Dynamic EMT: a multi-tool for tumor progression.

The process of epithelial-mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety of complementary cancer features, such as tumor cell stemness, tumorigenicity, resistance to therapy and adaptation to changes in the microenvironment. In this review, we summarize recent findings related to these various classical and non-classical functions, and introduce EMT as a true tumorigenic multi-tool, involved in many aspects of cancer. We suggest that therapeutic targeting of the EMT process will-if acknowledging these complexities-be a possibility to concurrently interfere with tumor progression on many levels.

RACGAP1 promotes the progression and poor prognosis of lung adenocarcinoma through its effects on the cell cycle and tumor stemness.

OBJECTION: Investigating the key genes and mechanisms that influence stemness in lung adenocarcinoma. METHODS: First, consistent clustering analysis was performed on lung adenocarcinoma patients using stemness scoring to classify them. Subsequently, WGCNA was utilized to identify key modules and hub genes. Then, machine learning methods were employed to screen and identify the key genes within these modules. Lastly, functional analysis of the key genes was conducted through cell scratch assays, colony formation assays, transwell migration assays, flow cytometry cell cycle analysis, and xenograft tumor models. RESULTS: First, two groups of patients with different stemness scores were obtained, where the high stemness score group exhibited poor prognosis and immunotherapy efficacy. Next, LASSO regression analysis and random forest regression were employed to identify genes (PBK, RACGAP1) associated with high stemness scores. RACGAP1 was significantly upregulated in the high stemness score group of lung adenocarcinoma and closely correlated with clinical pathological features, poor overall survival (OS), recurrence-free survival (RFS), and unfavorable prognosis in lung adenocarcinoma patients. Knockdown of RACGAP1 suppressed the migration, proliferation, and tumor growth of cancer cells. CONCLUSION: RACGAP1 not only indicates poor prognosis and limited immunotherapy benefits but also serves as a potential targeted biomarker influencing tumor stemness.

UTP11 promotes the growth of hepatocellular carcinoma by enhancing the mRNA stability of Oct4.

BACKGROUND: Several publications suggest that UTP11 may be a promising gene engaged for involvement of hepatocellular carcinoma (HCC) pathology. However, there are extremely limited biological, mechanistic and clinical studies of UTP11 in HCC. METHODS: To anayze the UTP11 mRNA expression in HCC and normal clinical samples and further investigate the correlation between UTP11 expression and pathology and clinical prognosis via the Cancer Tissue Gene Atlas (TCGA) database. The protein levels of UTP11 were checked using the Human Protein Atlas (HPA) database. GO-KEGG enrichment was performed from Cancer Cell Line Encyclopedia (CCLE) database and TCGA dataset. The levels of UTP11 were tested with qRT-PCR and western blotting assays. Cell viability, immunofluorescence and flow cytometry assays and animal models were used to explore the potential involvement of UTP11 in regulating HCC growth in vitro and in vivo. The correlation of UTP11 and tumor stemness scores and stemness-associated proteins from TCGA database. The mRNA stability was treated with Actinomycin D, followed by testing the mRNA expression using qRT-PCR assay. RESULTS: UTP11 was highly expressed in HCC samples compared to normal tissues from TCGA database. Similarly, UTP11 protein expression levels were obviously elevated in HCC tissue samples from HPA database. Furthermore, UTP11 levels were correlated with poor prognosis in HCC patient samples in TCGA dataset. In addition, the UTP11 mRNA levels was notably enhanced in different HCC cell lines than in normal liver cells and knocking down UTP11 was obviously reduced the viability and cell death of HCC cells. UTP11 knockdown suppressed the tumor growth of HCC in vivo experiment and extended the mice survival time. GO-KEEG analysis from CCLE and TCGA database suggested that UTP11 might involve in RNA splicing and the stability of mRNA. Further, UTP11 was positively correlated with tumor stemness scores and stemness-associated proteins from TCGA database. Knockdown of UTP11 was reduced the expression of stem cell-related genes and regulated the mRNA stability of Oct4. CONCLUSIONS: UTP11 is potentially a diagnostic molecule and a therapeutic candidate for treatment of HCC.

LINC00853 contributes to tumor stemness of gastric cancer through FOXP3-mediated transcription of PDZK1IP1.

