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Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma, and the tumour growth and metastasis of ccRCC are related to prognosis. N4-acetylcytidine (ac4C) is one of the major modifications of RNA and is known to be mediated by N-acetyltransferase 10 (NAT10). The role of NAT10 in cancer is gradually being revealed, although the role of NAT10-mediated RNA ac4C modification in ccRCC has not been reported. In this study, NAT10 was found to be upregulated in ccRCC tissues and associated with a poor prognosis in patients. HIF-1α activated NAT10 expression at the transcriptional level. CCK8, EdU, Transwell and scratch assays after NAT10 knockdown or overexpression showed that NAT10 promoted cell proliferation and migration. The results of subcutaneous xenograft and caudal vein injection showed that NAT10 promoted tumour growth and metastasis in vivo, while Remodelin inhibited tumour growth. The acRIP-seq, RIP, RNA stability and dual luciferase reporter experiments showed that NAT10 activated ac4C acetylation of NFE2L3 mRNA and promoted NFE2L3 mRNA stability. The ChIP-seq results showed that NFE2L3 regulated the expression of LASP1 and thus activated the AKT/GSK3β signalling pathway. In summary, our results suggest that NAT10 mediates ac4C acetylation of NFE2L3 mRNA, promotes its mRNA stability, regulates the LASP1-AKT/GSK3β/β-catenin axis and promotes the progression of renal clear cell carcinoma.

Lysomembrane-associated protein 1 (LAMP1), known to exhibit differential expression in various tumor types and play a crucial role in the development of tumors. Clear cell Renal Cell Carcinoma (ccRCC) is still the most common pathological type of renal carcinoma with poor prognosis. However, the expression of LAMP1 and its underlying molecular mechanism with ccRCC remain elusive. Firstly, the expression of LAMP1 in ccRCC and its clinical significance were analyzed using various databases. Next, Weston Blot was performed to detect the expression of LAMP1 protein in cancer tissues and adjacent tissues from 60 pairs of clinical ccRCC patients. The correlation between LAMP1 expression and different clinical indicators as well as the relationship with patient prognosis was analyzed. Furthermore, molecular cell biology experiments were conducted to validate the effects of LAMP1 gene expression on cell proliferation, invasion and migration. Additionally, we investigated the impact of VHL, a key gene in renal cancer, and LC3C, an autophagy-related gene, on LAMP1 expression through molecular biology experiments to elucidate the potential underlying mechanism. Bioinformatics analysis revealed significant underexpression of LAMP1 in ccRCC (P<0.001), which correlated with poorer prognosis. In multivariate survival analysis, LAMP1 emerged as an independent prognostic marker for overall survival(OS)(P<0.05). Analysis of cancer and paracancer tissue samples from ccRCC patients demonstrated significantly lower levels of LAMP1 in tumors compared to paracancerous tissues (P<0.001), confirming its prognostic impact. Cell functionality experiment revealed that elevated LAMP1 inhibited cell proliferation, migration, and invasion. LAMP1 expression remained unchanged during autophagy modulation but decreased with LC3C knockdown and vice versa. Notably, VHL(+) cells expressed less LAMP1 than VHL(-) cells. These findings indicate that low expression levels of LAMP1 is associated with poor prognosis in ccRCC. Therefore, LAMP1 emerges as a novel biomarker associated with the diagnosis and prognosis of renal cancer. Furthermore, we have also described the potential mechanism of action of LAMP1 in renal cancer. LAMP1 is a promising target for the treatment of ccRCC.

BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC, with unknown effects on tumor pathobiology.METHODSWe investigated the landscape of ccRCCs and paired normal kidney tissues using integrated transcriptomic, metabolomic, and metallomic approaches in a cohort of white males who were long-term current smokers (LTS) or were never smokers (NS).RESULTSAll 3 Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OXPHOS) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine, and histidine. Cadmium, copper, and inorganic arsenic accumulated in LTS tumors, showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. A gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas ccRCC tumors that was independent of genomic alterations.CONCLUSIONThe work identified the TS-related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OXPHOS status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC, highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.FUNDINGDepartment of Defense, Veteran Administration, NIH, ACS, and University of Cincinnati Cancer Institute.

