BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability.

Chromosome instability (CIN) is a common contributor driving the formation and progression of anaplastic thyroid cancer (ATC), but its mechanism remains unclear. The BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is responsible for the alignment of mitotic chromosomes, which has not been thoroughly studied in ATC. Our research demonstrated that BUB1 was remarkably upregulated and closely related to worse progression-free survival. Knockdown of BUB1 attenuated cell viability, invasion, migration and induced cell cycle arrests, whereas overexpression of BUB1 promoted the cell cycle progression of papillary thyroid cancer cells. BUB1 knockdown remarkably repressed tumour growth and tumour formation of nude mice with ATC xenografts and suppressed tumour metastasis in a zebrafish xenograft model. Inhibition of BUB1 by its inhibitor BAY-1816032 also exhibited considerable anti-tumour activity. Further studies showed that enforced expression of BUB1 evoked CIN in ATC cells. BUB1 induced CIN through phosphorylation of KIF14 at serine1292 (Ser1292 ). Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN.

Comparison of diagnostic performance of AFP, DCP and two diagnostic models in hepatocellular carcinoma: a retrospective study.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) may be diagnosed using the GAAP and ASAP models; our goal was to verify and evaluate their diagnostic effectiveness compared to alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and AFP & DCP for both HCC and HCC caused by the hepatitis B virus (HBV). PATIENTS AND METHODS: GAAP and ASAP models were validated and compared using a retrospective investigation of 938 patients from our hospital between July 2020 and July 2021. RESULTS: Both the GAAP and ASAP models had better diagnostic efficacy than AFP, DCP, AFP & DCP. The GAAP model achieved better performance in section A for the detection of HCC and in section C for the detection of HBV-HCC than the ASAP model. The Hosmer-Lemeshow test showed that the GAAP and ASAP models were well-calibrated for the diagnoses of these two groups. To be more specific, the area under curve (AUC) of the GAAP model for HCC detection in section A was 0.862 [95% confidence interval (CI): 0.838-0.883], and that of the ASAP model was 0.850 [95% CI: 0.826-0.872]. The AUC of the GAAP model for HBV-HCC detection in section C was 0.897 [95% CI: 0.872-0.918], and that of the ASAP model was 0.878 [95% CI: 0.852-0.902]. CONCLUSIONS: The GAAP model was more accurate and reliable than the AFP, DCP, AFP and DCP, as well as the ASAP model in section A for the detection of HCC and in section C for the detection of HBV-HCC.

Identification of differentially methylated genes as diagnostic and prognostic biomarkers of breast cancer.

BACKGROUND: Aberrant DNA methylation is significantly associated with breast cancer. METHODS: In this study, we aimed to determine novel methylation biomarkers using a bioinformatics analysis approach that could have clinical value for breast cancer diagnosis and prognosis. Firstly, differentially methylated DNA patterns were detected in breast cancer samples by comparing publicly available datasets (GSE72245 and GSE88883). Methylation levels in 7 selected methylation biomarkers were also estimated using the online tool UALCAN. Next, we evaluated the diagnostic value of these selected biomarkers in two independent cohorts, as well as in two mixed cohorts, through ROC curve analysis. Finally, prognostic value of the selected methylation biomarkers was evaluated breast cancer by the Kaplan-Meier plot analysis. RESULTS: In this study, a total of 23 significant differentially methylated sites, corresponding to 9 different genes, were identified in breast cancer datasets. Among the 9 identified genes, ADCY4, CPXM1, DNM3, GNG4, MAST1, mir129-2, PRDM14, and ZNF177 were hypermethylated. Importantly, individual value of each selected methylation gene was greater than 0.9, whereas predictive value for all genes combined was 0.9998. We also found the AUC for the combined signature of 7 genes (ADCY4, CPXM1, DNM3, GNG4, MAST1, PRDM14, ZNF177) was 0.9998 [95% CI 0.9994-1], and the AUC for the combined signature of 3 genes (MAST1, PRDM14, and ZNF177) was 0.9991 [95% CI 0.9976-1]. Results from additional validation analyses showed that MAST1, PRDM14, and ZNF177 had high sensitivity, specificity, and accuracy for breast cancer diagnosis. Lastly, patient survival analysis revealed that high expression of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 were significantly associated with better overall survival. CONCLUSIONS: Methylation pattern of MAST1, PRDM14, and ZNF177 may represent new diagnostic biomarkers for breast cancer, while methylation of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 may hold prognostic potential for breast cancer.

