Para-tumor Tissues Research Articles

Growth differentiation factor 7 alleviates the proliferation and metastasis of hepatocellular carcinoma

Background and aimInflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma (HCC). However, the tumor-protective functions of growth differentiation factors (GDFs) in HCC are yet to be clarified. In this study, we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC. MethodsThe gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues. A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression. Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC. ResultsThe mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors (P < 0.001). Kaplan–Meier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival (5-year rate: 61.8% vs. 27.5%, P < 0.001) and increased recurrence risk (P < 0.001). Multivariate Cox regression analysis demonstrated that low GDF7 expression, the presence of microvascular invasion, and elevated alpha-fetoprotein (AFP) levels were independent risk factors for tumor recurrence and poor survival. Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model. GDF7 knockdown promoted migration and invasion via epithelial–mesenchymal transition. Meanwhile, a negative correlation between JunB proto-oncogene (JUNB) and GDF7 was observed in HCC tissues. Modulating JUNB levels altered GDF7 protein expression. ConclusionGDF7 is a potential biomarker for predicting superior outcomes in patients with HCC. GDF7 amplification is a potential therapeutic option for HCC.

Identification and analysis of microplastics in para-tumor and tumor of human prostate

While microplastics are widely found in various human organs and tissues, the relationship between microplastics and human health, especially prostate health, remains unclear. This study aims to identify and quantify the properties, types, and abundance of microplastics in paired para-tumor and tumor tissues of human prostate. Additionally, the potential correlation between microplastics abundance and prostate cancer are investigated. Paired para-tumor and tumor samples of the prostate were collected from 22 patients who underwent robot-assisted radical prostatectomy. A combination of laser direct infrared spectroscopy, scanning electron microscopy and pyrolysis-gas chromatography-mass spectrometry was utilized to analyse the properties, type and abundance of microplastics. Correlations between microplastics abundance, demographic characteristics and clinical features of patients were also examined. Laser direct infrared analysis revealed the presence of microplastics, including polyamide, polyethylene terephthalate, and polyvinyl chloride, in both para-tumor and tumor tissues of human prostate. However, polystyrene was exclusively detected in tumor tissues. The particle size distribution in the prostate tissue mainly ranged from 20 to 100μm. Approximately 31.58% of para-tumor samples exhibited sizes between 20 and 30μm, while 35.21% of tumor samples displayed sizes between 50 and 100μm. The shapes of these microplastics varied considerably with irregular forms being predominant. Additionally, microplastics were detected by pyrolysis-gas chromatography-mass spectrometry in 20 paired prostate tissues. The mean abundance of microplastics was found to be 181.0μg/g and 290.3μg/g in para-tumor and tumor of human prostate samples, respectively. Among the 11 target types microplastics polymers, only polystyrene, polypropylene, polyethylene, and polyvinyl chloride were detected. Notably, polystyrene, polyethylene, and polyvinyl chloride, except for polypropylene, demonstrated significantly higher abundance in tumor tissues compared to their respective paired para-tumor. Furthermore, a positive correlation was observed between polystyrene abundance in the tumor samples of human prostate and frequency of take-out food consumption. This research provides both qualitative and quantitative evidence of the microplastics presence as well as their properties, types, and abundance in paired para-tumor and tumor samples of human prostate. Correlations between microplastics abundance, demographics, and clinical characteristics of patients need to be further validated in future studies with a larger sample size. This work was supported by the National Key Research and Development Program of China (2022YFC2702600) and the National Natural Science Foundation of China (Grant No. 82071698, No. 82101676, and No. 82271630).

The influence of cancer on the reprogramming of lipid metabolism in healthy thyroid tissues of patients with papillary thyroid carcinoma.