BACKGROUND: The incidence and mortality of gastric cancer (GC) are high worldwide. Tumor stemness is a major contributor to tumorigenesis and development of GC, in which long non-coding RNAs (lncRNAs) are deeply involved. The purpose of this study was to investigate the influences and mechanisms of LINC00853 in the progression and stemness of GC. METHODS: The level of LINC00853 was assessed based on The Cancer Genome Atlas (TCGA) database and GC cell lines by RT-PCR and in situ hybridization. An evaluation of biological functions of LINC00853 including cell proliferation, migration, and tumor stemness was conducted via gain-and loss-of-function experiments. Furthermore, RNA pull-down and RNA immunoprecipitation (RIP) assay were utilized to validate the connection between LINC00853 and the transcription factor Forkhead Box P3 (FOXP3). Nude mouse xenograft model was used to identify the impacts of LINC00853 on tumor development. RESULTS: We identified the up-regulated levels of lncRNA-LINC00853 in GC, and its overexpression correlates with poor prognosis in GC patients. Further study indicated that LINC00853 promoted cell proliferation, migration and cancer stemness while suppressed cell apoptosis. Mechanistically, LINC00853 directly bind to FOXP3 and promoted FOXP3-mediated transcription of PDZK1 interacting protein 1(PDZK1IP1). Alterations of FOXP3 or PDZK1IP1 reversed the LINC00853-induced biological effects on cell proliferation, migration and stemness. Moreover, xenograft tumor assay was used to investigate the function of LINC00853 in vivo. CONCLUSIONS: Taken together, these findings revealed the tumor-promoting activity of LINC00853 in GC, expanding our understanding of lncRNAs regulation on GC pathogenesis.

Hypoxia-induced RBBP7 promotes esophagus cancer progression by inducing CDK4 expression.

Hypoxia-induced epigenetic regulation calls for more effective therapeutic targets for esophageal cancer. We used GEPIA and UALCAN databases to screen survival-related and cancer stage-associated genes. Eca109 and KYSE450 esophageal cancer cell lines were cultured under normoxia, hypoxia, or CoCl-induced hypoxia conditions, which were further transfected with plasmids expressing RB binding protein 7 (RBBP7), hypoxia-inducible factor 1 (HIF1)-α, or RBBP7 shRNA. Colony formation and MTT assays were used to detect cell proliferation. Tumor sphere formation and stemness marker detection were applied to assess cell stemness. RT-PCR and western blot analysis were used to detect the relative mRNA level and protein expression, respectively. Luciferase assay was utilized to detect the direct interaction between HIF1α and RBBP7. Up-regulated RBBP7 was identified as one of the most prominent survival-related genes, which is negatively correlated with the overall survival (OS), disease recurrence-free survival (DFS), and tumor stages. Hypoxia-induced HIF1α up-regulates RBBP7 expression, which promotes esophagus cancer cell viability, proliferation, and stemness with increased cyclin-dependent kinase 4 (CDK4) expression. Luciferase reporter assay verified that HIF1α transcriptionally regulates the expression of RBBP7. We conclude that hypoxia induces high expression of RBBP7 which is at least partially mediated by HIF1α, up-regulates the expression of downstream CDK4, and thereby promotes tumor progression in esophageal cancer cells.

Alteration in stemness causes exclusivity between Epstein-Barr virus-positivity and microsatellite instability status in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a leading cause of cancer morbidity and mortality worldwide. This is due to the heterogeneous features of GC, which consist of a diverse molecular phenotype. Epstein-Barr virus (EBV)-positive GC and microsatellite instability (MSI)-high GC encompass similar epigenetic traits, including high levels of DNA methylation in CpG islands; however, EBV-positive and MSI-high GCs are mutually exclusive. We aimed to elucidate the underlying mechanism of this exclusivity. METHODS: We knocked out MLH1 in EBV-positive GC cell lines SNU-719 and NCC24 via CRISPR-Cas9, and evaluated the modified cellular properties in vitro and in vivo. The MSI status of each cell line was screened with two marker capillary electrophoresis, and further diagnosed with five marker capillary electrophoresis and parallel sequencing using 21 markers. RESULTS: Initial evaluation showed that cell growth, migration, invasion, and MSI status were not affected by MLH1 silencing. However, with prolonged passage, GC cell lines gradually gained MSI and NCC24 cells were transformed to EBV-positive/MSI-high GC cells after 12 months. Furthermore, MLH1 silencing reduced tumor stemness in SNU-719 and NCC24 regardless of the MSI status in vitro and in vivo. CONCLUSIONS: Our findings suggest that EBV-positivity and MSI-high status are mutually exclusive due to the immediate disadvantage in tumor stemness when MLH1 is silenced, whereas the establishment of MSI-high status in EBV-positive GCs required a longer period.

