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Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of sclerostin domain-containing protein 1 (SOSTDC1) in regulating malignant biological behaviors of cervical cancer (CC) cells and its molecular mechanism through in vitro experiments. Methods: Fifty-three cervical cancer tissues and corresponding paracancerous tissues were collected from biopsy or surgical resection at Fujian Cancer Hospital between August 2020 and May 2022, immunohistochemistry was used to investigate SOSTDC1 expression in CC and adjacent cervical tissue specimens. qPCR was performed to detect SOSTDC1 mRNA expression levels in normal cervical tissues and CC cells. CC cells SiHa and CaSki transfected with SOSTDC1 over-expression lentiviruses (OE-sostdc1) and negative control (NC) viruses were divided into SiHa-OE-sostdc1 group, SiHa-NC group, CaSki-OE-sostdc1 group and CaSki-NC group. WST-1, colony formation, and Transwell assays were used to detect the proliferative, colony-formative, migratory and invasive abilities of SiHa and CaSki cells in all the groups. The expressions of proteins related to BMP, Wnt/β -catenin signaling pathways, and epithelial mesenchymal transition (EMT) were detected by Western blotting. qPCR and WB arrays were performed on CC cells treated with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5'-Aza-CdR) to detect the changes in the expressions of SOSTDC1 mRNA and proteins. Methylation-specific PCR (MSP) assay was performed to analyze the level of gene promoter methylation of SOSTDC1 in 5 pairs of CC and para-cancerous tissue samples, while qPCR was used to detect SOSTDC1 mRNA levels in the tissues. Results: The expression of SOSTDC1 protein was significantly reduced in CC tissues compared with para-cancerous tissues (P<0.01), and low SOSTDC1 expression was found to be correlated with lymph node metastasis and FIGO staging (all P<0.05). The expression levels of SOSTDC1 mRNA were significantly reduced in C33A, HeLa, SiHa and CaSki cells compared with normal cervical HUCEC cells. Over-expression of SOSTDC1 significantly inhibited the proliferative, migratory, and invasive abilities of SiHa and CaSki cells (all P<0.05). WB analysis showed that over-expression of SOSTDC1 significantly inhibited the expressions of p-Smad, Dvl2/3, β -catenin, vimentin, N-cadherin and Snail proteins in SiHa and CaSki cells (all P<0.05). The levels of SOSTDC1 mRNA and protein in SiHa and CaSki cells treated with 5'-Aza- CdR treatment were significantly increased (all P<0.05). MSP analysis showed that compared with in para-cancerous tissues, the SOSTDC1 gene promoter was highly methylated in CC tissues, while the expression of SOSTDC1 mRNA was down-regulated (P<0.01). Conclusion: SOSTDC1 is downregulated in cervical cancer tissues, and low SOSTDC1 expression is correlated with malignant progression of tumors. SOSTDC1 may suppress the proliferative, migratory, and invasive abilities of SiHa and CaSki cells through blocking BMP and Wnt/β-catenin signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of adhesion molecule with Ig like domain 2 (AMIGO2) in the proliferation of nasopharyngeal carcinoma (NPC) cells and its mechanisms. Methods: A total of 10 NPC tissue samples and 10 normal nasopharyngeal epithelial tissue samples collected at Fujian Cancer Hospital during September 2017 and November 2017 were used for this study; in addition, NPC cell lines (CNE-1, CNE-2, SUNE-1, 6-10B, C666-1) and human immobilized nasopharyngeal epithelial cell line NP69 were also collected. The relative expression ofAMIGO2 mRNAin above mentioned tissues and cell lines was detected by qPCR. Lentivirus vectors were constructed to interfere AMIGO2 mRNA expression, and qPCR was used to verify its interference efficiency. CCK-8 method, Clonal formation and Flow cytometry were performed to evaluate the effect of AMIGO2 interference on proliferation, clone formation and apoptosis of NPC cells. The influence of AMIGO2 interference on PI3K/AKT/mTOR signaling pathway and proliferation related molecular markers in NPC cells was assessed by Western blotting. Results: The results of qPCR showed that AMIGO2 was highly expressed in NPC tissues, CNE-2, and SUNE-1 cells (all P<0.01). The interference efficiency of AMIGO2 in CNE-2 and SUNE-1 cells could reach over 50%. The interfering of AMIGO2 expression significantly inhibited the proliferation and clone formation of CNE-2 and SUNE-1 cells (all P<0.01), promoted cell apoptosis (all P<0.01), reduced the phosphorylated protein expression levels of PI3K, AKT and mTOR in SUNE-1 cells (all P<0.01), as well as down-regulated the protein expressions of survivin and PCNA (all P<0.01). Conclusion: AMIGO2 may promote the proliferation as well as inhibit apoptosis of NPC cells by activating the PI3K/AKT/mTOR signaling pathway, suggesting that AMIGO2 may be a potential target for NPC therapy. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the third leading cause of cancer deaths and the fourth most prevalent malignancy worldwide. The high incidence and mortality rates of gastric cancer result from multiple factors such as ineffective screening, diagnosis, and limited treatment options. In our study, we sought to systematically identify predictive molecular networks and key regulators to elucidate complex interacting signaling pathways in GC. We performed an integrative network analysis of the transcriptomic data in The Cancer Genome Atlas (TCGA) gastric cancer cohort and then comprehensively characterized the predictive subnetworks and key regulators by the matched genetic and epigenetic data. We identified 221 gene subnetworks (modules) in GC. The most prognostic subnetworks captured multiple aspects of the tumor microenvironment in GC involving interactions among stromal, epithelial and immune cells. We revealed the genetic and epigenetic underpinnings of those subnetworks and their key transcriptional regulators. We computationally predicted and experimentally validated specific mechanisms of anticancer effects of GKN2 in gastric cancer proliferation and invasion in vitro. The network models and the key regulators of the tumor microenvironment in GC identified here pave a way for developing novel therapeutic strategies for GC. What's new? Gene signatures have been identified for diagnosis and classification of gastric cancer (GC) as well as prediction of therapeutic response. However, key molecular mechanisms underlying prognosis remain to be revealed. Our study systematically identifies and characterizes predictive molecular networks and key regulators. The most prognostic subnetworks capture multiple aspects of the tumor microenvironment in GC involving interactions among stromal, epithelial, and immune cells. The authors computationally predicted and experimentally validated specific mechanisms of anti‐cancer effects of GKN2 in GC proliferation and invasion in vitro. These network models and key regulators pave the way for developing novel therapeutic strategies for GC. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8 + T cells. Genetic ablation of SRC-1 in mice also decreases PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, these findings highlight a crucial role of SRC-1 in regulating PD-L1 expression and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Cellular senescence (CS) is thought to be the primary cause of cancer development and progression. This study aimed to investigate the prognostic role and molecular subtypes of CS-associated genes in gastric cancer (GC)., Materials and Methods: The CellAge database was utilized to acquire CS-related genes. Expression data and clinical information of GC patients were obtained from The Cancer Genome Atlas (TCGA) database. Patients were then grouped into distinct subtypes using the "Consesus- ClusterPlus" R package based on CS-related genes. An in-depth analysis was conducted to assess the gene expression, molecular function, prognosis, gene mutation, immune infiltration, and drug resistance of each subtype. In addition, a CS-associated risk model was developed based on Cox regression analysis. The nomogram, constructed on the basis of the risk score and clinical factors, was formulated to improve the clinical application of GC patients. Finally, several candidate drugs were screened based on the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset., Results: According to the cluster result, patients were categorized into two molecular subtypes (C1 and C2). The two subtypes revealed distinct expression levels, overall survival (OS) and clinical presentations, mutation profiles, tumor microenvironment (TME), and drug resistance. A risk model was developed by selecting eight genes from the differential expression genes (DEGs) between two molecular subtypes. Patients with GC were categorized into two risk groups, with the high-risk group exhibiting a poor prognosis, a higher TME level, and increased expression of immune checkpoints. Function enrichment results suggested that genes were enriched in DNA repaired pathway in the low-risk group. Moreover, the Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that immunotherapy is likely to be more beneficial for patients in the low-risk group. Drug analysis results revealed that several drugs, including ML210, ML162, dasatinib, idronoxil, and temsirolimus, may contribute to the treatment of GC patients in the high-risk group. Moreover, the risk model genes presented a distinct expression in single-cell levels in the GSE150290 dataset., Conclusion: The two molecular subtypes, with their own individual OS rate, expression patterns, and immune infiltration, lay the foundation for further exploration into the GC molecular mechanism. The eight gene signatures could effectively predict the GC prognosis and can serve as reliable markers for GC patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)