Increasing evidence indicates that the dysregulation of circular RNAs (circRNAs) plays important roles in tumor progressions. In this study, we first analyzed circ-FOXO3 level in bladder cancers (BCs), and then BC cell lines were transfected with circ-FOXO3 expression vector, and cell proliferation, migration, and invasion abilities were analyzed. We also used bioinformatics tools to predict potential-binding miRNAs for circ-FOXO3, and luciferase reporter assay was used for the verification of binding miRNAs. For the further study, we analyzed potential downstream-binding mRNA for miRNA, and cell proliferation, migration and invasion abilities of it were also studied. We found that circ-FOXO3 was significantly down-regulated in bladder cancer (BC) tissues compared to normal bladder tissues. We also found that circ-FOXO3 overexpression inhibited cell proliferation, migration and invasion in BC cell lines. Moreover, we demonstrated that TGFBR2 was regulated by circ-FOXO3 through sponging miR-9-5p, the knockdown of TGFBR2 or the overexpression of miR-9-5p all related to the increased BC cell proliferation, migration, and invasion. In summary, our data showed that circ-FOXO3 was significantly down-regulated in bladder cancers. circ-FOXO3 overexpression inhibits BC cell progression and metastasis. Furthermore, circ-FOXO3 regulates TGFBR2 expression through sponging miR-9-5p in BC cell lines.

Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck, and currently lacks satisfactory therapeutic targets. Platelet activating factor acetylhydrolase 1B3 (PAFAH1B3), a cancer-relevant metabolic driver, is reported to play a critical role in controlling tumorigenesis and aggressiveness in several types of cancers. However, the role of PAFAH1B3 in HSCC progression has not yet been identified. The expression pattern of PAFAH1B3 was examined using immunohistochemistry in 83 HSCC tumor tissues and 44 paired adjacent non-tumor samples. Univariate and multivariate analyses were conducted to explore its association with prognosis of HSCC. In vitro loss-of-function assays were performed to explore the impact of PAFAH1B3 knockdown on the biological phenotype of the human HSCC cell line, ie, FaDu cells. PAFAH1B3 was overly expressed in the HSCC tumor tissues compared with the adjacent non-tumor samples. Moreover, high expression of PAFAH1B3 was positively correlated with cervical lymph node metastasis. PAFAH1B3 overexpression was associated with poor outcome in HSCC, but it was not an independent prognostic indicator. Furthermore, in vitro loss-of function experiments demonstrated that PAFAH1B3 knockdown suppressed cell proliferation by inducing apoptosis and disrupting cell cycle process, and the migratory and invasive capacities were also attenuated in the absence of PAFAH1B3. This study for the first time demonstrated the clinical value and the role of PAFAH1B3 in the biological function of HSCC. This work suggested that PAFAH1B3 might serve as a potential therapeutic target for HSCC patients.

Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies. Distant metastasis represents the major cause of death in patients with RCC. Recent studies have implicated the AAA+ ATPase pontin in many cellular activities that are highly relevant to carcinogenesis. In this study, we demonstrate for the first time that pontin was up-regulated in RCC, and plays a previously unknown pro-invasive role in the metastatic progression of RCC through epithelial-to-mesenchymal transition (EMT) pathway. 28 pairs of freshly frozen clear cell RCC samples and the matched normal renal tissues analyzed by quantitative RT-PCR and western blotting demonstrated that pontin was up-regulated in clear cell RCC tissues than in normal renal tissues. In addition, immunohistochemistry was used to evaluate subcellular pontin expression in 95 RCC patients, and found that overexpression of pontin in cytoplasm positively correlated with the metastatic features, predicting unfavorable outcomes of RCC patients. Furthermore, in vitro experiments show pontin was predominantly expressed in cytoplasm of RCC cell lines, and a significant suppression of cell migration and invasion in pontin siRNA treated RCC cell lines was observed. Mechanistic studies show that pontin depletion up-regulated the E-cadherin protein and down-regulated vimentin protein, and decreased nuclear β-catenin expression, suggesting the involvement of EMT in pontin induced metastatic progression. Together, our data suggest pontin as a potential prognostic biomarker in RCC, and provide new promising therapeutic targets for clinical intervention of kidney cancers.

Abnormal tumor vasculature creates a permissive microenvironment that fuels the malignant progression of bladder cancer (BCa). While Leucine‐rich alpha‐2 glycoprotein 1 (LRG1) is known to regulate angiogenesis, its specific role in remodeling the BCa microenvironment remains poorly defined.We integrated single‐cell RNA sequencing (scRNA‐seq) with bulk transcriptomic datasets to identify key cellular subclusters. Functional validation was performed using subcutaneous and orthotopic BCa mouse models, neutrophil depletion, DNase I treatment, and clinical specimens. The molecular interactome was mapped via pull‐down assays, mass spectrometry, and confocal imaging.LRG1 is significantly upregulated in BCa and correlates with hematogenous metastasis and poor prognosis. Mechanistically, tumor‐derived LRG1 binds to Annexin A2 (ANXA2) on neutrophils through its LRR domain, impeding the mitochondrial translocation of Akt and triggering mtROS‐dependent release of Neutrophil Extracellular Traps (NETs). These NETs directly cause vascular destabilization by stripping mural cell coverage. Blockade of the LRG1‐NETosis axis induces vascular normalization, effectively overcoming microenvironmental barriers to increase drug delivery and T‐cell infiltration, thereby profoundly sensitizing BCa to cisplatin and anti‐PD‐1 therapy.The LRG1‐neutrophil‐NETosis axis is a critical driver of vascular dysfunction and therapeutic resistance in BCa. Targeting this axis represents a promising translational strategy to improve clinical outcomes.

