Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood. Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo. We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3β/β-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and β-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model. In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients.

Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 have emerged as a revolutionary treatment strategy for human cancer patients. However, as the response rate to ICI therapy varies widely among different types of tumours, we are beginning to gain insight into the mechanisms as well as biomarkers of therapeutic response and resistance. Numerous studies have highlighted the dominant role of cytotoxic T cells in determining the treatment response to ICIs. Empowered by recent technical advances, such as single-cell sequencing, tumour-infiltrating B cells have been identified as a key regulator in several solid tumours by affecting tumour progression and the response to ICIs. In the current review, we summarized recent advances regarding the role and underlying mechanisms of B cells in human cancer and therapy. Some studies have shown that B-cell abundance in cancer is positively associated with favourable clinical outcomes, while others have indicated that they are tumour-promoting, implying that the biological function of B cells is a complex landscape. The molecular mechanisms involved multiple aspects of the functions of B cells, including the activation of CD8+ T cells, the secretion of antibodies and cytokines, and the facilitation of the antigen presentation process. In addition, other crucial mechanisms, such as the functions of regulatory B cells (Bregs) and plasma cells, are discussed. Here, by summarizing the advances and dilemmas of recent studies, we depicted the current landscape of B cells in cancers and paved the way for future research in this field. Graphical Abstract

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Ferroptosis is a newly defined form of cell death, distinguished by different morphology, biochemistry, and genetics, and involved in CRC progression and treatment. This study aims to establish a predictive model to elucidate the relationship between ferroptosis and prognosis of CRC patients, to explore the potential value of ferroptosis in therapeutic options. Methods: The ferroptosis-related genes were obtained from the GeneCards and FerrDb websites. The limma R package was used to screen the differential ferroptosis-related genes (DEGs) in CRC from The Cancer Genome Atlas (TCGA) dataset. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regressions were to establish the 10-gene prognostic signature. The survival and receiver operating characteristic (ROC) curves were illustrated to evaluate the predictive effect of the signature. Besides, independent prognostic factors, downstream functional enrichment, drug sensitivity, somatic mutation status, and immune feature were analyzed. Moreover, all these conclusions were verified by using multiple datasets in International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Results: Ten ferroptosis-related gene signature (TFAP2C, SLC39A8, NOS2, HAMP, GDF15, FDFT1, CDKN2A, ALOX12, AKR1C1, ATP6V1G2) was established to predict the prognosis of CRC patients by Lasso cox analysis, demonstrating a good performance on Receiver operating characteristic (ROC) and Kaplan–Meier (K–M) analyses. The CRC patients in the high- or low-risk group showed significantly different fractions of immune cells, such as macrophage cells and CD8+ T cells. Drug sensitivity and somatic mutation status like TP53 were also closely associated with the risk scores. Conclusions: In this study, we identified a novel ferroptosis-related 10-gene signature, which could effectively predict the prognosis and survival time of CRC patients, and provide meaningful clinical implications for targeted therapy or immunotherapy. Targeting ferroptosis is a good therapeutic option for CRC patients. Further studies are needed to reveal the underlying mechanisms of ferroptosis in CRC.

N-myc downstream-regulated gene 1 (NDRG1) has been reported to act as a key regulatory molecule in tumor progression-related signaling pathways, especially in tumor metastasis. However, the related mechanism has not been fully discovered yet. Herein we demonstrated that the novel molecule of cell migration and invasion, caveolin-1, has direct interaction with NDRG1 in human colorectal cancer (CRC) cells. Moreover, we discovered that NDRG1 reduces caveolin-1 protein expression through promoting its ubiquitylation and subsequent degradation via the proteasome in CRC cells. In addition, caveolin-1 mediates the suppressive function of NDRG1 in epithelial–mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to fulfill the potential mechanisms of NDRG1 in anti-metastatic treatment for human colorectal cancer.

Kaempferol (KF), a flavonoid compound isolated from herbal medicines, has been reported to play a significant role in inhibiting certain types of cancer. Although recent studies reported that KF exerted inhibitive activity on liver cancer, they failed to elucidate the signaling pathways and synergistic effects in combination with chemotherapeutic drugs currently in use in the clinical setting. In the present study, the signaling pathways and synergistic effects of KF in liver cancer cells were investigated. Nine liver cancer cell lines were used to assess the inhibitive activity and synergistic effects of KF. Cellular behavioral experiments, such as viability, colony formation, cell cycle arrest, apoptotic, wound healing, and Transwell assays were used to assess the effects of KF on the proliferation, apoptosis, migration, and invasion of liver cancer cells. Western blotting was performed to validate the key signaling pathway elements underlying those cellular behaviors. KF exhibited inhibitory effects on nine liver cancer cell lines in time‑ and dose‑dependent manners and was mostly nontoxic to the normal hepatocyte cells. The combination of KF and doxorubicin revealed a stronger inhibitive effect on the viability of liver cancer cells. Combination therapy also revealed higher suppressive effects on colony formation, cell cycle progression, survival, DNA damage response, and mitochondrial function. By western blotting assay, mitochondrial and caspase signaling pathways were determined to be involved in proliferation inhibition. In wound healing and Transwell invasion assays, combination therapy also exhibited more robust inhibitory activity in blocking the migration and invasion of liver cancer cells. PI3K/mTOR/MMP protein pathways were also revealed to be related to cell migration inhibition. KF alone exhibited an inhibitory effect on proliferation, migration, and invasion of liver cancer cells, and its synergistic effects revealed stronger inhibitory activities. The present data indicated that KF is a promising candidate as a complementary medicine to conventional chemotherapeutic drugs.