Over the years we observed changes in the metabolism of glucose, amino acids, fatty acids (FA) and nucleotides in cancer cells in order to maintain their viability and proliferate. Moreover, as the latest data show, cancer also forces a complete change in the behavior of other tissues. For instance, fat-filled adipocytes are often found in the vicinity of invasive solid human tumors. We investigated the effects of papillary thyroid carcinoma (PTC) on the lipid metabolism of healthy tissue distant from the tumor. Thyroid tissue was collected from female patients immediately after surgical removal of the entire thyroid gland. Blood samples were collected from PTC patients and healthy volunteers. Real-time PCR assays were performed to analyze the expression of lipogenic genes and a broad panel of FA was determined using the gas chromatography-mass spectrometry method. The concentration of lipids was higher in paratumor tissue than in healthy thyroid tissue (p = 0.005). The lipogenic genes tested were significantly increased in paratumor tissue compared to healthy tissue, especially enzymes related to the synthesis of very long-chain saturated and polyunsaturated FAs (VLCSFAs and PUFAs, respectively) (p < 0.001). The FA profile also showed increased levels of C22-C26, VLCSFAs and almost all PUFAs in paratumor tissue (p < 0.05). Our study suggests that a restructuring of lipid metabolism occurs in the adjacent healthy thyroid gland and that the metabolism of VLCSFAs and PUFAs is higher in the paratumor tissue than in the distant tissue of the healthy thyroid gland.

The expression and clinical significance of CFAP65 in colon cancer

BackgroundCFAP65 (cilia and flagella associated protein 65) is a fundamental protein in the development and formation of ciliated flagella, but few studies have focused on its role in cancer. This study aimed to investigate the prognostic significance of CFAP65 in colon cancer.MethodsThe functionally enriched genes related to CFAP65 were analyzed through the Gene Ontology (GO) database. Subsequently, CFAP65 expression levels in colon cancer were evaluated by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) and immunoblotting in 20 pairs of frozen samples, including tumors and their matched paratumor tissue. Furthermore, protein expression of CFAP65 in 189 colon cancer patients were assessed via immunohistochemical staining. The correlations between CFAP65 expression and clinical features as well as long-term survival were statistically analyzed.ResultsCFAP65-related genes are significantly enriched on cellular processes of cell motility, ion channels, and GTPase-associated signaling. The expression of CFAP65 was significantly higher in colon cancer tissue compared to paratumor tissue. The proportion of high expression and low expression of CFAP65 in the clinical samples of colon cancer were 61.9% and 38.1%, respectively, and its expression level was not associated with the clinical parameters including gender, age, tumor location, histological differentiation, tumor stage, vascular invasion and mismatch repair deficiency. The five-year disease-free survival rate of the patients with CFAP65 low expression tumors was significantly lower than that those with high expression tumors (56.9% vs. 72.6%, P = 0.03), but the overall survival rate has no significant difference (69% vs. 78.6%, P = 0.171). The cox hazard regression analysis model showed that CFAP65 expression, tumor stage and tumor location were independent prognostic factors.ConclusionsIn conclusion, we demonstrate CFAP65 is a potential predictive marker for tumor progression in colon cancer.

Diagnostic and prognostic role of LINC01767 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs are emerging markers for HCC diagnosis, prognosis, and therapeutic target. No study of LINC01767 in HCC was published. To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time. DESeq2 Package was used to analyze different gene expressions. Receiver operating characteristic curves assessed the diagnostic performance. Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis. The least absolute shrinkage and selection operator (LASSO)-Cox was used to identify the prediction model. Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction, next generation sequencing was performed following LINC01767 over expression (GSE243371), and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out. In vitro experiment in Huh7 cell was carried out. LINC01767 was down-regulated in HCC with a log fold change = 1.575 and was positively correlated with the cancer stemness. LINC01767 was a good diagnostic marker with area under the curve (AUC) [0.801, 95% confidence interval (CI): 0.751-0.852, P = 0.0106] and an independent predictor for overall survival (OS) with hazard ratio = 1.899 (95%CI: 1.01-3.58, P = 0.048). LINC01767 nomogram model showed a satisfied performance. The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways. LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC > 0.75. LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line; the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 in vitro. LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.

BATF promotes tumor progression and association with FDG PET-derived parameters in colorectal cancer

