Hao Gu

Background: Portal vein tumor thrombus is a lethal complication of HCC for which effective biomarkers are urgently needed. Methods: Through proteomic profiling, functional and mechanistic assays, and machine learning-based evaluation of serum NSUN6 in 472 HCC patients with external validation ( n = 98), we characterized an epitranscriptomic regulator of HCC metastasis. Results: NSUN6 was downregulated in PVTT and suppressed metastasis by catalyzing m⁵C modification of SAV1 mRNA, stabilizing its transcript and activating Hippo signaling. Furthermore, NSUN6 was released from HCC cells via extracellular vesicle-associated and non-canonical pathways. Circulating NSUN6 levels were inversely associated with metastasis in both discovery and validation cohorts, and lower levels predicted shorter metastasis-free survival. Conclusion: Our findings establish the NSUN6–SAV1–YAP axis as a key epitranscriptomic tumor-suppressive mechanism and support circulating NSUN6 as a potential biomarker for early risk stratification in HCC.

Craniomaxillofacial bone marrow mesenchymal stromal cells (BMSCs) retaining neural crest–derived neurogenic niche is driven by lineage memory and niche homeostasis. Elucidating how the neurogenic potential is maintained is critical for neurological health. Here, we explored a neural crest-like progenitor niche in BMSCs with high neurogenic and proliferative capacity by single-cell transcriptomics. In which, ANKRD1 is a pivotal regulator sustaining the neurogenic reservoir. Importantly, ANKRD1 expression in this niche declines with aging and lineage commitment, coinciding with its redistribution from a diffuse nucleoplasmic pattern to perinuclear enrichment along the nuclear lamina and loss of neural potential. Mechanistically, ANKRD1 preserves neurogenic capacity by directly binding super-enhancers of neural marker genes (SOX2, NESTIN) and maintaining open chromatin architecture. Critically, neuron-targeted ANKRD1 delivery rescues spatial memory deficits in aged mice. These findings establish ANKRD1 as a therapeutically tractable regulator that sustains neurogenic chromatin reservoirs to support neurocognitive resilience, opening avenues to counter cognitive aging.

Objective: Colorectal cancer (CRC) is the third most prevalent malignant tumor type and the second leading cause of cancer-related death. Sequence similarity family 50 member A (FAM50A) plays a vital role in numerous disease processes, including tumor progression. This study aimed to evaluate the prognostic significance of FAM50A in CRC and to explore its role in CRC cell proliferation. Methods: TCGA and GTEX databases and immunohistochemical staining (IHC) was used to study the expression of FAM50A in CRC tissues. Patient survival data were used to assess the prognostic significance of FAM50A in CRC using Kaplan–Meier analysis and Cox regression analysis. The Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and colony-formation assays were employed to assess the impact of FAM50A on tumor cell proliferation. Flow cytometry was used to detect the changes of cell cycle. The cell cycle and cycle-related proteins were measured via western blotting (WB) to explore the potential mechanisms involving in cancer progresses. Results: The results of IHC revealed a notable upregulation of FAM50A expression levels in CRC tissue compared with adjacent normal tissue. Moreover, FAM50A expression was positively correlated with N and TNM stages in 145 patients with CRC. Cox regression analysis and construction of a nomogram revealed that high FAM50A expression was a prognostic indicator for poor overall survival in patients with CRC. Knockdown of FAM50A decreased cell proliferation ability, the proportion of EdU positive cells, and the number of CRC cell colonies, whereas overexpressing FAM50A promoted proliferative phenotypes. Knocking down FAM50A induced a significant increase in the number of cells in the S phase. Meanwhile, CyclinA2 and CDK2 were significantly reduced after FAM50A knocking down. Conclusion: FAM50A may be a novel prognostic marker for CRC, and may participate in regulating tumor progression by targeting the CyclinA2/CDK2 signal pathway.