Background Concerns regarding end-of-life (EOL) chemotherapy are being increasingly raised. Tumor chemosensitivity may influence the decision for aggressive chemotherapy near the EOL. Data on EOL chemotherapy in highly chemosensitive tumors, such as small cell lung cancer (SCLC), are scarce. Method A total of 143 SCLC decedents were consecutively included. Data about clinical factors and treatment modalities were obtained from the electronic medical records. The relationships among EOL chemotherapy, clinical features, overall survival (OS), and aggressive care were investigated. Results About 64% of patients had chemosensitive disease. In total, 30.8 and 16.1% of patients received EOL chemotherapy within the last 1 and 2 months of life, respectively. Younger age was associated with a higher rate of EOL chemotherapy. We determined that EOL chemotherapy was related to inferior OS not only in the entire group, but also in the chemosensitive subgroup. Furthermore, more intensive care was observed among patients who underwent EOL chemotherapy compared with those who did not. Conclusions EOL chemotherapy was correlated with shorter survival and more aggressive care in patients with SCLC. More research is needed to develop indications for terminating palliative chemotherapy, to help physicians and patients with their difficult choices.

Background: Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck, and currently lacks satisfactory therapeutic targets. Platelet activating factor acetylhydrolase 1B3 (PAFAH1B3), a cancer-relevant metabolic driver, is reported to play a critical role in controlling tumorigenesis and aggressiveness in several types of cancers. However, the role of PAFAH1B3 in HSCC progression has not yet been identified. Methods: The expression pattern of PAFAH1B3 was examined using immunohistochemistry in 83 HSCC tumor tissues and 44 paired adjacent non-tumor samples. Univariate and multivariate analyses were conducted to explore its association with prognosis of HSCC. In vitro loss-of-function assays were performed to explore the impact of PAFAH1B3 knockdown on the biological phenotype of the human HSCC cell line, ie, FaDu cells. Results: PAFAH1B3 was overly expressed in the HSCC tumor tissues compared with the adjacent non-tumor samples. Moreover, high expression of PAFAH1B3 was positively correlated with cervical lymph node metastasis. PAFAH1B3 overexpression was associated with poor outcome in HSCC, but it was not an independent prognostic indicator. Furthermore, in vitro loss-of function experiments demonstrated that PAFAH1B3 knockdown suppressed cell proliferation by inducing apoptosis and disrupting cell cycle process, and the migratory and invasive capacities were also attenuated in the absence of PAFAH1B3. Conclusion: This study for the first time demonstrated the clinical value and the role of PAFAH1B3 in the biological function of HSCC. This work suggested that PAFAH1B3 might serve as a potential therapeutic target for HSCC patients. Keywords: hypopharyngeal squamous cell carcinoma, platelet activating factor acetylhydrolase 1B3, prognosis, cell proliferation, migration, invasion

Introduction Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck and frequently involves regional metastasis. However, the mechanism underlying the aggressiveness of HSCC remains elusive. S100A4 is a well-established metastasis-promoting regulator in a variety of malignancies, but its role in HSCC has not yet been identified. Objectives Our objectives were to explore the expression levels of S100A4 in HSCC tumors and its association with clinicopathological parameters and the clinical prognosis of HSCC and to confirm its role in the metastatic process of the HSCC FaDu cell line in vitro. Methods We assessed the expression levels of S100A4 with immunohistochemistry (IHC) in HSCC tumors ( n  = 71) and adjacent normal tissues ( n  = 44). In vitro experiments were performed to explore the impact of S100A4 knockdown on biological phenotypes of human HSCC FaDu cell line, including migration, invasion, proliferation, apoptosis, and cell cycle. Results The expression of S100A4 was elevated in HSCC tumors compared with adjacent normal tissues and positively correlated with cervical lymph node metastasis in this HSCC patient cohort. In vitro experiments showed that S100A4 knockdown significantly impaired migration and invasion and increased the proportion of cells in G0/G1 phase with no change in proliferation or apoptosis in FaDu cells. Additionally, nuclear S100A4 expression proved to be an independent prognostic indicator in patients with HSCC. Conclusion This study demonstrated for the first time that S100A4 expression is upregulated in HSCC tumors and that this upregulation is positively correlated with cervical lymph node metastasis of this malignancy. The metastasis-promoting role of S100A4 was further validated in the HSCC FaDu cell line, indicating that S100A4 is a potential therapeutic target for HSCC. Furthermore, this study suggests that nuclear S100A4 expression could be considered a prognostic biomarker for HSCC.