Comprehensive profiling identifies a novel signature with robust predictive value and reveals the potential drug resistance mechanism in glioma.

BACKGROUND: Gliomas are the most common and malignant brain tumors. The standard therapy is surgery combined with radiotherapy, chemotherapy, and/or other comprehensive methods. However, the emergence of chemoresistance is the main obstacle in treatment and its mechanism is still unclear. METHODS: We firstly developed a multi-gene signature by integrated analysis of cancer stem cell and drug resistance related genes. The Chinese Glioma Genome Atlas (CGGA, 325 samples) and The Cancer Genome Atlas (TCGA, 699 samples) datasets were then employed to verify the efficacy of the risk signature and investigate its significance in glioma prognosis. GraphPad Prism, SPSS and R language were used for statistical analysis and graphical work. RESULTS: This signature could distinguish the prognosis of patients, and patients with high risk score exhibited short survival time. The Cox regression and Nomogram model indicated the independent prognostic performance and high prognostic accuracy of the signature for survival. Combined with a well-known chemotherapy impact factor-MGMT promoter methylation status, this risk signature could further subdivide patients with distinct survival. Functional analysis of associated genes revealed signature-related biological process of cell proliferation, immune response and cell stemness. These mechanisms were confirmed in patient samples. CONCLUSIONS: The signature was an independent and powerful prognostic biomarker in glioma, which would improve risk stratification and provide a more accurate assessment of personalized treatment. Additional file 8 Video abstract.

NOTCH3 expression is linked to breast cancer seeding and distant metastasis.

BACKGROUND: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. METHODS: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. RESULTS: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+ and TNBC models. ERα+ breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhigh phenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. CONCLUSIONS: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.

KYNU Expression Promotes Cisplatin Resistance in Esophageal Cancer.

Background: Chemotherapy resistance is a barrier to effective cancer prognoses. Cisplatin (CDDP) resistance is a major challenge for esophageal cancer (EC) therapy. A deeper understanding of the fundamental mechanisms of cisplatin resistance and improved targeting strategies are required in clinical settings. This study was performed to identify and characterize a marker of cisplatin resistance in EC cells. Method: KYSE140 and Eca-109 cells were subjected to escalating concentrations of cisplatin, resulting in the development of cisplatin-resistant KYSE140/CDDP and Eca-109/CDDP cell lines, respectively. RNA Sequencing (RNA-seq) was utilized to screen for the genes exhibiting differential expression between cisplatin-resistant and parental cells. Reverse transcription quantitative PCR was conducted to assess gene expression, and western blotting was employed to analyze protein levels. A sphere-formation assay was performed to validate tumor cell stemness. Cell counting kit-8 (CCK-8) experiments were conducted to confirm the sensitivity of cells to cisplatin. We examined the relationship between target genes and the clinicopathological features of patients with EC. Furthermore, the expression of target genes in EC tissues was evaluated via western blotting and fluorescence probe in situ hybridization (FISH). Results: KYNU was upregulated in cisplatin-resistant EC cells (KYSE140/CDDP and Eca-109/CDDP cells) and in EC tissues compared to that in the respective parental cell lines (KYSE140 and Eca-109 cells) and non-carcinoma tissues. Downregulation of KYNU increased cell sensitivity to cisplatin and suppressed tumor stemness, whereas abnormal KYNU expression had the opposite effect. KYNU expression was correlated with the expression of tumor stemness-associated factors (SOX2, Nanog, and OCT4) and the tumor size. Conclusions: KYNU may promote drug resistance in EC by regulating cancer stemness, and could serve as a biomarker and therapeutic target for EC.