The underlying mechanisms between cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) remain unclear. In this study, we identified TGIF2 as a target gene of CSC using sncRNA and machine learning. TGIF2 is closely related to the expression of SOX2, EGFR, and E-cadherin, indicating poor prognosis. Mechanistically, TGIF2 promoted the EMT phenotype and CSC properties following the activation of SOX2, Slug, CD44, and ERGF/MAPK signaling, which were rescued by SOX2 silencing. TGIF2 silencing contributes to the opposite phenotype via SOX2. Notably, Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter, which in turn promotes EMT and CSC signaling by transactivating Slug and EGFR, respectively. The transactivation of EGFR/MAPK signaling by SOX2 promotes TGIF2 nuclear translocation, forming a positive feedback loop in vitro. Moreover, the interaction of TGIF2 and SOX2 with EGFR inhibitors promoted subcutaneous tumors and liver metastasis in vivo. Thus, the TGIF2/SOX2 axis contributes to CSC, EMT, and chemoresistance, providing a promising target for PC therapy.

Recent discoveries in hepatocellular carcinoma (HCC) unveil key molecules. However, due to liver cancer's high heterogeneity, predicting patient prognosis is challenging. This study aims to construct a model for predicting HCC prognosis using multiple key genes. TCGA provided RNA expression and clinical data, differentially analyzed by DESeq2, edgeR, and Limma. The hub gene was pinpointed via CytoHubba's degree algorithm in Cytoscape. GO and KEGG analyses illuminated potential pathways. Single-cell sequencing detailed key gene expression in diverse cell types. The LASSO regression model predicted patient prognosis. In the RNA-seq analysis using three R packages, we identified 762 differentially expressed genes, with Cytoscape revealing ten key genes showing significant prognostic value (P < 0.05). GO and KEGG analyses highlighted key biological processes and pathways. IHC confirmed higher expression in cancer tissues. Reduced immune cell infiltration was observed in HCC tissues, and immune checkpoint analysis showed a strong correlation between PD1, CTLA4, and hub genes. Single-cell sequencing indicated higher expression of key genes in immune cells than hepatocytes. Cox analysis validated the riskScore as a reliable, independent prognostic marker (HR = 4.498, 95% CI: 2.526-8.007). The results from differential analysis using three R packages are robust, revealing genes closely linked to immune cell infiltration in the tumor microenvironment. Additionally, a validated prognostic model for liver cancer was established based on key genes.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with increasing global prevalence and is one of the leading causes of cancer-related mortality in the human population. Developing robust clinical prediction models and prognostic stratification strategies is crucial for developing individualized treatment plans. A range of novel forms of programmed cell death (PCD) plays a role in the pathological progression and advancement of HCC, and in-depth study of PCD is expected to further improve the prognosis of HCC patients. Sixteen patterns (apoptosis, autophagy, anoikis, lysosome-dependent cell death, immunogenic cell death, necroptosis, ferroptosis, netosis, pyroptosis, disulfidptosis, entotic cell death, cuproptosis, parthanatos, netotic cell death, alkaliptosis, and oxeiptosis) related to PCD were collected from the literatures and used for subsequent analysis. Supervised (Elastic net, Random Forest, XgBoost, and Boruta) and unsupervised (Nonnegative Matrix Factorization, NMF) clustering algorithms were applied to develop and validate a novel classifier for the individualized management of HCC patients at the transcriptomic, proteomic and single-cell levels. Multiple machine learning algorithms developed a programmed cell death index (PCDI) comprising five robust signatures (FTL, G6PD, SLC2A1, HTRA2, and DLAT) in four independent HCC cohorts, and a higher PCDI was predictive of higher pathological grades and worse prognoses. Furthermore, a higher PCDI was found to be correlated with the presence of a repressive tumor immune microenvironment (TME), as determined through an integrated examination of bulk and single-cell transcriptome data. In addition, patients with TP53 mutation had higher PCDI in comparison with TP53 WT patients. Three HCC subtypes were identified through unsupervised clustering (NMF), exhibiting distinct prognoses and significant biological processes, among the three subtypes, PCDcluster 3 was of particular interest as it contained a large proportion of patients with high risk and low metabolic activity. Construction and evaluation of the Nomogram model was drawn based on the multivariate logistic regression analysis, and highlighted the robustness of the Nomogram model in other independent HCC cohorts. Finally, to explore the prognostic value, we also validated the frequent upregulation of DLAT in a real-world cohort of human HCC specimens by qPCR, western blot, and immunohistochemical staining (IHC). Together, our work herein comprehensively emphasized PCD-related patterns and key regulators, such as DLAT, contributed to the evolution and prognosis of tumor foci in HCC patients, and strengthened our understanding of PCD characteristics and promoted more effective risk stratification strategies.