Natural medicinal ingredients induce tumor ferroptosis and related mechanisms.

Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxide accumulation, which is different from cell apoptosis, pyroptosis, necrosis or autophagy. Ferroptosis plays an important role in the regulation of tumorigenesis and tumor development. Recent studies have shown that natural medicinal ingredients can induce ferroptosis in tumor cells through glutathione (GSH)/glutathione peroxidase 4 (GPx4) pathway, iron metabolism, lipid metabolism or other mechanisms. It has been reported that more than 30 natural medicinal ingredients can induce ferroptosis in tumor cells with multiple pathways and multiple targets. This article reviews the current research progress on the antitumor effects of natural medicinal ingredients through inducing cell ferroptosis.

Identification of key microRNAs and hub genes in non-small-cell lung cancer using integrative bioinformatics and functional analyses.

Non-small-cell lung cancer (NSCLC) is an extremely debilitating respiratory malignancy. However, the pathogenesis of NSCLC has not been fully clarified. The main objective of our study was to identify potential microRNAs (miRNAs) and their regulatory mechanism in NSCLC. Using a systematic review, two NSCLC-associated miRNA data sets (GSE102286 and GSE56036) were obtained from Gene Expression Omnibus, and the differentially expressed miRNAs (DE-miRNAs) were accessed by GEO2R. Survival analysis of candidate DE-miRNAs was conducted using the Kaplan-Meier plotter database. To further illustrate the roles of DE-miRNAs in NSCLC, their potential target genes were predicted by miRNet and were annotated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) program. Moreover, the protein-protein interaction (PPI) and miRNA-hub gene regulatory network were established using the STRING database and Cytoscape software. The function of DE-miRNAs in NSCLC cells was evaluated by transwell assay. Compared with normal tissues, a total of eight DE-miRNAs was commonly changed in two data sets. The survival analysis showed that six miRNAs (miR-21-5p, miR-31-5p, miR-708-5p, miR-30a-5p, miR-451a, and miR-126-3p) were significantly correlated with overall survival. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that target genes of upregulated miRNAs were enriched in pathways in cancer, microRNAs in cancer and proteoglycans in cancer, while the target genes of downregulated miRNAs were mainly associated with pathways in cancer, the PI3K-Akt signaling pathway and HTLV-I infection. Based on the miRNA-hub gene network and expression analysis, PTEN, EGFR, STAT3, RHOA, VEGFA, TP53, CTNNB1, and KRAS were identified as potential target genes. Furthermore, all six miRNAs exhibited significant effects on NSCLC cell invasion. These findings indicate that six DE-miRNAs and their target genes may play important roles in the pathogenesis of NSCLC, which will provide novel information for NSCLC treatments.

Prognostic value of angiopoietin-2 in non-small cell lung cancer patients: a meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide. The targeted therapy had made important progress in recent years, but few potential predictive biomarkers for prognosis of NSCLC patients were identified. Angiopoietin-2 (Ang-2), a cytokine upregulated in tumor endothelial cells and some tumor cells including NSCLC, is a partial agonist and antagonist of angiopoietin-1 (Ang-1). Ang-1 is another ligand for the tyrosine kinase receptor Tie2; it promotes recruitment of pericytes and smooth muscle cells, stabilizing vascular networks by binding to Tie2. Although many studies mainly considered that Ang-2 correlated with progression and prognosis of NSCLC significantly, there are much conflicting and controversial data. Therefore, we conducted a meta-analysis to assess the relationship between Ang-2 and prognosis, a clinical outcome of NSCLC. METHODS: The search was based on major databases from PubMed, Cochrane Library, EMBASE, and CNKI, and 20 eligible publications (range from 2002 to 2015) are included in our meta-analysis with 2011 NSCLC patients in total. These studies illuminated the correlation between the expression of Ang-2 and NSCLC, based on either prognostic factors or clinicopathological features. Pooled calculations were carried out on the odds ratio (OR) and the corresponding 95 % confidence interval (CI) to perform this meta-analysis, and all statistical analyses were carried out by STATA 12.0 and Review Manager 5.3. RESULTS: According to our results, the expression of Ang-2 in NSCLC tissues was significantly higher than that in normal lung tissues, indicating that Ang-2 over-expression may be a predictive marker (pooled OR = 5.09, corresponding 95 % confidence interval (95 % CI) 3.10-8.36, p = 0.000). In addition, our pooled data showed that Ang-2 expression was positively correlated with tumor stages (pooled OR = 3.58, 95 % CI 2.40-5.35, p = 0.000), differentiation (pooled OR = 0.65, 95 % CI 0.45-0.94, p = 0.02), lymphatic invasion (pooled OR = 3.15, 95 % CI 1.97-5.03, p = 0.000), and poor survival (pooled OR = 1.93, 95 % CI 1.47-2.52, p = 0.000) of NSCLC, but seems to have no significant impact on tumor size (pooled OR = 1.09, 95 % CI 0.59-2.00, p = 0.78). CONCLUSIONS: These results demonstrate that Ang-2 expression significantly correlated with poor prognosis for patients with NSCLC.