Identification of tumor stemness and immunity related prognostic factors and sensitive drugs in head and neck squamous cell carcinoma.

The presence of cancer stem cells (CSCs) contributes significantly to treatment resistance in various cancers, including head and neck squamous cell carcinoma (HNSCC). Despite this, the relationship between cancer stemness and immunity remains poorly understood. In this study, we aimed to identify potential immunotherapeutic targets and sensitive drugs for CSCs in HNSCC. Using data from public databases, we analyzed expression patterns and prognostic values in HNSCC. The stemness index was calculated using the single-sample gene set enrichment analysis (ssgsea) algorithm, and weighted gene co-expression network analysis (WGCNA) was employed to screen for key stemness-related modules. Consensus clustering was then used to group samples for further analysis, and prognosis-related key genes were identified through regression analysis. Our results showed that tumor samples from HNSCC exhibited higher stemness indices compared to normal samples. WGCNA identified a module highly correlated with stemness, comprising 187 genes, which were significantly enriched in protein digestion and absorption pathways. Furthermore, we identified sensitive drugs targeting prognostic genes associated with tumor stemness. Notably, two genes, HLF and CCL11, were found to be highly associated with both stemness and immunity. In conclusion, our study identifies a stemness-related gene signature and promising drug candidates for CSCs of HNSCC. Additionally, HLF and CCL11, which are associated with both stemness and immunity, represent potential targets for immunotherapy in HNSCC.

Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

QPH-FR: A Novel Quinoa Peptide Enhances Chemosensitivity by Targeting Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 in Colorectal Cancer.

Chemoresistance is one of the difficulties in the treatment of colorectal cancer (CRC), and the enhanced stemness of tumor cells is the underlying contributing factor. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a classical marker of CRC stem cells and can be an important potential target for CRC chemotherapy. Quinoa, a protein-rich plant, offers potential as a source of high-quality active peptides. Novelly, the study obtained quinoa protein hydrolysate (QPH) from whole quinoa grains by simulated digestion. In vivo experiments revealed that the tumor volume in the 5-FU+QPH group decreased from 145.90 ± 13.35 to 94.49 ± 13.05 mm3 in the 5-FU group, suggesting that QPH enhances the chemosensitivity of CRC. Further, the most effective peptide QPH-FR from 631 peptides in QPH was screened by activity prediction, molecular docking, and experimental validation. Mechanistically, QPH-FR competitively suppressed the formation of the LGR5/RSPO1 complex by binding to LGR5, causing RNF43/ZNRF3 to ubiquitinate the FZD receptor, thereby suppressing the Wnt/ß-catenin signaling pathway and exerting stemness inhibition. In summary, the study proposes that a novel peptide QPH-FR from quinoa elucidates the mechanism by which QPH-FR targets LGR5 to enhance chemosensitivity, providing theoretical support for the development of chemotherapeutic adjuvant drugs based on plant peptides.

Receptor-interacting protein kinase 2 is associated with tumor immune infiltration, immunotherapy-related biomarkers, and affects gastric cancer cells growth in vivo.

Background: The objective of this study was to analyze the research trend of four RIPK genes (RIPK1, RIPK2, RIPK3, and RIPK4), their expression variations in tumors, and the correlation between RIPK2 expression and immune-related biomarkers in gastric cancer (GC). Methods: The PubMed database was utilized to investigate the research trend surrounding four RIPKs genes in tumors. The ULCAN database was employed to analyze the differential expression of these four RIPKs genes. TCGA data were utilized to examine the association between RIPK2 expression and various factors including tumor immune infiltration and immune-related biomarkers. Lastly, the impact of targeting RIPK2 on the growth of GC cells was confirmed through tumor formation assay, immunohistochemistry, and Tunnel assays. Results: In the field of tumor biology, there has been a sustained increase in research focused on the four RIPKs genes over the past decade. Four RIPKs genes are differentially expressed in a majority of tumors. Furthermore, this investigation has unveiled a connection between the expression of RIPK2 and the infiltration of four immune cells, as well as the presence of RNA methylation modifying enzymes, specifically m1A, m6A, and m5C, in GC. Additionally, RIPK2 expression was associated with the genes related to immune checkpoint regulation, as well as genes associated with immunoinhibitors and immunostimulators. It was also revealed that RIPK2 expression was correlated to immunotherapy response biomarkers, namely MSI and TMB, and tumor stemness. Ultimately, it was demonstrated that targeting the RIPK2 effectively regulated GC cells growth through the suppression of PCNA expression and the induction of apoptosis. Conclusion: The expression of RIPK2 is correlated with immune cell infiltration, RNA methyltransferase activity, tumor stemness, checkpoint-related genes, and immunotherapy-related biomarkers. Suppression of RIPK2 impedes the growth of GC cells in vivo. Consequently, RIPK2 holds promise as a viable immunotherapy target for various types of cancer.