PurposeThe purpose of the study was to evaluate the expression and function of basic leucine zipper ATF-like transcription factor (BATF) in colorectal cancer (CRC), and its correlation with 2-deoxy-2[18F]fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters.MethodsThe TIMER database, GEPIA database, TCGA, and GEO database were used to analyze the expression profile of BATF in human cancers. The reverse transcription‑quantitative PCR and western blot analyses were used to evaluate the mRNA level and protein expression in different CRC cell lines. The expression of BATF in SW620 and HCT116 cells was silenced and cell counting kit-8 assays and clonogenic assay were utilized to evaluate the role of BATF in CRC proliferation. The expression of tumor BATF and glucose transporter 1 (GLUT-1) were examined using immunohistochemical tools in 37 CRC patients undergoing preoperative 18F-FDG PET/CT imaging. The correlation between the PET/CT parameters and immunohistochemical result was evaluated.ResultsIn database, BATF was highly expressed in pan-cancer analyses, including CRC, and was associated with poor prognosis in CRC. In vitro, the results showed that knocking down of BATF expression could inhibit the proliferation of SW620 and HCT116 cells. In CRC patients, BATF expression was upregulated in tumor tissues compared with matched para-tumoral tissues, and was related with gender and Ki-67 levels. BATF expression was positively related to GLUT-1 expression and PET/CT parameters, including tumor size, maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis. The multiple logistic analyses showed that SUVmax was an independent predictor of BATF expression. With 15.96 g/cm3 as the cutoff, sensitivity was 85.71%, specificity 82.61%, and area-under-the-curve 0.854.ConclusionBATF may be an oncogene associated with 18F-FDG PET/CT parameters in CRC. SUVmax may be an independent predictor of BATF expression.

Fusobacterium nucleatum to promote esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of macrophages to the tumour micro environment.

e14668 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignant tumor in China. Recent studies have shown that Fusobacterium nucleatum ( F. nucleatum) promotes ESCC progression through various mechanisms. One of them is about changing the tumor micro- environment through cytokine–cytokine receptor interaction. Methods: From January 2022 to June 2023, a total of 34 patients with ESCC from 4th Hospital of Hebei Medical University thoracic surgery were enrolled. All of the patients did not apply any neoadjuvant therapy before and received radical resection. Real-time reverse transcriptase - PCR (RT-PCR) were performed to examine the expressions of F. nucleatum in tumor tissues and para-tumor tissue. According to the CT values of the RT-PCR results, the level of the F. nucleatum infection could be separated in two groups - positive group and negative group. Immunohistochemistry (IHC) staining were used to examine the expressions of chemokine CCL20 in both groups. Immunofluorescence (IF) was characterised homing receptors CCR6 on CD206+ macrophages. In addition, transwell assay was carried on to quantify macrophages migration ability towards chemokines CCL20 in vitro. Results: F. nucleatum DNA positivity was significantly associated with higher expression of chemokine CCL20 and accumulation of CD68+CD206+ macrophages. F. nucleatum DNA positivity was also significantly correlated with worse histopathological grading. Otherwise, there were no significant correlation between F. nucleatum infection and gender, age, tobacco or alcohol use, T or N grade, TNM stage, tumor locations, blood vessel or nerve invasion and tumor size. IHC showed that the expression of CCL20 were higher in F. nucleatum DNA positive tumor tissue. After coculture with F. nucleatum and KYSE30 cell lines in vitro, the CCL20 production by KYSE30 cells were accelerated. In addition, immunofluorescence showed that CCL20 could recruit M2-like macrophages into the tumor environment by bonding CCR6 existed on the cell surface. Furthermore, the migration ability of macrophages was distinctly elevated by CCL20 result from F. nucleatum infection. Conclusions: F. nucleatum promotes esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of M2-like macrophages to the tumor micro- environment and deteriorates the suppression of the local immune micro- environment within the tumor. Such bacteria may be a biomarker to predict the efficacy of immunotherapy in ESCC. [Table: see text]

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma

ObjectiveHepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. MethodsA mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-β, IL-1β, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. ResultsDihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-β in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. ConclusionDihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Identification of Long Noncoding RNAs Expression Profiles Between Gallstone and Gallbladder Cancer Using Next-Generation Sequencing Analysis.

Gallstone disease (GS) is an important risk factor for Gallbladder cancer (GBC). However, the mechanisms of the progression of GS to GBC remain unclear. Long non-coding RNA (lncRNA), modulates DNA/RNA/proteins at epigenetic, pre-transcriptional, transcriptional and posttranscriptional levels, and plays a potential therapeutic role in various diseases. This study aims to identify lncRNAs that have a potential impact on GS-promoted GBC progression. Six GBC patients without GS, six normal gallbladder tissues, nine gallstones and nine GBC patients with GS were admitted to our hospital. The next-generation RNA-sequencing was performed to analyze differentially expressed (DE) lncRNA and messenger RNA (mRNA) in four groups. Then overlapping and specific molecular signatures were analyzed. We identified 29 co-DEGs and 500 co-DElncRNAs related to gallstone or GBC. The intersection and concatenation of co-DEGs and co-DElncRNA functionally involved in focal adhesion, Transcriptional misregulation in cancers, Protein digestion and absorption, and ECM-receptor interaction signaling pathways may contribute to the development of gallbladder cancer. Further exploration is necessary for early diagnosis and the potential treatment of GBC. FXYD2, MPZL1 and PAH were observed in both co-DEGs and co-DElncRNA and validated by qRT-PCR. Our data identified a series of DEGs and DElncRNAs, which were involved in the progression of GBC and GS-related metabolism pathways. Compared to GBC, the GS profile was more similar to para-tumor tissues in transcriptome level and lower risk of cancer. Further exploration is necessary from GBC patients with different periods of follow-up gallstone.

