Hepatocellular carcinoma (HCC), characterized by elevated incidence and mortality rates, has a considerable economic impact worldwide. The function of ferroptosis within the tumor microenvironment of HCC is crucial, and the specific contributions of ferroptosis-related genes (FRGs) are yet to be fully explored. FRG expression levels and relevant clinical data were sourced from The Cancer Genome Atlas. Two distinct ferroptosis-related subtypes were identified in liver cancer and their interrelationships were comprehensively examined. Using Cox regression and least absolute shrinkage and selection operator regression analysis, we created a predictive model based on FRGs to forecast overall survival and assess the potential benefits of immunotherapy in patients with HCC. Quantitative reverse transcription-polymerase chain reaction and IHC assays were conducted on clinical HCC specimens to validate the key FRGs. Significant differences in gene mutations, immune reactions, and prognostic outcomes were observed between the 2 distinct ferroptosis-related subtypes. An eight-gene signature consisting of SLC1A5, KIF20A, SLC7A11, CARS1, MYCN, PRDX6, GPX4, and KLF2 was established as a predictive model for liver cancer and was validated against data from GSE76427 and the International Cancer Genome Consortium cohorts. According to the FRG model, individuals classified as low-risk exhibited more favorable survival prospects compared to their high-risk counterparts (P < .05). Overall, our investigation highlights the promise of FRGs as prognostic biomarkers and immunotherapy response in HCC, providing a novel approach for personalized patient management.

PurposeCancer remains a major global cause of death, with rising incidence influenced by environmental factors. The THOC5 gene, part of the THO complex, has emerged as a potential regulator in cancer biology. This study investigates THOC5 expression across various cancers, its role in prognosis, and its potential therapeutic implications, particularly in liver hepatocellular carcinoma (LIHC).MethodsWe analyzed THOC5 expression and its prognostic significance across various cancer types using globally available public datasets. Single-cell RNA sequencing, in-house RNA-seq, immunohistochemistry, and proteomic analysis were employed to further validate THOC5 expression and prognosis in LIHC. Functional assays, including wound-healing and Transwell migration, were performed following THOC5 knockdown in LIHC cell lines. A drug sensitivity analysis was performed to identify therapeutic agents associated with THOC5 expression levels.ResultsResults indicate that THOC5 is overexpressed in various cancers and correlates with unfavorable prognosis. In LIHC, both THOC5 mRNA and protein was confirmed to be overexpressed in LIHC elevated THOC5 correlated with advanced tumor stages and poor survival outcomes. THOC5 knockdown suppressed in vitro cell proliferation, migration, and invasion. Additionally, high THOC5 expression was linked to increased immune cell infiltration and enhanced sensitivity to certain chemotherapy agents, though it predicted poor response to immune checkpoint blockade therapy. Furthermore, high THOC5 was also indicated to activate several tumor signaling pathways, such as EGFR, Hypoxia and MAPK pathways.ConclusionTHOC5 could be a prognostic biomarker and therapeutic target in LIHC and various cancers, providing alternative treatment options when immunotherapy fails.

PURPOSE:We aimed to develop and validate a combined model integrating radiomic features derived from Contrast-Enhanced Ultrasound (CEUS) images and clinical parameters for preoperative prediction of CK19-positive status in hepatocellular carcinoma (HCC). METHODS:A total of 434 patients who underwent CEUS and surgical resection from January 2020 to December 2023 were included. Patients were randomly divided into a training cohort (n = 304) and a validation cohort (n = 130). Radiomic features were extracted from multiphase CEUS images, including two-dimensional ultrasound (US), arterial, portal venous, and delayed phases, and combined to derive a Radscore model. Subsequently, a Combined Model was constructed using the Radscore and clinical parameters. Model performance was assessed using calibration, discrimination, and clinical utility. RESULTS:Multivariate logistic regression analysis identified Radscore (OR = 10.054, 95% CI: 5.931-19.120, p < 0.001) and AFP levels > 200 ng/mL (OR = 5.027, 95% CI: 2.089-12.784, p < 0.001) as significant predictors in the combined model. The AUC (Area Under the Curve) for the Combined Model was 0.954 in the training cohort and 0.927 in the validation cohort, compared to 0.939 and 0.917 for the Radscore Model alone. Calibration curves demonstrated strong concordance between predicted and actual outcomes. Decision curve analysis (DCA) showed that both the Radscore Model and the Combined Model exhibited good net benefits across a wide range of threshold values in both the training and validation cohorts. CONCLUSION:The Radscore based on CEUS, combined with the serum markers AFP > 200 ng/L to construct a Combined Model, shows good predictive performance for CK19 + hepatocellular carcinoma (HCC).