Knockdown of YTHDF2 initiates ERS-induced apoptosis and cancer stemness suppression by sustaining GLI2 stability in cervical cancer.

Cervical cancer ranks fourth in women in terms of incidence and mortality. The RNA-binding protein YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) contributes to cancer progression by incompletely understood mechanisms. We show how YTHDF2 controls the fate of cervical cancer cells and whether YTHDF2 could be a valid target for the therapy of cervical cancer. Sphere formation and alkaline phosphatase staining assays were performed to evaluate tumor stemness of cervical cancer cells following YTHDF2 knockdown. Apoptosis was detected by flow cytometry and TUNEL assay. The compounds 4PBA and SP600125 were used to investigate the correlation between JNK, endoplasmic reticulum stress, tumor stemness, and apoptosis. Data from The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) revealed that GLI family zinc finger 2 (GLI2) might be the target of YTHDF2. The transcription inhibitor actinomycin D and dual-luciferase reporter gene assays were employed to investigate the association between the GLI2 mRNA and YTHDF2. Nude mouse xenografts were generated to assess the effects of YTHDF2 knockdown on cervical cancer growth in vivo. Knockdown of YTHDF2 up-regulated the expression of GLI2, leading to JNK phosphorylation and endoplasmic reticulum stress. These processes inhibited the proliferation of cervical cancer cells and their tumor cell stemness and promotion of apoptosis. In conclusion, the knockdown of YTHDF2 significantly affects the progression of cervical cancer cells, making it a potential target for treating cervical cancer.

Correlation between S100A7 and immune characteristics, methylation, tumor stemness and tumor heterogeneity in pan-cancer and its role in chemotherapy resistance in breast cancer.

OBJECTIVE: To explore the relationships between S100A7 and the immune characteristics, tumor heterogeneity, and tumor stemness pan-cancer as well as the effect of S100A7 on chemotherapy sensitivity in breast cancer. METHODS: TCGA-BRCA and TCGA-PANCANCER RNA-seq data and clinical follow-up survival data were collected from the University of California Santa Cruz database. Survival analyses were performed to explore the relationship between S100A7 expression and pan-cancer prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and Gene Set Enrichment Analysis (GSEA) were used to identify the potential pathways related to the differentially expressed genes in breast cancer. Spearman's and Wilcoxon's tests were used to investigate the relationships between S100A7 expression and immune characteristics, methylation, tumor heterogeneity, and tumor stemness. The potential functions of S100A7 and its influence on chemotherapy sensitivity in breast cancer were elucidated using reverse transcription-quantitative PCR, Cell Counting Kit-8 (CCK-8) assay, Transwell assay, and wound healing assay. RESULTS: S100A7 was highly expressed in most types of tumors and was associated with poor prognosis. S100A7 was closely associated with immunomodulators, immune checkpoint and immune cell infiltration. Further, S100A7 was related to tumor mutational burden, tumor heterogeneity, methylation and tumor stemness in breast cancer. High S100A7 expression was associated with the invasiveness, migration, proliferation and chemotherapy resistance of breast cancer cells in vitro experiments. CONCLUSION: High S100A7 expression was related with poor prognosis and chemotherapy resistance in breast cancer, making it a potential immune and chemotherapy resistance biomarker.

Tumor Cell Stemness and Stromal Cell Features Contribute to Oral Cancer Outcome Disparity in Black Americans.