Exploration of the protection of riboflavin laurate on oral mucositis induced by chemotherapy or radiotherapy at the cellular level: what is the leading contributor?

Oral or gastrointestinal mucositis is a frequent phenomenon in cancer patients receiving chemotherapy or radiotherapy. In addition, several clinical investigations have demonstrated in recent years that riboflavin laurate has the potential to protect the patients from the disease induced by chemotherapy or radiotherapy. In our studies, it is observed that riboflavin laurate can ameliorate either chemotherapy- or radiotherapy-induced toxicities on Helf cells, and the effect is greater than that of riboflavin. In addition, riboflavin laurate is able to transport through the Caco-2 cell monolayer as the prototype, indicating the protective effects may be produced by the prototype of riboflavin laurate, rather than simply by the released riboflavin.

Novel cell subtypes of SPP1 + S100P+, MS4A1-SPP1 + S100P+ were key subpopulations in intrahepatic cholangiocarcinoma.

BACKGROUND: In this study, we integrated single-cell RNA sequencing (scRNA-seq) data to investigate cell heterogeneity and utilized MSigDB and CIBERSORTx to explore the pathways of major cell types and the relationships between different cell subtypes. Subsequently, we explored the correlation of cell subtypes with survival and used Gene Set Enrichment Analysis (GSEA) analyses to assess the pathways associated with the infiltration of specific cell subtypes. Finally, multiplex immunohistochemistry in tissue microarray cohort were performed to validate differences in protein level and their correlation with survival. RESULTS: iCCA presented a unique immune ecosystem, with increased proportions of Epi (epithelial)-SPP1-2, Epi-S100P-1, Epi-DN (double negative for SPP1 and S100P expression)-1, Epi-DN-2, Epi-DP (double positive for SPP1 and S100P expression)-1, Plasma B-3, Plasma B-2, B-HSPA1A-1, B-HSPA1A-2 cells, and decreased proportions of B-MS4A1. High level of Epi-DN-2, Epi-SPP1-1, Epi-SPP1-2, B-MS4A1, and low level of Epi-DB-1, Epi-S100P-1, and Epi-S100P-2 was significantly associated with longer overall survival (OS), and high level of B-MS4A1_Low_Epi-DN-2_Low was associated with the shortest OS. Moreover, the results of MsigDB and GSEA suggest that bile acid metabolism is a crucial process in iCCA. Finally, we found that S100P+, SPP1+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ were highly expressed, whereas MS4A1 was lowly expressed in iCCA, and patients with high level of S100P+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ exhibited shorter survival. CONCLUSIONS: We identified the cell heterogeneity of iCCA, found that iCCA is a unique immune ecosystem with many cell subtypes, and showed that the novel cell subtypes of SPP1 + S100P+ and MS4A1-SPP1 + S100P+ were key subpopulations in iCCA.

The Heterogeneity of Tumour-Associated Macrophages Contributes to the Recurrence and Outcomes of Glioblastoma Patients.