RAC1high NK cell-based immunotherapy in hepatocellular carcinoma via STAT3-NKG2D axis

Natural killer (NK) cells exert an indispensable role in innate immune responses against cancer progression, however NK cell dysfunction has been rarely reported in hepatocellular carcinoma (HCC). This study sought to uncover the immunoregulatory mechanisms of tumor-infiltrating NK cells in HCC. A consensus NK cell-based signature (NKS) was constructed using integrative machine learning algorithms based on multi-omics data of HCC patients. HCC tumors had lower numbers of infiltrating NK cells than para-tumor normal liver tissues. Based on the NK cell-associated genes, the NKS was built for HCC prognostic prediction and clinical utilities. Drug targets and novel compounds were then identified for high-NKS groups. RAC1 was confirmed as the hub gene in the NKS genes. RAC1 was upregulated in HCC tumors and positively correlated with shorter survival time. RAC1 overexpression in NK-92 cells facilitated the cancer-killing capacity by the anticancer cytotoxic effectors and the upregulated NKG2D. The survival time of PDX-bearing mice was also prolonged upon NK-92RAC1 cells. Mechanistically, RAC1 interacted with STAT3 and facilitated its activation, thereby enabling its binding to the promoter region of NKG2D and functioning as a transcriptional regulator in NK-92 via molecular docking, Co-IP assay, CHIP and luciferase experiments. Collectively, our study describes a novel function of RAC1 in potentiating NK cell-mediated cytotoxicity against HCC, highlighting the clinical utilities of NKS score and RAC1high NK cell subset in HCC immunotherapy.

Humoral immune response to tumor-associated antigen Ubiquilin 1 (UBQLN1) and its tumor-promoting potential in lung cancer

BackgroundThis study aims to investigate the expression of UBQLN1 in lung cancer (LC) tissue and the diagnostic capability of autoantibody to UBQLN1 (anti-UBQLN1) in the detection of LC and the discrimination of pulmonary nodules (PNs).MethodsSera from 798 participants were used to discover and validate the level of autoantibodies via HuProt microarray and Enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was applied to establish model. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic potential. Immunohistochemistry was performed to detect UBQLN1 expression in 88 LC tissues and 88 para-tumor tissues. qRT-PCR and western blotting were performed to detect the expression of UBQLN1 at the mRNA and protein levels, respectively. Trans-well assay and cell counting kit-8 (CCK-8) was used to investigate the function of UBQLN1.ResultsAnti-UBQLN1 was identified with the highest fold change by protein microarray. The level of anti-UBQLN1 in LC patients was obviously higher than that in NC or patients with benign lung disease of validation cohort 1 (P<0.05). The area under the curve (AUC) of anti-UBQLN1 was 0.610 (95%CI: 0.508-0.713) while reached at 0.822 (95%CI: 0.784-0.897) when combining anti-UBQLN1 with CEA, CYFRA21-1, CA125 and three CT indicators (vascular notch sign, lobulation sign and mediastinal lymph node enlargement) in the discrimination of PNs. UBQLN1 protein was overexpressed in lung adenocarcinoma (LUAD) tissues compared to para-tumor tissues. UBQLN1 knockdown remarkably inhibited the migration, invasion and proliferation of LUAD cell lines.ConclusionsAnti-UBQLN1 might be a potential biomarker for the diagnosis of LC and the discrimination of PNs.

Intratumoral CXCR4hi neutrophils display ferroptotic and immunosuppressive signatures in hepatoblastoma.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

Identification and prognostic analysis of ferroptosis‑related gene HSPA5 to predict the progression of lung squamous cell carcinoma.

Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, is implicated in the development and therapeutic responses of cancer. However, the role of ferroptosis-related gene profiles in lung squamous cell carcinoma (LSCC) remains largely unknown. The present study aimed to identify the prognostic roles of ferroptosis-related genes in LSCC. Sequencing data from the Cancer Genome Atlas were analyzed and ferroptosis-related gene expression between tumor and para-tumor tissue was identified. The prognostic role of these genes was also assessed using Kaplan-Meier analyses and univariate and multivariate Cox proportional hazards regression model analyses. Immunological correlation, tumor stemness, drug sensitivity and the transcriptional differences of heat shock protein (HSP)A5 in LSCC were also analyzed. Thereafter, the expression of HSPA5 in 100 patients with metastatic LSCC was evaluated using immunohistochemistry (IHC) and the clinical significance of these markers with different risk factors was assessed. Of the 22 ferroptosis-related genes, the expression of HSPA5, HSPB1, glutathione peroxidase 4, Fanconi anemia complementation group D2, CDGSH iron sulfur domain 1, farnesyl-diphosphate farnesyltransferase 1, nuclear factor erythroid 2 like 2, solute carrier (SLC)1A5, ribosomal protein L8, nuclear receptor coactivator 4, transferrin receptor and SLC7A11 was significantly increased in LSCC compared with adjacent tissues. However, only high expression of HSPA5 was able to predict progression-free survival (PFS) and disease-free survival in LSCC. Although HSPA5 was also significantly elevated in patients with lung adenocarcinoma, HSPA5 expression did not predict the prognosis of patients with lung adenocarcinoma. Of note, a higher expression of HSPA5 was related to higher responses to chemotherapy but not to immunotherapy. In addition, HSPA5 expression was positively correlated with 'ferroptosis', 'cellular responses to hypoxia', 'tumor proliferation signature', 'G2M checkpoint', 'MYC targets' and 'TGFB'. IHC analysis also demonstrated that a high expression of HSPA5 in patients with metastatic LSCC in the study cohort was associated with shorter PFS and overall survival. In conclusion, the present study demonstrated that the expression of the ferroptosis-related gene HSPA5 may be a negative prognostic marker for LSCC.

Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc–ODC1 nexus

BackgroundHypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown.MethodsHIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis.ResultsIncreased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines.ConclusionsOur results demonstrated that HIGD1A activated c-Myc–ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC.

Serum Lipid Level in Evaluating Chinese Pancreatic Neuroendocrine Neoplasms: A Retrospective Study.

Pancreatic neuroendocrine neoplasms (p-NENs) are relatively rare and highly heterogeneous. Dyslipidemia may be related to the risk of developing p-NENs, although dyslipidemia in patients with p-NENs is rarely reported. In this study, the clinical characteristics of p-NENs patients with different lipid levels and their prognostic value in p-NENs patients were evaluated. Patients (n=211) with p-NENs hospitalized at Jiangsu Neuroendocrine Tumor Centre of Jiangsu Province Hospital from December 2018 to December 2022 were enrolled. Clinical data related to p-NENs were collected. Based on the EGA database, the related lipoprotein, low-density lipoprotein receptor (LDLR) and high-density lipoprotein binding protein (HDLBP) mRNA in p-NENs and paratumoral tissues and the follow-up information of p-NENs were evaluated. A total of 175 p-NENs patients ultimately met the inclusion criteria. The ki67 index was higher in p-NENs patients with elevated lipid with the proportion of≥5, and in those with AJCC stage III and stage IV than p-NENs patients with low-level lipid. In p-NENs patients, the expression of HDLBP mRNA was downregulated in p-NENs tissues compared to the paratumoral tissues. Survival analysis showed that serum lipids had no effect on the prognosis of p-NENs; however, high LDLR level p-NENs were at the risk of poor survival. Serum lipid level in p-NENs can affect the grading and staging, but the correlation with the prognosis of p-NENs is not significant. However, dyslipidemia may be a potential predictor of p-NENs.

