Background & Aims The circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of the circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involvement in IBD still are unclear. Methods Disorder of the circadian clock including chronic social jet lag and circadian clock gene deficiency mice ( Bmal1 -/- , and Per1 -/- Per2 -/- ) were established. Dextran sulfate sodium (DSS) and/or azoxymethane were used to induce mouse models of colitis and its associated colorectal cancer. Flow cytometry, immunohistochemistry, immunofluorescence, Western blot, and reverse-transcription quantitative polymerase chain reaction were used to analyze the characteristics of immune cells and their related molecules. Results Mice with disorders of the circadian clock including chronic social jet lag and circadian clock gene deficiency were susceptible to colitis. Functionally, regulatory B (Breg) cells highly expressing Programmed cell death 1 ligand 1 (PDL1) in intestinal intraepithelial lymphocytes (IELs) helped to alleviate the severity of colitis after DSS treatment and was dysregulated in DSS-treated Bmal1 -/- mice. Notably, interleukin 33 in the intestinal microenvironment was key for Bmal1-regulated PDL1 + Breg cells and interleukin 33 was a target of Bmal1 transcriptionally. Dysregulated PDL1 + B cells induced cell death of activated CD4 + T cells in DSS-treated Bmal1 -/- mice. Consequently, circadian clock disorder was characterized as decreased numbers of Breg + PDL1 + cells in IELs and dysfunction of CD4 + T cells promoted colitis-associated colorectal cancer (CRC) in mice. In clinical samples from CRC patients, low expression of Bmal1 gene in paracancerous tissues and center area of tumor was associated closely with a poorer prognosis of CRC patients. Conclusions Our study uncovers the importance of the circadian clock regulating PDL1 + Breg + cells of IELs in IBD and IBD-associated CRC.
Background Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). Methods The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Results Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. Conclusions SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.
Background Breast cancer is the leading cause of death among women with malignant tumors worldwide. Bone metastasis is the main factor affecting the prognosis of breast cancer. Therefore, both antitumor and anti‐breast‐cancer‐induced osteolysis agents are urgently needed. Methods We examined the effect of Asperolide A (AA), a marine‐derived agent, on osteolysis and RANKL‐induced phosphoinositide 3‐kinase (PI3K)/AKT/mTOR/c‐FOS/nuclear factor‐activated T cell 1 (NFATc1) pathway activation, F‐actin ring formation, and reactive oxygen species (ROS) generation in vitro. We evaluated AA effect on breast cancer MDA‐MB‐231 and MDA‐MB‐436 cells in vitro through CCK8 assay, wound healing assay, transwell assay, Annexin V‐FITC/PI staining for cell apoptosis, and cell cycle assay. Furthermore, we assessed the effect of AA in vivo using a breast cancer‐induced bone osteolysis nude mouse model, followed by micro‐computed tomography, tartrate‐resistant acid phosphatase staining, and hematoxylin and eosin staining. Results Asperolide A inhibited osteoclast formation and differentiation, bone resorption, F‐actin belt formation, ROS activity, and osteoclast‐specific gene and protein expressions and prevented PI3K/AKT/mTOR/c‐FOS/NFATc1 signaling activation in a dose‐dependent manner in vitro. AA also inhibited breast cancer growth and breast cancer‐induced bone osteolysis by reducing osteoclast formation and function and inactivated PI3K/AKT/mTOR signaling in vivo. Conclusions Our study demonstrated that AA suppressed bone metastatic breast cancer. These findings indicate AA as a potential, novel curative drug candidate for patients with bone metastatic breast cancer.
Papillary thyroid carcinoma(PTC) is the most common thyroid malignancy, to investigate the intratumoral heterogeneity of PTC, we analyzed single-cell RNA-sequencing data and identified 10 major cell types from primary papillary thyroid carcinoma, lymph metastatic, or paired normal thyroid tissue samples. In this study, we verified that the increase in the proportion of CD4+Tregs may be key factor responsible for the immunosuppressive property of PTC. Inhibitory checkpoints, such as TIGIT and CD96 may be better targets for immune therapy in lymph metastatic papillary thyroid carcinoma. Our results will further the understanding of the heterogeneity among papillary thyroid carcinoma and provide an essential resource for drug discovery in the future.
The mechanisms and key factors involved in tumor environments for lung metastasis of CRC are still unclear. Here, using clinical samples from lung metastases of CRC patients, we found that intestinal immune network for IgA production was significantly dysregulated in lung metastases of CRC. Single-cell RNA sequencing discovered a subtype of B cells positive for Erbin, one member of the leucine-rich repeat and PDZ domain (LAP) family, was involved in the lung metastases. Erbin deletion in B cells suppressed lung metastasis of CRC in vivo. And, deletion of Erbin in B cells enhanced the killing effects of CD8+ T cells on tumor cells. Mechanistically, Erbin knockout attenuated TGFβ-mediated suppression of migration of CXCR5+ IgA+ cells and STAT6-mediated PD1 expression. Our study uncovered a key role of Erbin in regulating PD1+ IgA+ B cells in lung metastasis of CRC. Targeting Erbin as well as combined use of neutralizing B cells and antibodies neutralizing PD1 suppresses lung metastasis of CRC in mice, suggesting the potential option for treatment of lung metastasis of CRC.
Purpose: The 8th edition of the American Joint Committee on Cancer (AJCC) tumor-lymph node-metastasis (TNM) staging system for gallbladder cancer (GBC) recommended that at least six lymph nodes (LNs) should be examined. But most patients with GBC had fewer than six LNs resected. This study aimed to establish an alternative index for assessing the LN status during the staging system for GBC patients with fewer than six LNs retrieved. Patients and Methods: Patient data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database (cases between 2004 and 2013). X-tile software was used to determine the optimal cutoff value for lymph node ratio (LNR) and a concordance index (C-index) was used to evaluate the discriminatory powers of the two staging systems. Results: The majority of GBC patients in our cohort (1353, 78.5%) had fewer than six LNs examined. Among patients with inadequate LN examination, the higher number of LNs examined correlated with a lower proportion of patients. Using the TNM staging system, the C-index for patients with fewer than six LNs and patients with six or more LNs screened were 0.636 and 0.704, respectively. Using the staging system based on LNR (TNrM), the C-index for patients with fewer than six LNs retrieved and patients with six or more LNs retrieved were 0.649 and 0.694, respectively. Similar results were observed in patients with gallbladder adenocarcinoma (GBA). Conclusion: TNrM might be superior to the 8th AJCC TNM staging system for stratifying GBC patients with fewer than six LNs examined, and it can complement TNM for more accurate risk stratification. Future prospective studies are needed to validate our findings.
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