BACKGROUND:Distant metastasis is the primary cause of mortality in patients with colorectal cancer (CRC). Angiogenesis plays a critical role in cancer development, invasion, and metastasis. However, the signaling mechanisms driving angiogenesis were not fully elucidated. This study investigated the role of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) in CRC metastasis. METHODS:The impact of LRPPRC was assessed in CRC cells and a mouse xenograft model. The correlation between LRPPRC expression level and clinicopathological features was analyzed through immunohistochemical (IHC) staining on CRC tissue microarrays. LRPPRC-induced proliferation and angiogenesis were evaluated using immunoblotting, immunofluorescence, HUVEC-based tube formation, co-immunoprecipitation, and invasion assays. Gain-of-function experiments were performed to assess the function of LRPPRC in cell proliferation and angiogenesis. RESULTS:LRPPRC expression level was significantly upregulated in CRC tissues, and a higher LRPPRC expression level was associated with a progressive prognosis and poorer survival in CRC patients. The mouse xenograft model indicated that overexpression of LRPPRC significantly promoted CRC development via angiogenesis. Additionally, LRPPRC induced vascular endothelial growth factor (VEGF) expression level, and the restoration of VEGF rescued the angiogenesis suppression caused by LRPPRC knockdown. LRPPRC promoted the activation of hypoxia-inducible factor 1-alpha (HIF-1α) by interacting with it in CRC cells. CONCLUSION:It was revealed that LRPPRC effectively promoted CRC growth and angiogenesis by activation of the HIF-1α/VEGF signaling pathway. The findings may provide a new treatment target and a potential prognostic biomarker for CRC development.

Cucurbitacin B (CuB) is a member of the cucurbitacin family, which has shown potent anticancer pharmacological activity. Prolonged or severe endoplasmic reticulum stress (ERS) induces apoptosis; therefore, the present study investigated whether CuB may activate the ERS pathway to induce apoptosis. HT-29 and SW620 colorectal cancer (CRC) cells were treated with a range of concentrations of CuB for 48 h, and the viability and proliferation of cells were determined using Cell Counting Kit 8 (CCK8) and colony formation assays. Subsequently, the appropriate CuB concentration (5 µM) was selected for treatment of CRC cells for 48 h. Western blot analysis was used to measure the expression levels of ERS-related proteins, flow cytometry was used to evaluate apoptosis, the dichlorodihydrofluorescein diacetate fluorescent probe was used to detect reactive oxygen species (ROS) production, and the relationship between ROS and ERS was determined by western blot analysis. Furthermore, flow cytometry was used to evaluate apoptosis after treatment with the ERS inhibitor 4-phenylbutyric acid, the ROS inhibitor N-acetylcysteine and following knockdown of CHOP expression. In addition, western blot analysis was performed to measure Bax and Bcl2 protein expression levels, and a CCK8 assay was performed to evaluate the viability of cells following knockdown of CHOP. Notably, CuB treatment increased apoptosis and inhibited cell proliferation in CRC cell lines, and these effects were mediated by ROS and ROS-regulated activation of the PERK and XBP1 ERS pathways. In conclusion, CuB may induce apoptosis in HT-29 and SW620 CRC cells via ROS and ERS.