Cellular heterogeneity and immune cell molecular phenotypes may be involved in the malignant progression of glioblastoma (GBM). In this study, we aimed to know whether the heterogeneity of tumour-associated macrophages contributes to the recurrence and outcomes of glioblastoma patients. Single-cell RNA sequencing (scRNA-Seq) data were used to assess the heterogeneity of CD45 + immune cells in recurrent GBM and analyse differentially expressed genes (DEGs) in master cells. Then, a prognostic signature based on the identified DEGs was established and validated, the correlation between risk score and tumour microenvironment (TME) was explored. The correlation between immune infiltration and LGMN, an important DEG in GBM tumour-associated macrophages (TAMs) was illuminated, using integrated bioinformatics analyses. Finally, immunohistochemistry and multiplex immunohistochemistry (mIHC) were used to analyse the expression of LGMN in GBM tissues from our hospital. scRNA-Seq analysis showed that the heterogeneity of recurrent GBM mainly comes from TAMs, which can be divided into 8 cell subclusters. Among these subclusters, TAM1 (markers: CXCL10, ADORA3), TAM3 (markers: MRC1, CFP), TAM4 (markers: GPNMB, PLTP), and TAM5 (markers: CCL4, IRAK2) were specifically present in recurrent GBM. After 342 DEGs in TAMs were identified, a prognostic signature was established based on 13 TAM-associated DEGs, and this signature could serve as an excellent prognostic predictor for patients with GBM. LGMN, one of 13 TAM-associated DEGs, was an important gene in lysosome pathway, we found that macrophage infiltration levels were higher after LGMN upregulation. GBM tissues from our hospital were collected for histopathologic validation, then LGMN was co-expressed with CD68, which is associated with the immune regulation of GBM. In conclusion, cell heterogeneity of TAMs is important for recurrent GBM, a prognostic signature based on 13 TAM-related DEGs can predict the survival outcome of GBM patients. An important DEG, LGMN may regulate the immune cell infiltration of GBM.

Identification and validation of subclusters of papillary thyroid carcinoma based on Human Phenotype Ontology.

Background: The increase in the diagnosis of papillary thyroid carcinoma (PTC) has prompted researchers to establish a diagnostic model and identify functional subclusters. The Human Phenotype Ontology (HPO) platform is widely available for differential diagnostics and phenotype-driven investigations based on next-generation sequence-variation data. However, a systematic and comprehensive study to identify and validate PTC subclusters based on HPO is lacking. Methods: We first used the HPO platform to identify the PTC subclusters. An enrichment analysis was then conducted to examine the key biological processes and pathways associated with the subclusters, and a gene mutation analysis of the subclusters was conducted. For each subcluster, the differentially expressed genes (DEGs) were selected and validated. Finally, a single-cell RNA-sequencing data set was used to verify the DEGs. Results: In our study, 489 PTC patients from The Cancer Genome Atlas (TCGA) were included. Our analysis demonstrated that distinct subclusters of PTC are associated with different survival times and have different functional enrichment, and that C-C motif chemokine ligand 21 (CCL21) and zinc finger CCHC-type containing 12 (ZCCHC12) were the common down- and upregulated genes, respectively, in the 4 subclusters. Additionally, 20 characteristic genes were identified in the 4 subclusters, some of which have previously been reported to have roles in PTC. Further, we found that these characteristic genes were mainly expressed in thyrocytes, endothelial cells, and fibroblasts, and were rarely expressed in immune cells. Conclusions: We first identified subclusters in PTC based on HPO and found that patients with distinct subclusters have different prognoses. We then identified and validated the characteristic genes in the 4 subclusters. These findings are expected to serve as a crucial reference that will improve our understanding of PTC heterogeneity and the use of novel targets.

[Corrigendum] Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, for the scratch wound assay experiments shown in Fig. 1 on p. 2413, the panels showing the '0 h' experiments for the respective incubations with VEGF or BC001 were apparently identical. The authors were able to re­examine their original data files, and realized that this figure had been inadverently assembled incorrectly. The revised version of Fig. 1, containing the correct data for the '0 h / BC001' panel, is shown below. Note that the revisions made to this figure do not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [International Journal of Oncology 45: 2411­2420, 2014; DOI: 10.3892/ijo.2014.2690].

Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: Assessing its role in tumor prognosis and immune response.

Ubiquitin-specific peptidase 10 (USP10) is a member of the ubiquitin-specific protease family that removes the ubiquitin chain from ubiquitin-conjugated protein substrates. We performed a literature search to evaluate the structure and biological activity of USP10, summarize its role in tumorigenesis and tumor progression, and discuss how USP10 may act as a tumor suppressor or a tumor-promoting gene depending on its mechanism of action. Subsequently, we elaborated further on these results through bioinformatics analysis. We demonstrated that abnormal expression of USP10 is related to tumorigenesis in various types of cancer, including liver, lung, ovarian, breast, prostate, and gastric cancers and acute myeloid leukemia. Meanwhile, in certain cancers, increased USP10 expression is associated with tumor suppression. USP10 was downregulated in kidney renal clear cell carcinoma (KIRC) and associated with reduced overall survival in patients with KIRC. In contrast, USP10 upregulation was associated with poor prognosis in head and neck squamous cell carcinoma (HNSC). In addition, we elucidated the novel role of USP10 in the regulation of tumor immunity in KIRC and HNSC through bioinformatics analysis. We identified several signaling pathways to be significantly associated with USP10 expression, such as ferroptosis, PI3K/AKT/mTOR, TGF-ß, and G2/M checkpoint. In summary, this review outlines the role of USP10 in various forms of cancer, discusses the relevance of USP10 inhibitors in anti-tumor therapies, and highlights the potential function of USP10 in regulating the immune responses of tumors.

Associations of DDX60L With the Clinical Features and Prognosis of Hepatocellular Carcinoma.

OBJECTIVE: Although the pathogenesis of hepatocellular carcinoma (HCC) is still unclear, hepatitis C virus (HCV) infection is considered a common cause of HCC. It has been reported that DDX60L can inhibit HCV replication, but its role in HCC is still poorly understood. METHODS: The expression levels of DDX60L in HCC tissues and in tissues adjacent to the tumor and their correlation with the clinicopathological features of patients were analyzed. We also used Kaplan-Meier curves of overall survival (OS) with Cox regression analysis and log-rank test to investigate the prognostic value of DDX60L in HCC. We further performed cell proliferation, Transwell, and wound healing assays to elucidate the role of DDX60L in HCC using the siRNA-DDX60L Hep3B or HCCLM3 cell line. RESULTS: Univariate analysis showed that sex, Edmondson grade, microvascular invasion, tumor stage (III-IV/I-II), AFP, and DDX60L expression were strongly associated with the prognosis of HCC patients. The results of multivariate analysis further suggested that DDX60L might be an independent prognostic factor for OS in patients with HCC (P moderate/low = 0.015, P high/low = 0.011). The low DDX60L expression in HCC patients with no-metastasis, age ≥55 years, tumor size <5 cm, Edmondson grade = I-II, microvascular invasion, no cirrhosis, HBV positivity, tumor stage = III-IV, AFP >20 µg/L, and multiple tumor was associated with poorer prognosis (P <0.05). Moreover, the expression of DDX60L was significantly lower in HCC samples (N = 285) than in the normal tissues adjacent to the tumor (N = 167, P <0.001). There were no HCV-related HCC patients in this study. Additionally, we found that DDX60L knockdown can promote the proliferation of Hep3B cells, migration and invasion ability of Hep3B and HCCLM3 cells. CONCLUSION: We found that the downregulation of DDX60L expression correlated with poor prognosis in patients with HCC, which may be independent of the HCV-related pathway. Furthermore, DDX60L significantly inhibited the proliferation of Hep3B cells, migration and invasion of Hep3B and HCCLM3 cells. Therefore, DDX60L can serve as a prognostic biomarker and therapeutic target for HCC.

Low expression of moonlight gene ALAD is correlated with poor prognosis in hepatocellular carcinoma.

