagnostic and therapeutic targets of peritoneal metastasis in CRC. Conclusions The expression of IL-6, IL-10 and IL-17 in plasma and their correlation with leukocyte infiltration are proven potential diagnostic, prognostic, and therapeutic biomarkers for peritoneal management of CRC.

For a long time, myeloid-derived suppressor cells (MDSCs) dilated in circulation system of colorectal cancer (CRC) patients have been puzzling clinicians. Various evidence shows that MDSCs constitute the bulk of immunosuppression in CRC, which is related to tumor growth, adhesion, invasion, metastasis, and immune escape. However, the mechanisms underlying these cells formation remain incompletely understood. In this study, we reported that CRC cell-derived LC3-dependent extracellular vesicles (LDEVs)-mediated M-MDSCs formation via TLR2-MYD88 pathway. Furthermore Hsp60 was the LDEVs surface ligand that triggered these MDSCs induction. In clinical studies, we reported that accumulation of circulating M-MDSCs as well as IL-10 and arginase1 secretion were reliant upon the levels of tumor cell-derived LDEVs in CRC patients. These findings indicated how local tumor cell-derived extracellular vesicles influence distal hematopoiesis and provided novel justification for therapeutic targeting of LDEVs in patients with CRC.

Aims: Primary choledocholithiasis is a common digestive disease with high morbidity and relapse. However, the compositions and functions of the bile microbial ecosystem and the pathogenesis of microfloral regulation of host metabolism resulting in stone formation are poorly understood. Main methods: Biliary samples collected from patients with acute cholangitis induced by benign biliary stricture (nonlithiasis group, n = 17) and primary choledocholithiasis (lithiasis group, n = 33) were subjected to multiomics analyses. Furthermore, clinicopathological features collected over a 24-month follow-up period were examined to evaluate the predictive value of candidate microbes. Key findings: Five alpha diversity indices of the bile microbiome were significantly decreased in the lithiasis group. Furthermore, we identified 49 differential bile flora between the two groups, and the relative abundances of 6 bacteria, Actinobacteria, Actinobacteriota, Staphylococcales, Micrococcales, Altererythrobacter and Carnobacteriaceae, were associated with primary choledocholithiasis relapse conditions. Multiomics analyses showed that specific changes in disease-related bacterial taxa were closely related to metabolite variation (low-molecular weight carboxylic acids, sterol liquid and acylcarnitine), which might reflect disease prognosis. According to microbiomic and metabolomic pathway analyses, we revealed that bacterial infections, microbiota-derived amino acid metabolites and secondary bile acid-related pathways were significantly enriched in the stone-formation group, suggesting a novel host-microbial metabolic mechanism of primary choledocholithiasis. Significance: Our study first indicates bile host-microbial dysbiosis modulates the abnormal accumulation of metabolites might further disrupt calcium homeostasis and generate insoluble saponification. Additionally, we determined the predictive value of Actinomycetes phylum reduction for recurrence in primary common bile duct stone patients.

Background Cuproptosis is a novel type of mediated cell death strongly associated with the progression of several cancers and has been implicated as a potential therapeutic target. However, the role of cuproptosis in cholangiocarcinoma (CCA) for prognostic prediction, subgroup classification, and therapeutic strategies remains largely unknown. Methods A systematic analysis was conducted among 146 cuproptosis-related genes (CRGs) and clinical information based on independent mRNA and protein datasets to elucidate the potential mechanisms and prognostic prediction value of CRGs. A ten-CRG prediction model was constructed, and its effects on CCA prognosis were significantly connected to poor patient survival. Additionally, the expression patterns of our model included genes that were validated with several CCA cancer cell lines and a normal biliary epithelial cell line. Results First, a ten-CRG signature (ADAM9, ADAM17, ALB, AQP1, CDK1, MT2A, PAM, SOD3, STEAP3 and TMPRSS6) displayed excellent predictive performance for the overall survival of CCA. The low-cuproptosis group had a significantly better prognosis than the high-cuproptosis group with transcriptome and protein cohorts. Second, compared with the high-risk and low-risk groups, the two groups displayed distinct tumor microenvironments, reduced proportions of endothelial cells and increased levels of cancer-associated fibroblasts based on CIBERSORTx and EPIC analyses. Third, patients’ sensitivities to chemotherapeutic drugs and immune checkpoints revealed distinctive differences between the two groups. Finally, in replicating the expression patterns of the ten genes, these results were validated with qRT‒PCR results validating the abnormal expression pattern of the target genes in CCA. Conclusions Collectively, we established and verified an effective prognostic model that could separate CCA patients into two heterogeneous cuproptosis subtypes based on the molecular or protein characteristics of ten CRGs. These findings may provide potential benefits for unveiling molecular characteristics, and defining subgroups could improve the early diagnosis and individualized treatment of CCA patients.