The sensitivity of cells to chemotherapeutic agents has a major effect on disease outcome in breast cancer patients. Unfortunately, there are numerous factors involved in the regulation of chemosensitivity, and the mechanisms need to be further investigated. Autophagy/Beclin 1 regulator 1 (Ambra1) is a key protein in the crosstalk between autophagy and apoptosis. It controls the switch between these two processes, which determines whether cells survive or die. Induction of apoptosis is the primary mechanism by which most chemotherapeutic drugs eliminate cancer cells. Recently, Ambra1 has been shown to modulate paclitaxel-induced apoptosis in breast cancer cells via the Bim/mitochondrial pathway, thereby modifying the sensitivity of cells to paclitaxel. However, how Ambra1 regulates Bim expression remains unclear. Here, we further confirmed that Bim plays an indispensable role in Ambra1's regulation of apoptosis and chemosensitivity in breast cancer cells. Furthermore, Ambra1 was found to regulate Bim expression at the transcriptional level through the Akt-FoxO1 pathway. Therefore, we propose a novel pathway, Ambra1-Akt-FoxO1-Bim, which regulates apoptosis and chemosensitivity in breast cancer cells. Thus, Ambra1 may represent a potential target for breast cancer treatment.

Objectives: The purpose of this research was to confirm the prognostic value of bestrophin-2 (BEST2), one of the hub genes in colon cancer, via bioinformatics analysis and validation in public databases and immunohisto-chemistry detection. Methods: The GEO2R online tool and Venn diagram software were utilized to identify differentially expressed genes (DEGs) from expression profiles, including GSE20916, GSE44861 and GSE74602, from the Gene Expres-sion Omnibus (GEO). The overall survival (OS) and disease-free survival (DFS) of colon cancer patients from The Cancer Genome Atlas (TCGA) were analyzed through Kaplan-Meier survival curves. Verification of the signifi-cance of BEST2 in colon cancer was based on TCGA, Genotype Tissue Expression (GTEx) and 10 datasets from GEO. BEST2 expression was detected with immunohistochemistry (IHC) in 330 colon tissue samples on micro-arrays including 165 colon cancer and 165 adjacent normal tissues. For further validation, comprehensive analysis from tissue microarrays and multiple datasets was performed by the summarizing of receiver operating characteristic (SROC) curves and the standard mean differences (SMDs). BEST2 expression in various kinds of colon cancer tissues and cell lines in the context of pancancer was obtained from the Expression Atlas database. The CBioPortal database was queried to identify BEST2 gene alterations and mutation status in colon cancer. Correlated genes (CEGs) with BEST2 and DEGs from public database data were assembled for functional and pathway enrichment analysis. Results: We identified 85 DEGs from the three datasets and screened out BEST2 as a prognostic predictor via the TCGA database. Colon cancer patients with high expression of BEST2 had better survival than patients with low BEST2 (HR = 0.5, P = 0.006) as shown in Kaplan-Meier survival curves in GEPIA. In all, 1463 colon cancer tissues and 1023 colon normal tissues were gathered via public databases as well as in-house tissue microarrays. The comprehensive expression analysis suggested low-expression of BEST2 in colon cancer (SMD =-2.48, 95% CI [-3.15-1.80]) and the notable efficacy of BEST2 expression in differentiating colon cancer from noncancer samples (AUC = 0.97). Gene alteration status of BEST2 occurred in 5% of colon cancer cases, mostly missense mutations and deep deletions. Genes positively correlated with BEST2 and DEGs primarily aggregated in path-ways such as anion absorption, digestive juice secretion, cAMP signaling and so on (P < 0.05). Conclusion: Ample evidence supports the role of BEST2 in distinguishing colon cancer from normal tissues in this research. Low expression of BEST2 is correlated with a shorter OS, which implies that BEST2 can be employed as a potential biomarker and therapeutic target in colon cancer.