Immune characteristics of dedifferentiated retroperitoneal liposarcomas and the reliability of regional samples in evaluating their tumor immune microenvironments

BackgroundTumor immunotherapy is a new treatment breakthrough for retroperitoneal liposarcoma (RPLS), which is highly invasive and has few effective treatment options other than tumor resection. However, the heterogeneity of the tumor immune microenvironment (TIME) leads to missed clinical diagnosis and inappropriate treatment. Therefore, it is crucial to evaluate whether the TIME of a certain part of the tumor reliably represents the whole tumor, particularly for very large tumors, such as RPLS.MethodsWe conducted a prospective study to evaluate the TIME in different regions of dedifferentiated RPLS (DDRPLS) by detecting the expressions of markers such as CD4+, CD8+, Foxp3+, CD20+, CD68+, LAMP3+, PD-1+ tumor-infiltrating lymphocytes (TILs), and PD-L1 in tumors and corresponding paratumor tissues via immunohistochemistry and RNA sequencing.ResultsIn DDRPLS, very few TILs were observed. Differentially expressed genes were significantly enriched in cell part and cell functions, as well as the metabolic pathway and PI3K-Akt signaling pathway. In addition, for most tumors (70–80%), the TIME was similar in different tumor regions.ConclusionsFor most tumors (70–80%), the TIME in any region of the tumor reliably represents the whole tumor. DDRPLS may regulate cell functions by modulating the metabolic and PI3K-Akt signaling pathways to promote its malignant behavior.

Hematological and Neurological Expressed 1 Promotes Tumor Progression Through mTOR Signaling in Ovarian Cancer.

Ovarian cancer (OV) is a highly aggressive malignancy with poor prognosis due to recurrence and drug resistance. Therefore, it is imperative to investigate the key molecular mechanisms underlying OV progression in order to develop promising diagnostic and therapeutic interventions. Although the importance of hematological and neurological expressed 1 (HN1) protein in hemopoietic cell and neurological development has been well-established, its function in cancer, particularly in OV, remains uncertain. In this study, we compared the expression of HN1 in ovarian cancers and para-tumor tissues and predicted potential related signaling pathways through enrichment analysis. In order to confirm the role of HN1 in vitro and vivo, we carried out a variety of experiments including bioinformation analysis, colony formation, flow cytometry analysis, and subcutaneous tumor models. The results demonstrated that HN1 was upregulated in OV and was negatively associated with clinical prognosis. Moreover, we observed that HN1 enhances cell proliferation, migration, and drug resistance, while suppressing apoptosis in OV cells. Notably, we discovered that HN1 functions as a novel regulator of mTOR pathways. Our findings suggest that HN1-mediated mTOR regulation facilitates OV advancement and targeting HN1 could provide a promising therapeutic approach for clinical OV treatment.

Increased Thyroid DPP4 Expression Is Associated With Inflammatory Process in Patients With Hashimoto Thyroiditis.

Dipeptidyl peptidase-4 (DPP4) is originally described as a surface protein in lymphocytes. Lymphocyte infiltration and subsequent destruction of thyroid tissue have been considered as the central pathological mechanism in Hashimoto thyroiditis (HT). The present study aimed to investigate DPP4 expression in peripheral blood and thyroid tissue in HT patients, and explore the role of DPP4 in the pathophysiological process of HT. This case-control study recruited 40 drug-naive HT patients and 81 control individuals. Peripheral blood and thyroid specimens were collected for assessing the expression and activity of DPP4. Moreover, single-cell RNA sequencing (scRNA-seq) analysis of 6 "para-tumor tissues" samples from scRNA-seq data set GSE184362 and in vitro cell experiments were also conducted. The HT patients had similar DPP4 serum concentration and activity as the controls. However, the expression and activity of DPP4 was significantly increased in the thyroid of the HT group than in the control group. The scRNA-seq analysis showed that DPP4 expression was significantly increased in the HT group, and mainly expressed in T cells. Further in vitro studies showed that inhibition of lymphocyte DPP4 activity with sitagliptin downregulated the production of inflammatory factors in co-cultured thyroid cells. DPP4 expression was significantly increased in the thyroid of the HT group compared with the control group, and was mainly localized in the lymphocytes. Inhibition of lymphocyte DPP4 activity reduced the production of inflammatory factors in co-cultured thyroid cells. Therefore, inhibition of DPP4 may have a beneficial effect by alleviating inflammatory reactions in HT patients.

The enrichment of the gut microbiota Lachnoclostridium is associated with the presence of intratumoral tertiary lymphoid structures in hepatocellular carcinoma.