Objective: Colorectal cancer (CRC) is the third most prevalent malignant tumor type and the second leading cause of cancer-related death. Sequence similarity family 50 member A (FAM50A) plays a vital role in numerous disease processes, including tumor progression. This study aimed to evaluate the prognostic significance of FAM50A in CRC and to explore its role in CRC cell proliferation. Methods: The Cancer Genome Atlas (TCGA) database was used to assess the mRNA expression levels of FAM50A in CRC. Immunohistochemical staining was used to study the expression of FAM50A in CRC tissues. Patient survival data were used to assess the prognostic significance of FAM50A in CRC using Kaplan–Meier analysis and Cox regression analysis. The Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, and colony-formation assays were employed to assess the impact of FAM50A knockdown on tumor cell proliferation. Co-expression and correlation heatmaps were used to identify genes whose expression levels were highly correlated with FAM50A, and to further investigate the possible mechanism of action of FAM50A in CRC cell proliferation. Results: Analysis of data from TCGA database revealed a notable upregulation of FAM50A expression levels in CRC tissue compared with adjacent normal tissue. Moreover, FAM50A expression was positively correlated with N, M, and TNM stages in 145 patients with CRC. Cox regression analysis and construction of a nomogram revealed that high FAM50A expression was a prognostic indicator for poor overall survival in patients with CRC. Knockdown of FAM50A decreased cell proliferation ability, the proportion of EdU positive cells, and the number of CRC cell colonies, whereas overexpressing FAM50A promoted proliferative phenotypes. The expression levels of three genes in CRC were significantly negatively correlated, while the expression levels of 18 genes were significantly positively correlated, with the expression level of FAM50A. Conclusion: FAM50A may be a novel prognostic marker for CRC, and may participate in regulating tumor progression by interacting with some highly correlated molecules that drive CRC cell proliferation.

Proto-oncogenic MYC is frequently dysregulated in colorectal cancer (CRC). In the past decades, long noncoding RNAs (lncRNAs) have emerged as important regulators in cancers, acting as scaffolds, molecular decoys, post-transcriptional regulators, and others. Interestingly, lncRNAs are able to control MYC expression both at transcriptional and post-transcriptional levels. It is suggested that the reciprocal interaction of MYC and lncRNAs often occurs in CRC. MYC can affect the cell fate by promoting or inhibiting the transcription of some lncRNAs. At the same time, some lncRNAs can also affect MYC expression or transcriptional activity, and in turn decide the cell fate. In this review we summarized the current knowledge about the MYC and lncRNA axis, focusing on its mutual regulation, roles in CRC, and proposed potential therapeutic prospects for CRC treatment.

Tongue squamous cell carcinoma (TSCC) exhibits an aggressive biological behavior of lymph node and distant metastasis, which contributes to poorer prognosis and results in tongue function loss or death. In addition to known regulators and pathways of cell migration in TSCC, it is important to uncover pivotal switches governing tumor metastasis. Cancer cell migration-associated transcriptional and epigenetic characteristics were profiled in TSCC, and the specific super-enhancers (SEs) were identified. Molecular function and mechanism studies were used to investigate the pivotal switches in TSCC metastasis. Ameboidal-type cell migration-related genes accompanied by transcriptional and epigenetic activity were enriched in TSCC. Meanwhile, the higher-ranked SE-related genes showed significant differences between 43 paired tumor and normal samples from the TCGA TSCC cohort. In addition, key motifs were detected in SE regions, and transcription factor-related expression levels were significantly associated with TSCC survival status. Notably, BATF and ATF3 regulated the expression of ameboidal-type cell migration-related MMP14 by switching the interaction with the SE region. SEs and related key motifs transcriptional regulate tumor metastasis-associated MMP14 and might be potential therapeutic targets for TSCC.