MedComm – Oncology最新文献

Cystoscopy is the current gold standard for diagnosing bladder cancer (Bca), but its invasive nature often results in patient discomfort. This study aims to debise a new strategy to enhance BCa detection. We collected data from 30 BCa patients between January and June 2022. We obtained spontaneously voided urine specimens from these patients before and after administering extracorporeal bladder vibration. These specimens underwent routine cytologic examination and fluorescence in situ hybridization (FISH). Furthermore, we conducted a follow-up 3 months postoperation. We recollected urine specimens before and after extracorporeal bladder vibration, repeating the cytologic examination and FISH. Our findings indicated an increase in the number of exfoliated cells in patients' urine postvibration compared to previbration. The liquid-based cell staining results showed an increased detection rate of abnormal cells in the urinary sediment of patients with both low and high-grade urothelial carcinoma postvibration. Similarly, the FISH results revealed an increased detection rate of CEP3 and CEP7 positive cells postvibration. Additionally, 3 months postoperation, we found abnormal cells in the urine of one patient previbration and in three patients postvibration. Further cystoscopic biopsy confirmed that these three patients had developed tumor recurrence. Our study substantiates that the extracorporeal bladder vibration assay significantly enhances BCa detection and the prediction of tumor recurrence. This method is simple, quick, and cost-effective, making it a promising approach worthy of widespread clinical application.

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. More than half of UM cases develop distant metastasis to the liver, lung, bone, and other organs, which frequently results in patient death. However, the mechanisms underlying UM metastasis remain largely unknown. Here, we report that protein tyrosine kinase 2 (PTK2), a nonreceptor protein tyrosine kinase also known as focal adhesion kinase (FAK), was overexpressed in most examined UM specimens. Furthermore, we identified PTK2 expression as a novel independent risk factor that predicts poor prognosis of UM patients. Mechanistic studies revealed that PTK2 promotes the EMT phenotype, leading to metastasis of UM cells. We showed that PTK2, located on chromosome 8q, is a functional gene of chromosome 8q gain to UM metastasis, which may represent the molecular mechanism for the aberrant expression and activation of PTK2 in UM. Our data reveal a novel role and mechanism of PTK2 in the metastatic process of UM, suggesting PTK2 may be a potential prognostic biomarker for UM metastasis and a promising therapeutic target for UM treatment.

Glioma is a highly heterogeneous malignancy with a high mortality rate and poor prognosis. m¹A methylation modifications are associated with gliomagenesis. However, whether single nucleotide polymorphisms (SNPs) of m¹A modification genes are associated with glioma risk is unclear. We successfully genotyped 20 SNPs of m¹A-modified genes TRMT10C, TRMT61B, TRMT6, TRM61, ALKBH1, YTHDC1, YTHDF1, and YTHDF2 in 314 pediatric glioma patients and 380 cancer-free controls using TaqMan probes. Associations of polymorphisms with glioma risk were assessed by the odds ratios and 95% confidence intervals generated by logistic regression models. Stratified analysis was performed by age, gender, tumor subtype, and clinical stage. The results showed that TRMT10C rs2303476, TRMT10C rs4257518, TRM61 rs2296484, and YTHDF2 rs3738067 polymorphisms were significantly associated with an increased risk of glioma, TRMT61B rs4563180, YTHDC1 rs2293595, and YTHDC1 rs3813832 polymorphisms were significantly associated with a reduced risk of glioma. In addition, analysis of the expression quantitative trait loci-showed that the TRM61 rs2296484 T allele significantly increased TRM61 messenger RNA (mRNA) expression, the YTHDF2 rs3738067 G allele significantly increased YTHDF2 mRNA expression, and the TRMT61B rs4563180 C allele significantly decreased TRMT61B mRNA expression. Overall, we identified several promising candidates for m¹A modification gene polymorphisms as biomarkers of glioma risk.

Cuproptosis is a novel form of copper-induced programmed cell death. Here, we investigate the role of cuproptosis-related genes in head and neck squamous cell carcinoma (HNSCC), and the correlations between cuproptosis-related genes and tumor-infiltrating immune cells in the microenvironment. Gene expression data were downloaded from TCGA and analyzed using R. Protein–protein interaction analysis was conducted using STRING and GeneMANIA, while survival analyses examined the correlations between genes and overall survival. In addition, analyses of methylation and mutation sites were performed using Illumina HumanMethylation450 data and the cBioPortal data set, respectively. The correlations between gene expression level and infiltrating immune cells and predictive values of PD-1/PD-L1 blockade responses were also analyzed. Cuproptosis-promoting genes were downregulated, while two out of three cuproptosis-inhibiting genes, GLS and CDKN2A, showed upregulated expression. The CDKN2A expression level was identified as an independent prognostic factor for HNSCC through the multivariate Cox survival analysis. Meanwhile, levels of all cuproptosis-related genes correlated positively with CD4⁺ T cell infiltration. Furthermore, expression of the cuproptosis-promoting gene DLD was negatively correlated with immune score. All cuproptosis-related genes were expressed aberrantly and correlated positively with CD4⁺ T cell infiltration in HNSCC. Thus, copper homeostasis and cuproptosis could be targeted therapeutically as a potential means of enhancing the efficacy of immunotherapy.