Immunotherapies have formed an entirely new treatment paradigm for hepatocellular carcinoma (HCC). Tertiary lymphoid structure (TLS) has been associated with good response to immunotherapy in most solid tumors. Nonetheless, the role of TLS in human HCC remains controversial, and recent studies suggest that their functional heterogeneity may relate to different locations within the tumor. Exploring factors that influence the formation of TLS in HCC may provide more useful insights. However, factors affecting the presence of TLSs are still unclear. The human gut microbiota can regulate the host immune system and is associated with the efficacy of immunotherapy but, in HCC, whether the gut microbiota is related to the presence of TLS still lacks sufficient evidence. We performed pathological examinations of tumor and para-tumor tissue sections. Based on the location of TLS in tissues, all patients were divided into intratumoral TLS (It-TLS) group and desertic TLS (De-TLS) group. According to the grouping results, we statistically analyzed the clinical, biological, and pathological features; preoperative gut microbiota data; and postoperative pathological features of patients. In a retrospective study cohort of 60 cases from a single center, differential microbiota analysis showed that compared with the De-TLS group, the abundance of Lachnoclostridium, Hungatella, Blautia, Fusobacterium, and Clostridium was increased in the It-TLS group. Among them, the enrichment of Lachnoclostridium was the most significant and was unrelated to the clinical, biological, and pathological features of the patients. It can be seen that the difference in abundance levels of microbiota is related to the presence of TLS. Our findings prove the enrichment of Lachnoclostridium-dominated gut microbiota is associated with the presence of It-TLS in HCC patients.

ACTB may serve as a predictive marker for the efficacy of lenvatinib in patients with HBV-related early-stage hepatocellular carcinoma following partial hepatectomy: a retrospective cohort study.

The lack of effective biomarkers for the treatment of postoperative recurrence in hepatocellular carcinoma (HCC) persists despite lenvatinib therapy. This study aims to identify beta-actin (ACTB) as a predictive biomarker for lenvatinib that can facilitate individualized treatment for HCC. This retrospective study included a subset of patients with HCC who underwent partial hepatectomy, with some receiving postoperative lenvatinib treatment and others not receiving lenvatinib treatment. A propensity score matching (PSM) analysis of patients who underwent treatment with or without lenvatinib following HCC partial hepatectomy was performed. Immunohistochemistry was employed to determine the levels of ACTB expression in HCC samples obtained from matched patients (n=225) enrolled in this study. The X-Tile was employed to determine the optimal cut-off point of ACTB levels for predicting time to recurrence (TTR). To assess the correlation between ACTB levels and lenvatinib efficacy, a subgroup analysis of TTR was conducted. A Cox regression model with an interaction term was utilized to assess the predictive significance of the model. Subsequently, a nomogram was developed and its discriminative ability and predictive accuracy were assessed using the concordance index (C-index) and calibration curve. For the investigation of the ACTB expression, HCC and para-tumoral normal tissues were employed. The patient-derived xenograft (PDX) model was utilized to validate the correlation between ACTB levels and lenvatinib responsiveness. After PSM, a total of 76 patients who underwent postoperative lenvatinib treatment were included in the analysis, with a median TTR of 24.35 months. Early-stage HCC patients with lower levels of ACTB exhibited a more favorable response to lenvatinib therapy compared to those with higher levels. The reduced expression of ACTB was indicative of the benefits of lenvatinib, as opposed to higher levels {hazard ratio (HR) =0.243 [95% confidence interval (CI): 0.096-0.619], P<0.001, P value for interaction =0.014}. In approximately 81.8% of cases involving HCC patients, there was an observed increase in the expression of ACTB. Multivariate analysis of the lenvatinib cohort revealed Child-Pugh [HR =5.416 (95% CI: 1.390-21.104), P=0.015], Barcelona Clinic Liver Cancer (BCLC) stage [HR =2.508 (95% CI: 1.116-5.639), P=0.026], and ACTB [HR =5.879 (95% CI: 2.424-14.259), P<0.001] score as independent factors for TTR, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.76 (95% CI: 0.71-0.84). Moreover, the PDXs derived from tumors exhibiting low levels of ACTB expression demonstrated a heightened sensitivity to lenvatinib treatment. In patients with tumors treated with lenvatinib, low ACTB expression can predict a lower risk of recurrence. The validation of this potential biomarker in independent cohorts is necessary prior to its implementation for precision treatment stratification in patients undergoing partial hepatectomy for early-stage HCC.