BACKGROUND: Moonlighting genes may involve in the progression of hepatocellular carcinoma (HCC), and the establishment of a prognostic signature based on moonlighting genes may help predict the prognosis of HCC patients. METHODS: This study aimed to construct a prognostic signature based on moonlighting genes in HCC and determine whether there is a correlation with tumor microenvironment or immune responses. Then we used HCC cell lines and an HCC cDNA microarray to illuminate the role of moonlighting gene in prognosis of HCC. RESULTS: We constructed an original prognostic signature based on eight moonlighting genes (ABCB1, S100A9, NCL, PRDX6, ALAD, YBX1, POU2F1, RPL5) with strong prognosis prediction capability. The prognostic signature may demonstrate the immune status of patients with HCC, because high-risk subgroups had significantly higher scores for regulatory T cells, dendritic cells, T follicular helper cells, macrophages, and major histocompatibility complex-I, and different expression levels of immune checkpoint molecules. Importantly, patients in the high-risk subgroup exhibited higher tumor immune dysfunction and exclusion scores, suggesting that they might be less sensitive to immunotherapy. The roles of ABCB1, S100A9, NCL, PRDX6, YBX1, and POU2F1 in HCC have been reported. However, there have been no reports on the association between ALAD and HCC. Then we used bioinformatics to confirm that ALAD expression was lower in HCC and low expression of ALAD was an indicator of poor prognosis. Moreover, we found that ALAD expression was lower in HCC cells than that in normal human hepatocytes or tumor-adjacent tissues, it was negatively correlated with the pathological grade, and low expression of ALAD was related to poor prognosis in patients with HCC. CONCLUSION: We have successfully established a novel prognostic signature based on moonlighting genes, with a strong predictive capability for prognosis, immune status, and possible response to immunotherapy. Additionally, we have identified ALAD as a prognostic biomarker for HCC.

Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response.

JMJD6 is a member of the Jumonji (JMJC) domain family of histone demethylases that contributes to catalyzing the demethylation of H3R2me2 and/or H4R3me2 and regulating the expression of specific genes. JMJD6-mediated demethylation modifications are involved in the regulation of transcription, chromatin structure, epigenetics, and genome integrity. The abnormal expression of JMJD6 is associated with the occurrence and development of a variety of tumors, including breast carcinoma, lung carcinoma, colon carcinoma, glioma, prostate carcinoma, melanoma, liver carcinoma, etc. Besides, JMJD6 regulates the innate immune response and affects many biological functions, as well as may play key roles in the regulation of immune response in tumors. Given the importance of epigenetic function in tumors, targeting JMJD6 gene by modulating the role of immune components in tumorigenesis and its development will contribute to the development of a promising strategy for cancer therapy. In this article, we introduce the structure and biological activities of JMJD6, followed by summarizing its roles in tumorigenesis and tumor development. Importantly, we highlight the potential functions of JMJD6 in the regulation of tumor immune response, as well as the development of JMJD6 targeted small-molecule inhibitors for cancer therapy.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development.

ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.

Theoretical Investigation of Chitosan-Assisted Controlled Release of Digestive System Antitumor Drug Fluorouracil.

5-Fluorouracil (5-FU) has been applied to treat pancreatic cancer, which is one of the most common types of digestive system tumors. However, due to poor tumor selectivity, 5-FU's therapeutic effect has certain limitations. 5-FU's activity and selectivity against tumor cells can be improved by chitosan assisted drug delivery systems. Understanding the atomic interaction mechanism between chitosan and 5-FU is important. In this work, the interactions between 5-FU and different types of chitosan were systematically investigated by using molecular dynamics (MD) simulation. Based on the radial distribution function and the free energy calculation, our results demonstrate that the functional groups of chitosan could greatly regulate the interaction behavior between chitosan and 5-FU. Moreover, 5-FU could gradually release from chitosan at a more acidic pH (tumor tissues) environment. These results revealed the underlying atomic interaction mechanism between 5-FU and chitosan at various pH levels, and may be helpful in the design of chitosan-based drug delivery systems.

Can Immune-related adverse events serve as clinical biomarkers of PD-1/PD-L1 inhibitor efficacy in Pan-Cancer Patients?