Gliomas, the most lethal brain tumors, often exhibit resistance to conventional chemotherapy and/or radiotherapy. This study reveals that sertindole, a potent dopamine D2 receptor antagonist primarily designed as an antipsychotic medication for schizophrenia, effectively inhibits glioma progression. Our findings demonstrate that sertindole suppresses the proliferation of U251 and U87 tumor cells, impedes cell cycle progression in vitro, and curtails xenograft tumor growth in vivo. Moreover, we present compelling evidence demonstrating the ability of sertindole to enhance the cellular response to the chemotherapeutic agent temozolomide both in vitro and in vivo. Additionally, our findings reveal that sertindole effectively suppresses the self-renewal capacity and expression of stemness-associated genes, such as Nanog and Sox2, in glioma tumor cells and glioma stem cells. A mechanistic investigation demonstrated that sertindole enhances the formation of autophagosome–lysosome complexes while concurrently impeding autophagic flux through the inhibition of lysosomal hydrolytic enzymes CTSD and CTSB, ultimately resulting in decreased growth of tumor cells. In conclusion, our findings suggest that sertindole has the potential to develop into a potent antiglioma therapeutic agent.

Gastric cancer (GC) is one of the most commonly diagnosed malignancies worldwide. Compelling evidence indicates that circular RNA (circRNA) played critical roles in multiple cancers. However, the role and mechanisms of circRNAs in GC remains unclear. Here we first identified a notably overexpressed circular RNA hsa_circ_0025506 in GC by human circRNA microarray, designated as circGPRC5A(e2). Next, we found circGPRC5A(e2) was overexpressed in GC cell lines and clinical samples as well. Then, we confirmed that circGPRC5A(e2) was primarily located in the cytoplasm of GC cells and colocation phenomenon was observed with miR-665 via fluorescence in situ hybridization. Functionally, Cell Counting Kit-8, 5-Ethynyl-2′-deoxyuridine, clone formation assay, Transwell invasion assay, wound-healing assay, and animal experiments showed that circGPRC5A(e2) promoted GC proliferation, migration, and invasion in vitro, and tumorigenesis and metastasis in vivo. Mechanistically, we showed that circGPRC5A(e2) could serve as miR-665 sponges and facilitate GC growth and metastasis via modulating miR-665/LIM and SH3 protein 1 (LASP1) axis and activating phosphatidylinositol 3-kinase/AKT pathway. Taken together, this study revealed that circGPRC5A(e2) functioned as an oncogene in GC. The circGPRC5A(e2)/miR-665/LASP1 axis revealed by current research might provide novel biomarkers and promising therapeutic targets for GC.

Chimeric antigen receptor (CAR)-T cell therapy is a promising form of cancer immunotherapy that genetically modifies a patient's own T cells to express CARs for the specific recognition and eradication of cancer cells. Unfortunately, unlike the impressive advancements it achieves in hematologic cancer treatment, CAR-T cell therapy has encountered obstacles in treating solid tumors such as high cost, inadequate tumor infiltration, and immunosuppressive tumor microenvironment. Recently, the regional administration of CAR-T cells via hydrogel platforms has been investigated as a potential method to not only promote tumor infiltration, cell expansion, and anticancer efficacy of the CAR-T cells but also provide a multifunctional platform to introduce additional therapeutic agents for achieving potentiated cancer therapy. In this perspective, different design strategies of CAR-T cell delivery hydrogels are introduced. Besides, various types of therapeutic agents incorporated in the hydrogel platforms and diverse hydrogel formulations have been discussed. The current challenges and future research directions on CAR-T cell delivery hydrogels are also proposed. It is hoped that this perspective can help future researchers develop new CAR-T cell delivery hydrogels that can effectively fight against solid tumors.

In a study recently published in Nature, Liu et al. discovered that lactate directly inhibits SUMO-specific peptidase 1 (SENP1), resulting in the stabilization of anaphase promoting complex (APC) subunit 4 (APC4) SUMOylation, and transient binding of APC/cyclosome (APC/C) and ubiquitin conjugating enzyme E2 C (UBE2C), which promotes the ubiquitination and degradation of cyclin B1 and securin.¹ Furthermore, sustained accumulation of lactate was found to counteract the effects of anti-mitotic drugs by inducing mitotic slippage, which ultimately facilitates mitotic exit. This study shed light on a potential mechanism behind the observed high levels of lactate in rapidly dividing cells.