目的 探讨苦参碱(MT)逆转肺癌A549顺铂耐药株活性中的作用及分子机制.方法 对数生长期人肺腺癌耐顺铂细胞株A549/DDP细胞,用不同浓度MT(1,4,16,32μmol·L-1)处理,采用噻唑蓝(MTT)法在24 h检测细胞增殖抑制率.将细胞分为空白对照组及MT组(16μmol·L-1),光学显微镜、Transwell及免疫荧光检测两组细胞的细胞形态、侵袭能力、E-钙粘蛋白(E-cadherin)及波形蛋白(vimentin)细胞免疫荧光变化.另将细胞分为空白对照组、MT组(16μmol·L-1MT)、顺铂(DDP)组(3×10-3μmol·L-1DDP)和MT+DDP组(16μmol·L-1MT+3×10-3μmol·L-1DDP),Western blotting法检测上皮间充质转化(EMT)表型相关标志物E-caherin、vimentin、slug、p-p65等蛋白表达,流式细胞仪检测细胞凋亡率.结果 MT能明显抑制A549/DDP细胞的增殖及侵袭能力,MT处理后细胞呈现上皮细胞样形态及上皮表型.此外,与对照组及DDP组比较,MT+DDP组细胞凋亡率明显升高(P<0.05),E-cadherin蛋白表达水平明显升高(P<0.05),vimentin、slug及p-p65蛋白表达水平明显降低(P<0.05).结论 苦参碱具有逆转肺癌顺铂耐药的作用,其机制与抑制肺癌细胞上皮间质转化及抑制核因子NF-κB信号通路有关.

Our previous studies have initially identified HJURP, which encodes a Holliday junction recognizing protein, as a hepatocellular carcinoma (HCC) susceptibility gene. In this report, we showed that the HJURP is highly expressed in HCC tissues compared to adjacent normal tissues. Overexpression of HJURP in HCC tissues is mainly due to the hypomethylation of HJURP promoter region. Clinically, high expression of HJURP is significantly associated with poor overall survival and disease-free survival of patients with HCC, as well as in multiple other types of cancer. Gain- and loss-of functional studies demonstrated that HJURP promotes HCC cell proliferation, clone formation, migration and invasion. Additionally, HJURP enhances HCC tumorigenesis via reducing G0/G1 arrest and apoptosis. Mechanistically, by gene set enrichment analysis (GSEA) analysis, HJURP was identified as a modulator involved in CENPA-mediated centromere maintenance. Our results provide evidence of HJURP as an important oncogene that promotes HCC progression, and the HJURP pathway may be a potential target for the treatment of HCC.

BACKGROUND:Preoperative identification of hepatocellular carcinoma (HCC), combined hepatocellular-cholangiocarcinoma (cHCC-ICC), and intrahepatic cholangiocarcinoma (ICC) is essential for treatment decision making. We aimed to use ultrasound-based radiomics analysis to non-invasively distinguish histopathological subtypes of primary liver cancer (PLC) before surgery.METHODS:We retrospectively analyzed ultrasound images of 668 PLC patients, comprising 531 HCC patients, 48 cHCC-ICC patients, and 89 ICC patients. The boundary of a tumor was manually determined on the largest imaging slice of the ultrasound medicine image by ITK-SNAP software (version 3.8.0), and then, the high-throughput radiomics features were extracted from the obtained region of interest (ROI) of the tumor. The combination of different dimension-reduction technologies and machine learning approaches was used to identify important features and develop the moderate radiomics model. The comprehensive ability of the radiomics model can be evaluated by the area under the receiver operating characteristic curve (AUC).RESULTS:After digitally processing tumor ultrasound images, 5,234 high-throughput radiomics features were obtained. We used the Spearman + least absolute shrinkage and selection operator (LASSO) regression method for feature selection and logistics regression for modeling to develop the HCC-vs-non-HCC radiomics model (composed of 16 features). The Spearman + statistical test + random forest methods were used for feature selection, and logistics regression was applied for modeling to develop the ICC-vs-cHCC-ICC radiomics model (composed of 19 features). The overall performance of the radiomics model in identifying different histopathological types of PLC was moderate, with AUC values of 0.854 (training cohort) and 0.775 (test cohort) in the HCC-vs-non-HCC radiomics model and 0.920 (training cohort) and 0.728 (test cohort) in the ICC-vs-cHCC-ICC radiomics model.CONCLUSION:Ultrasound-based radiomics models can help distinguish histopathological subtypes of PLC and provide effective clinical decision making for the accurate diagnosis and treatment of PLC.

