Cancer gene therapy最新文献

Upon detachment from the primary tumour, epithelial ovarian cancer cells can form multicellular aggregates, also referred to as spheroids, that have the capacity to establish metastases at distant sites. These structures exhibit numerous adaptations that may facilitate metastatic transit and promote tumorigenic potential. One such adaptation is the acquisition of dormancy, characterized by decreased proliferation and molecular features of quiescence. One of the most frequently dysregulated genes in cancer is MYC, which encodes a transcription factor that promotes cell proliferation. In this study, we demonstrate that MYC protein abundance and associated gene expression is significantly decreased in EOC spheroids compared to adherent cells. This downregulation occurs rapidly upon cell detachment and is proteasome-dependent. Moreover, MYC protein abundance and associated gene expression is restored upon spheroid reattachment to an adherent culture surface. Overall, our findings suggest that suppression of MYC activity is a common feature of EOC spheroids and may contribute to the reversible acquisition of dormancy.

Previous studies have found that oncolytic virus (OVs) can improve the efficacy of TIL adoptive therapy in oral cancer, colon cancer, and pancreatic cancer. However, the curative effect in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the therapeutic effect and mechanism of OVs encoding 4-1BBL and IL15 (OV-4-1BBL/IL15) combined with TIL adoptive therapy on HCC. In this study, the role and immunological mechanism of armed OVs combined with TILs were evaluated by flow cytometry and ELISA in patient-derived xenograft and syngeneic mouse tumor models. Co-culturing with TILs can up-regulate the expression of antigen-presenting cell (APC) markers on the surface of OV-infected primary HCC cells, and promote the specific activation ability and tumor-killing ability of TILs. OV-4-1BBL/IL15 combined with TIL adoptive therapy could induce tumor volume reduction and anti-tumor immune memory in patient-derived xenograft and syngeneic mouse tumor models. Furthermore, OV combined with TIL adoptive therapy can endow tumor cells with aAPC characteristics, activate T cells at the same time, and reprogram tumor macrophages into anti-tumor phenotype. OV-4-1BBL/IL15 can stimulate the anti-tumor potential of TIL therapy in HCC, and possess broad clinical application prospects.

CDK1 is an oncogenic serine/threonine kinase known to play an important role in the regulation of the cell cycle. FOXM1, as one of the CDK1 substrates, requires binding of CDK1/CCNB1 complex for phosphorylation-dependent recruitment of p300/CBP coactivators to mediate transcriptional activity. Previous studies from our laboratory found that a novel peptide (M1-20) derived from the C-terminus of FOXM1 exhibited potent inhibitory effects for cancer cells. Based on these proofs and to explore the inhibitory mechanism of M1-20, we designed experiments and found that CDK1 served as an important target of M1-20. M1-20 enhanced the ubiquitination and degradation of CDK1 by CUL4-DDB1-DCAF1 complexes through the proteasome pathway. M1-20 could also affect the formation of CDK1/CCNB1 complexes. In addition, compared to RO3306, a CDK1 inhibitor, M1-20 exhibited excellent inhibitory effects in FVB/N MMTV-PyVT murine model of spontaneous breast cancer. These results suggested that M1-20 was a potential CDK1 inhibitor for the treatment of cancer.

Gastric cancer (GC) is one of the most lethal cancers. However, the underlying mechanisms are not yet fully understood. Here, we investigated the role of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in tumor initiation and progression in GC and proposed therapeutic strategies for CEACAM6-positive patients. In this article, we found that CEACAM6 overexpression promoted GC initiation and progression by overactivating FAO. CEACAM6 promotes SLC27A2 expression, contributing to enhanced fatty acid incorporation. CEACAM6 interacts with both SLC27A2 and USP29, facilitating the deubiquitination of USP29 on SLC27A2. Pharmacological inhibition of SLC27A2 attenuates the tumor-initiating ability of GC. Taken together, CEACAM6 overexpression facilitates GC progression by upregulating fatty acid uptake through SLC27A2, thereby contributing to FAO. Genetic ablation of SLC27A2 is a promising therapeutic strategy for patients with CEACAM6-positive GC.