Cancer cells exhibit a unique metabolic phenotype characterized by increased glucose uptake and reliance on aerobic glycolysis to fuel their rapid proliferation. This metabolic shift contributes to lactate accumulation, which is closely associated with cell proliferation; however, the precise mechanism of the latter remains unclear. APC/C is a member of the ubiquitin ligase family that plays a crucial role in regulating the metaphase-to-anaphase transition and mitotic exit by assembling K11-linked ubiquitin chains on substrates such as cyclin B1 and securin.² A recently published work by Liu et al. uncovered a link between lactate and APC/C activity, and elucidated the significance of this connection in cell cycle and cell proliferation modulation.

To explore the direct effect of elevated lactate levels on the entire proteome, Liu et al. treated native human embryonic kidney cell lysates with 15 or 25 mM l-lactate before conducting thermal proteomic profiling. They observed a significant shift in the thermostability of UBE2C, an E2 enzyme recruited by APC/C upon structural reorganization of its subunits. However, it is unlikely that lactate binds directly to UBE2C because of its low affinity. Moreover, no change in the abundance or posttranslational modification of UBE2C was detected, suggesting that l-lactate might enhance the interaction between UBE2C and APC/C. To verify this hypothesis, cells were first synchronized to pro-metaphase, a period during which APC/C is inhibited due to its interaction with the mitotic checkpoint complex. Subsequently, Liu et al. incubated cell lysates with 15 mM l-lactate and performed immunoprecipitation of APC/C, revealing that l-lactate significantly enhanced the binding between UBE2C and APC/C. In addition, mass spectrometry analysis of APC/C showed a lactate-dependent elevation of SUMO2/3 conjunctions. Previous studies have shown that SUMOylation of APC4 on residues K772 and K798 results in a substantial rearrangement of the WHB domain in APC2, facilitating the binding of UBE2C to APC/C for an efficient APC/C activation.^{3, 4} To further investigate the role of APC4 SUMOylation in lactate-

Pyroptosis is an immunogenic cell death and would trigger robust antitumor immunity. However, due to cytoxicity of pyroptosis executors, Gasdermin family proteins, it is indispensable to construct tumor-specific vectors. Here, we report the development of a novel vector named lipid-coated poly(lactide-co-glycolide) (PLGA) nanoparticles coloaded with Gasdermin E expressing plasmid DNA (GSDME-pDNA) with a heat-inducible mouse heat shock protein 70 (mHSP70) as the promoter and a photosensitizer indocyanine green (ICG) to activate the mHSP70 element. The cellular internalization and transfection rate of the vector were remarkably enhanced by photothermal treatment. And the mHSP70 promoter further improved the gene transfection rate for about 15-fold. With the combination of oxaliplatin (OXA), the mechanism switch between apoptosis and pyroptosis was fulfilled by cleavage of GSDME through activated caspase-3, which promoted damage-associated molecular patterns (DAMPs) release and increased the infiltration of immune cells at the tumor site. This combination strategy not only prominently inhibited the growth of the treated tumor, but also exhibited a lethal effect on the distal tumors. Besides, mouse colon cancer cell CT26 overexpressing GSDME after OXA treatment had the potential to be the preventive tumor vaccine. This study provides a novel thought and feasible method for the clinical treatment of colon cancer.

Gastric cancer (GC) faces a great challenge in clinical diagnosis, that it often is detected at advanced stages and there is a loss of optimum time for treatment. Thus, it is necessary to develop effective strategies for diagnosis of GC. In this study, 82 participants were enrolled, including 50 chronic superficial gastritis (CSG) patients, 7 early gastric cancer (EGC), and 25 advanced gastric cancer (AGC) ones. Metabolites profiling on patient plasma was performed. Furthermore, the proposed biomarkers were used to create random forest models, in which discrimination efficiency and accuracy were ascertained by receiver operating characteristic (ROC) curve analysis. l-carnitine, l-proline, pyruvaldehyde, phosphatidylcholines (PC) (14:0/18:0), lysophosphatidylcholine (14:0) (LysoPC 14:0), lysinoalanine were defined as the potential biomarker panel for the diagnosis among CSG and EGC patients. Compared with EGC patients, PC(O-18:0/0:0) and LysoPC(20:4(5Z,8Z,11Z,14Z)) were found to be upregulated in AGC patients, whereasl-proline, l-valine, adrenic acid, and pyruvaldehyde downregulated. Pathway analysis revealed several metabolism disorders, involving amino acids and lipid metabolism. ROC analysis demonstrated a high diagnostic performance in disease diagnosis between CSG and GC. The above results indicate that the biomarker panels are sensitive to early diagnosis of GC disease, which is expected to be a promising diagnostic tool for disease stratification studies.