The present study investigated the sensitization of 5-fluorouracil (5-FU)-resistant colon cancer cells in vitro, using oxymatrine, a Chinese herb, and a quinolizidine alkaloid compound extracted from the root of Sophora flavescens. The HCT-8 colon cancer cell line and its 5-FU-resistant subline HCT-8/5-FU were treated with 5-FU and oxymatrine, alone or in combination, at various doses. The cells were subsequently assessed for changes in cell viability, apoptosis and morphology and analyzed by fluorescence microscopy and western blotting. The data demonstrated that HCT-8/5-FU markedly increased the dose of 5-FU required for the suppression of tumor cell viability (78.77±1.90 µg/ml vs. 9.20±0.96 µg/ml in parental HCT-8 cells), whereas HCT-8/5-FU induced the tumor cell epithelial-mesenchymal transition (EMT). By contrast, oxymatrine alone and in combination with 5-FU altered HCT-8/5-FU cell morphology, apoptosis and EMT phenotypes. The combination of oxymatrine and 5-FU reduced the protein expression of snail family transcriptional repressor 2 and vimentin, phosphorylated p65 and induced the expression of E-cadherin, by inhibiting the nuclear factor κB (NF-κB) signaling pathway. In conclusion, the data from the present study demonstrated that EMT was associated with 5-FU chemoresistance in HCT-8/5-FU colon cancer cells, and that oxymatrine treatment was able to reverse such resistance. Oxymatrine may regulate tumor cell EMT and inactivate the NF-κB signaling pathway, and may therefore serve as a potential therapeutic drug to reverse 5-FU resistance in colon cancer cells.

Oxymatrine, a traditional Chinese herb extracted from Sophora flavescens Ait., displays strong anti-inflammatory and anticancer activities, but how oxymatrine exhibits anticarcinogenic effects in human colorectal cancer (CRC) remains uncertain. The present study aimed to elucidate the exact mechanism by which oxymatrine exhibits anticarcinogenic effects in CRC using the human colon cancer RKO cell line as the experimental model. CRC cells were treated with oxymatrine, and cell proliferation, migration and invasion were examined by colorimetric MTT, Transwell chamber and wound healing assays, respectively. In addition, epithelial-mesenchymal transition (EMT) markers and p65 were assessed by western blot analysis. Our study demonstrated that oxymatrine hindered the proliferation, migration and invasion of the CRC cells. Mechanistically, we found that oxymatrine modulated the expression of EMT markers including E-cadherin, Snail and N-cadherin, and reduced expression of p65 which is crucial to NF-κB activation. In conclusion, our results indicate that oxymatrine reduces the activation of the NF-κB signaling pathway and inhibits CRC invasion by modulating EMT.

Laryngocarcinoma is one of the most aggressive cancers that affects the head and neck region. The survival rate of patients with laryngocarcinoma is low due to late metastases and the resistance of the disease to chemotherapy and radiotherapy. Liriodenine, an alkaloid extracted from a number of plant species, has demonstrated antitumor effects on multiple types of cancer. However, the effects of liriodenine upon laryngocarcinoma, and the underlying mechanisms, are yet to be elucidated. The present study therefore investigated the potential antitumor effects of liriodenine on HEp-2 human laryngocarcinoma cells in vitro and HEp-2-implanted nude mice in vivo. Liriodenine induced significant apoptosis and inhibition of cell migration in the HEp-2 cells. Furthermore, the rate of tumor growth in the HEp-2-implanted nude mice was inhibited by the administration of liriodenine. The potential mechanism underlying the antitumor effects of liriodenine may result from an upregulative effect upon p53 expression, which ultimately induces cellular apoptosis. By contrast, the downregulation of p53 significantly reduced the antitumor effects of liriodenine. Together, these results suggest that liriodenine exhibits potent antitumor activities in laryngocarcinoma HEp-2 cells, in vitro and in vivo, via the upregulation of p53 expression. Liriodenine may therefore be a potential therapy for the treatment of laryngocarcinoma.