Black Americans (BAs) with head and neck cancer (HNC) have worse survival outcomes compared to the White patients. While HNC disparities in patient outcomes for BAs have been well recognized, the specific drivers of the inferior outcomes remain poorly understood. Here, we investigated the biologic features of patient tumor specimens obtained during the surgical treatment of oral cancers and performed a follow-up study of the patients' post-surgery recurrences and metastases with the aim to explore whether tumor biologic features could be associated with the poorer outcomes among BA patients compared with White American (WA) patients. We examined the tumor stemness traits and stromal properties as well as the post-surgery recurrence and metastasis of oral cancers among BA and WA patients. It was found that high levels of tumor self-renewal, invasion, tumorigenesis, metastasis, and tumor-promoting stromal characteristics were linked to post-surgery recurrence and metastasis. There were more BA than WA patients demonstrating high stemness traits and strong tumor-promoting stromal features in association with post-surgery tumor recurrences and metastases, although the investigated cases displayed clinically comparable TNM stages and histological grades. These findings demonstrated that the differences in tumor stemness and stromal property among cancers with comparable clinical diagnoses contribute to the outcome disparity in HNCs. More research is needed to understand the genetic and molecular basis of the biologic characteristics underlying the inferior outcomes among BA patients, so that targeting strategies can be developed to reduce HNC disparity.

Integrative Analysis Reveals Differential Characteristics of DDR1 Mutant and Wild-type Gastric Cancers and Constructs their Prediction Models.

INTRODUCTION: The molecular typing of gastric cancer by TCGA is significant for the precision treatment of gastric cancer. However, the molecular typing of gastric cancer by TCGA lacks the typing of the rare gene DDR1. Therefore, this study aimed to integrate the analysis to reveal the differential features of DDR1 mutant and wild-type gastric cancers and construct their prediction models. METHODS: RNAseq data from 375 gastric cancer patients were downloaded from the TCGA database to comprehensively compare the differences between mutant DDR1 and wild-type DDR1 gastric cancers and construct a prognostic model for wild-type DDR1 gastric cancer. RESULTS: First, the mutation rate of DDR1 in gastric cancer was 3.23%. Second, the upregulated genes of mutant DDR1 gastric cancer were different from those of wild-type DDR1 gastric cancer in terms of KEGG and GO enrichment. Next, both mutant DDR1 gastric cancers and wild-type DDR1 gastric cancers were associated with EPIC scores and tumour stemness in macrophages. In addition, mutant DDR1 gastric cancers were associated with the iron death-related genes RPL8, CS, and FANCD2 and the m6A-related gene RBM15, compared with wild-type DDR1 gastric cancers. Finally, the established LASSO regression model confirmed that the survival rate of the high-risk group of wild-- type DDR1 gastric cancer would be lower than that of the low-risk group. CONCLUSION: This study may provide a new molecular typing method for gastric cancer by comparing the differences between mutant DDR1 and wild-type DDR1 gastric cancer.

Interplay of RNA m6A Modification-Related Geneset in Pan-Cancer.

Background: N6-methyladenosine (m6A), is the most common modification found in mRNA and lncRNA in higher organisms and plays an important role in physiology and pathology. However, its role in pan-cancer has not been explored. Results: A total of 31 m6A modification regulators, including 12 writers, 2 erasers, and 17 readers are identified in the current study. The functional analysis of the regulators results in the enrichment of processes, primarily related to RNA modification and metabolism, and the PPI network reveals multiple interactions among the regulators. The mRNA expression analysis reveals a high expression for most of the regulators in pan-cancer. Most of the m6A regulators are found to be mutated across the cancers, with ZC3H13, VIRMA, and PRRC2A having a higher frequency rate. Significant correlations of the regulators with clinicopathological parameters, such as age, gender, tumor stage, and grade are identified in pan-cancer. The m6A regulators' expression is found to have significant positive correlations with the miRNAs in pan-cancer. The expression pattern of the m6A regulators is able to classify the tumors into different subclusters as well as into high- and low-risk groups. These tumor groups show differential patterns in terms of their immune cell infiltration, tumor stemness score, genomic heterogeneity score, expression of immune regulatory/checkpoint genes, and correlations between the regulators and the drugs. Conclusions: Our study provide a comprehensive overview of the functional roles, genetic and epigenetic alterations, and prognostic value of the RNA m6A regulators in pan-cancer.

Role of adhesion molecules in cancer and targeted therapy.

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.

Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.