Cancer Cell International最新文献

Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8⁺ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.

Background: Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it.

Methods: NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO₂, 94% N₂ and 1% O₂) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo.

Results: CCK8 assay showed that IC₅₀ of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC₅₀ value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells.

Conclusion: Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment.

Clinical trials and studies have implicated that E3 ubiquitin ligase BTBD3 (BTB Domain Containing 3) is a cancer-associated gene. However, the role and underlying mechanism of BTBD3 in colorectal cancer (CRC) is not fully understood yet. Herein, our study demonstrated that the mRNA and protein levels of BTBD3 were decreased in CRC tissues and associated with TYPO3 and Wnt/β-catenin pathway. Our results showed that circRAE1 knockdown and TYRO3 overexpression activated Wnt/β-catenin signaling pathway and the EMT process-associated markers, indicating that circRAE1/miR-388-3p/TYRO3 axis exacerbated tumorigenesis of CRC by activating Wnt/β-catenin signaling pathway. In addition, overexpression of BTBD3 reduced CRC cell migration and invasion in vitro and inhibited tumor growth in vivo. Our data demonstrated that BTBD3 suppressed CRC progression through negative regulation of the circRAE1/miR-388-3p/TYRO3 axis and the Wnt/β-catenin pathway. Our data further confirmed that BTBD3 bound and ubiquitinated β-catenin and led to β-catenin degradation, therefore blocked the Wnt/β-catenin pathway and suppressed the CRC tumorigenesis. This study explored the mechanism of BTBD3 involved in CRC tumorigenesis and provided a new theoretical basis for the prevention and treatment of CRC.

RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields.

CAR-T cell therapy is known as an effective therapy in patients with hematological malignancies. Since 2017, several autologous CAR-T cell (auto-CAR-T) drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of some kinds of relapsed/refractory hematological malignancies. However, some patients fail to respond to these drugs due to high manufacturing time, batch-to-batch variation, poor quality and insufficient quantity of primary T cells, and their insufficient expansion and function. CAR-T cells prepared from allogeneic sources (allo-CAR-Ts) can be an alternative option to overcome these obstacles. Recently, several allo-CAR-Ts have entered into the early clinical trials. Despite their promising preclinical and clinical results, there are two main barriers, including graft-versus-host disease (GvHD) and allo-rejection that may decline the safety and efficacy of allo-CAR-Ts in the clinic. The successful development of these products depends on the starter cell source, the gene editing method, and the ability to escape immune rejection and prevent GvHD. Here, we summarize the gene editing technologies and the potential of various cell sources for developing allo-CAR-Ts and highlight their advantages for the treatment of hematological malignancies. We also describe preclinical and clinical data focusing on allo-CAR-T therapy in blood malignancies and discuss challenges and future perspectives of allo-CAR-Ts for therapeutic applications.

Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors among oral cancers, and its treatment is based on radio-chemotherapy and surgery, which always produces more serious side effects and sequelae. Traditional medicine can compensate for the shortcomings of modern medical treatments and play a better therapeutic role. Currently, active ingredients derived from plants are attracting the attention of researchers and clinical professionals. We examined capsaicin (CAP), an active ingredient isolated from Capsicum annuum (family Solanaceae), and explored the effect of CAP combined with cisplatin (DDP) on epithelial-mesenchymal transition (EMT) and TSCC cells migration. Our results demonstrated that Transforming growth factor-β1(TGF-β1) induced EMT and promoted cell migration in TSCC cells. CAP combined with DDP inhibits non-TGF-β1-induced or TGF-β1-induced EMT and migration. Mechanistically, the inhibition of non-TGF-β1-induced EMT and migration by CAP combined with DDP was mediated by the AMPK/mTOR pathway, whereas TGF-β1-induced EMT and migration were regulated by the Claudin-1/PI3K/AKT/mTOR pathway. A nude lung metastasis mouse model was established for in vivo validation. These results support our hypothesis that the combination of CAP and DDP inhibits TSCC metastasis. These data set the stage for further studies aimed at validating CAP as an effective active ingredient for enhancing chemotherapy efficacy and reducing the dosage and toxicity of chemotherapeutic drugs, ultimately paving the way for translational research and clinical trials for TSCC eradication.