Introduction Acute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear. Methods An integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo. Results The numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10–3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10–8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation. Discussion In summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression.

Linderalactone is one of the main extracts of Linderae Radix, which is widely used in traditional Chinese medicine. There have been few studies on the antitumor effect of linderalactone in the past. In this study, we explored the anti-pancreatic cancer activity of linderalactone in vitro and in vivo. The results showed that linderalactone inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Cell migration and invasion were significantly inhibited by linderalactone. The cell cycle was arrested in the G2/M phase, and the expression levels of cell cycle-associated proteins changed significantly with linderalactone treatment. In addition, linderalactone induced cell apoptosis and altered the expression of apoptotic markers, such as caspase 3 and PARP1. Mechanistically, linderalactone suppressed the PI3K/AKT signaling pathway by downregulating the phosphorylation of PI3K and AKT. The xenograft study results were consistent with the in vitro results, and there was no obvious chemical toxicity. Thus, our research demonstrated that linderalactone exhibits antitumor activity against pancreatic cancer and may be developed as a potential anti-pancreatic cancer agent in the future.

Background: Cholangiocarcinoma (CCA) is a rare malignant carcinoma characterized by high mortality, challenging diagnosis, and poor prognosis. A powerful prediction biomarker is urgently needed for the early diagnosis and individualized treatment of CCA patients. Methods: A systematic bioinformatics analysis was conducted based on mRNA expression data and clinical information from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and National Genomics Data Center (NGDC) datasets. Differentially expressed genes (DEGs) between tumor tissues and adjacent counterpart controls were identified in the TCGA and GSE107943 datasets. A nine-gene prediction model was constructed, and its effects on CCA prognosis were analyzed using univariate, multivariate and LASSO Cox proportional hazards regression models, Kaplan-Meier plotter, CIBERSORT and OncoPredict in the discovery and validation cohorts. Additionally, the expression profiles of the target genes were determined via qRT-PCR and DEG analyses in an independent cohort. Results: A nine-gene signature (HELLS, HOXC6, MFSD2A, OTX1, PTGES, PYGB, SMOC1, TEX30 and ZBTB12) displayed excellent predictive performance for the overall survival of CCA. According to the prognostic signature, CCA patients were classified into high-risk and low-risk groups, with obvious differences in overall survival probabilities. The low-risk group had a significantly better prognosis than the high-risk group in both the discovery cohort (n = 66) and replication cohort (n = 255) (P < 0.0001, P < 0.0001). Additionally, five cancer drugs (Erlotinib, ML323, AGI-6780, Gallibiscoquinazole and AZD3759) presented clearly specific sensitivities for high-risk and low-risk group patients. Moreover, according to tumor microenvironment analyses, high-risk group patients had a higher level of M0 macrophage infiltration than low-risk group patients (P = 0.025, P = 0.0048). In replicating the expression patterns of the nine genes, eight of the nine genes (except TEX30) were found to have significant expression profiles between 15 tumor tissues and adjacent counterpart controls; moreover, the qRT-PCR results validated the abnormal expression pattern of the target genes in CCA. Conclusions: Collectively, we established an effective prognostic model for different populations of CCA patients based on nine DEGs. These findings may provide potential benefits for the development of new prognostic biomarkers and therapeutic targets for CCA.