Papillary thyroid microcarcinoma (PTMC), although frequently indolent, could be aggressive in a few patients, leading to lymph node metastasis (LNM) and worsened prognosis. To explore the role of protein profiling of small extracellular vesicles (sEVs) in the auxiliary diagnosis and risk stratification of PTMC, proteins in serum sEVs isolated from PTMC patients with (N = 10) and without (N = 10) LNM and benign thyroid nodule (BN) patients (N = 9) were profiled via a bioinformatics-integrated data-independent acquisition proteomic technique. The performance of candidate proteins as diagnostic and prognostic biomarkers in PTMC was assessed via receiver operating characteristic analysis. We found that serum sEVs from PTMC patients promoted the proliferation and migration of human papillary thyroid cancer (PTC) cells and tube formation in human lymphatic endothelial cells (HLECs). SEV proteins from PTMC patients with and without LNM have differential expression profiles, with bone marrow stromal cell antigen 2 (BST2) being best associated with PTMC progression. Through knockdown and overexpression, we proved that the high expression of sEV-derived BST2 was bound up with higher proliferation and migration ability of PTC cells as well as stronger lymphangiogenesis in HLECs. This study brought insight into the differential sEV-protein profile with or without LNM in PTMC. The serum sEV-BST2 may contribute to PTMC progression and LNM and may have diagnostic, prognostic, and therapeutic implications.

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained largely incurable owing to drug resistance and disease relapse, which requires novel therapeutic targets and treatment approaches. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) acts as an oncoprotein linked to the development of various tumors. However, the functional consequence of Pin1 overexpression in modulating MM biology has not been established. In the present study, we show that Pin1 expression is highly variable in myeloma cell lines and primary MMs and that high Pin1 expression is associated with poor survival of MM patients. Next, TOP2A is identified to be a Pin1 promoter-binding protein and CK2 activates TOP2A to promote the expression level of Pin1. Additionally, we demonstrate that Pin1 positively modulates the stability and function of Pyk2 to enhance bortezomib resistance in MM. Pin1 recognizes three phosphorylated Ser/Thr-Pro motifs in Pyk2 via its WW domain and increases the cellular levels of Pyk2 in an isomerase activity-dependent manner by inhibiting the ubiquitination and proteasomal degradation of Pyk2. Moreover, Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden both in vitro and in vivo. Altogether, our findings reveal the tumor-promoting role of Pin1 in MM and provide evidence that targeting Pin1 could be a therapeutic strategy for MM.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a pivotal epigenetic enzyme that contributes to several malignancies including malignant glioma. LSD1 is a flavin adenine dinucleotide dependent histone demethylase that specifically targets histone H3 lysine (K) 4 mono- (me1) and di-methylation (me2) and H3K9me1/2 for demethylation. Herein we report the development of an LSD inhibitor, S2172, which efficiently penetrates the blood-brain barrier. S2172 effectively suppresses LSD1 enzymatic activity, resulting in the depletion of cell growth both in vitro in glioma stem cells (GSCs) (mean half-maximal inhibitory concentration (IC₅₀) of 13.8 μM) and in vivo in a GSC orthotopic xenograft mouse model. Treatment with S2172 robustly reduced the expression of the stemness-related genes MYC and Nestin in GSC cells. Consistent with this, chromatin immunoprecipitation-sequencing revealed a significant S2172-dependent alteration in H3K4me2/H3K4me3 status. Furthermore, we identified 284 newly acquired H3K4me2 peak regions after S2172 treatment, which were encompassed within super-enhancer regions. The altered H3K4me2/H3K4me3 status induced by S2172 treatment affected the expression of genes related to tumorigenesis. Our data suggest that targeting LSD1 with S2172 could provide a promising treatment option for glioblastomas, particularly due to targeting of GSC populations.

Hepatocellular carcinoma (HCC) is a common type of cancer worldwide and ranks as the fourth leading cause of cancer-related deaths. This research investigation identified an upregulation of BAI1-associated protein 2-like 2 (BAIAP2L2) in HCC tissues, which was found to be an independent prognostic factor for overall survival in HCC patients. BAIAP2L2 was observed to enhance cell proliferation, metastasis, stemness, cell cycle progression, and inhibit apoptosis in HCC. Mechanistically, NFκB1 was found to stimulate BAIAP2L2 transcription by directly binding to its promoter region. BAIAP2L2 interacts with GABPB1 to inhibit its ubiquitin-mediated degradation and promote its nuclear translocation. BAIAP2L2 inhibits the levels of reactive oxygen species (ROS) by regulating GABPB1, thereby promoting cancer properties in HCC and reducing the sensitivity of HCC to lenvatinib. In summary, this study elucidates the role and underlying mechanism of BAIAP2L2 in HCC, providing a potential biomarker and therapeutic target for this disease.