Although PD-1/PD-L1 inhibitors are widely used as first-line treatment for patients with advanced tumors or as adjuvant therapy for patients with early-stage tumors, their efficacy is only 15-60%. Increasing evidence has demonstrated that biomarkers such as PD-L1 expression levels, microsatellite instability, and tumor mutation burden may assist in predicting the anti-tumor efficacy of PD-1/PD-L1 inhibitors. However, their clinical application value is limited, and there is currently a dearth of specific clinical markers to monitor or predict the efficacy of PD-1/PD-L1 inhibitors. Recently, studies have exposed that the efficacy of PD-1/PD-L1 inhibitors is positively correlated with immune-related adverse events (irAEs), suggesting that the latter may effectively predict anti-tumor efficacy. While there are controversies, a systematic understanding of the reasons and influencing factors of its correlation is still lacking. Therefore, this review aimed to introduce and discuss the latest research on the correlation between the efficacy of PD-1/PD-L1 inhibitors and irAEs. We identified that this positive correlation might be related to adipose tissue, T cells, pharmacokinetic characteristics, and antigen spread. In addition, the severity of irAEs, the duration of the use of PD-1/PD-L1 inhibitors, the comprehensive evaluation method of the severity of irAEs, and the genetic determinants are potentially the most significant bias factors when evaluating this correlation.

Genome-Wide Identification of m6A-Associated Single-Nucleotide Polymorphisms in Colorectal Cancer.

BACKGROUND: N6-methyladenosine (m6A)-associated single-nucleotide polymorphisms (SNPs) play important roles in cancers, with previous research suggesting potential associations between m6A-SNPs and cancer. However, the relationship between the genetic determinants of m6A modification and colorectal cancer (CRC) remains unclear. METHODS: An integrative method combining raw data and summary statistics of genome-wide association studies with expression quantitative trait loci (eQTL) and differential expression data was applied to screen potential candidate CRC-associated m6A-SNPs. RESULTS: A total of 402 m6A-SNPs were identified as being associated with CRC (p < 0.001), with 98 showing eQTL signals. In particular, three genes were found to harbor CRC-associated m6A-SNPs: rs178184 in NOVA1, rs35782901 in HTR4, and rs60571683 in SLCO1B3. These genes were differentially expressed in at least one publicly available dataset (p < 0.05), with NOVA1 (p = 3.41×10-11) and HTR4 (p = 5.56×10-7) being significantly downregulated in CRC (dataset: GSE89076), and SLCO1B3 was significantly overexpressed (datasets: GSE32323 [p = 3.27×10-5], GSE21510 [p = 1.09×10-6], and GSE89076 [p = 7.63×10-6]). CONCLUSION: This study identified three m6A-SNPs (rs178184, rs35782901, and rs60571683) that may be associated with CRC. However, the lack of analysis of primary CRC samples in order to further elucidate the underlying pathogenesis is a major limitation of this study. Future investigations are needed to validate these CRC-associated m6A-SNPs and explore the m6A-mediated pathogenic mechanism in CRC.

Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway.

Colorectal cancer stem cells (CSCs) have the potential for self-renewal, proliferation, and differentiation. And LGR5 is a stem cell marker gene of colorectal cancer. Curcumin can suppress oncogenicity of many cancer cells, yet the effect and mechanism of curcumin in LGR5(+) colorectal cancer stem cells (CSCs) have not been studied. In this study, we studied the effect of curcumin on LGR5(+) colorectal CSCs using the experiments of tumorsphere formation, cell viability and cell apoptosis. Then autophagy analysis, RNA-Seq, and real-time PCR were used to identify the mechanism responsible for the inhibition of LGR5(+) colorectal CSCs. Our results showed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner, and also promoted apoptosis of LGR5(+) colorectal CSCs. Next, we found curcumin induced autophagy of LGR5(+) colorectal CSCs. When LGR5(+) colorectal CSCs were co-treated with curcumin and the autophagy inhibitor (hydroxychloroquine), curcumin-induced cell proliferation inhibition decreased. In addition, we also found that curcumin inhibited the extracellular matrix (ECM)-receptor interaction pathway via the downregulation of the following genes: GP1BB, COL9A3, COMP, AGRN, ITGB4, LAMA5, COL2A1, ITGB6, ITGA1, and TNC. Further, these genes were transcriptionally regulated by TFAP2A, and the high expression of TFAP2A was associated with poor prognosis in colorectal cancer. In conclusion, curcumin suppressed LGR5(+) colorectal CSCs, potentially by inducing autophagy and repressing the oncogenic TFAP2A-mediated ECM pathway.