Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy

Luo, Xun-Jiang; Ji, Xiaoyu; Xie, Meng; Zhang, Tongyue; Wang, Yijun; Sun, Mengyu; Huang, Wenjie; Xia, Limin

doi:10.3390/cancers14051165

Cited by 9 publications

(6 citation statements)

References 177 publications

(280 reference statements)

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“…Moreover, disrupting the binding ability of those TFs would aid with viral eradication for patients ( Turton et al, 2020 ). A recent study summarized the oncogenic features of the sex determining region Y-related high-mobility group box (SOX) TFs in HCC and found their close associations with numerous immune cells and immune-related molecules in HCC ( Luo et al, 2022 ). Also, another TF of pyruvate kinase M2 isoform (PKM2) was reported to induce monocyte-to-macrophage differentiation, leading to tumor microenvironment remodeling and HCC progression ( Hou et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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Background: Hepatocellular carcinoma (HCC) is one of the most common aggressive malignancies with increasing incidence worldwide. The oncogenic roles of transcription factors (TFs) were increasingly recognized in various cancers. This study aimed to develop a predicting signature based on TFs for the prognosis and treatment of HCC.Methods: Differentially expressed TFs were screened from data in the TCGA-LIHC and ICGC-LIRI-JP cohorts. Univariate and multivariate Cox regression analyses were applied to establish a TF-based prognostic signature. The receiver operating characteristic (ROC) curve was used to assess the predictive efficacy of the signature. Subsequently, correlations of the risk model with clinical features and treatment response in HCC were also analyzed. The TF target genes underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, followed by protein-protein-interaction (PPI) analysis.Results: A total of 25 differentially expressed TFs were screened, 16 of which were related to the prognosis of HCC in the TCGA-LIHC cohort. A 2-TF risk signature, comprising high mobility group AT-hook protein 1 (HMGA1) and MAF BZIP transcription factor G (MAFG), was constructed and validated to negatively related to the overall survival (OS) of HCC. The ROC curve showed good predictive efficiencies of the risk score regarding 1-year, 2-year and 3-year OS (mostly AUC >0.60). Additionally, the risk score independently predicted OS for HCC patients both in the training cohort of TCGA-LIHC dataset (HR = 2.498, p = 0.007) and in the testing cohort of ICGC-LIRI-JP dataset (HR = 5.411, p < 0.001). The risk score was also positively correlated to progressive characteristics regarding tumor grade, TNM stage and tumor invasion. Patients with a high-risk score were more resistant to transarterial chemoembolization (TACE) treatment and agents of lapatinib and erlotinib, but sensitive to chemotherapeutics. Further enrichment and PPI analyses demonstrated that the 2-TF signature distinguished tumors into 2 clusters with proliferative and metabolic features, with the hub genes belonging to the former cluster.Conclusion: Our study identified a 2-TF prognostic signature that indicated tumor heterogeneity with different clinical features and treatment preference, which help optimal therapeutic strategy and improved survival for HCC patients.

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Section: Introductionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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“…This hypothesis is reinforced by the major changes occurring in the niche surrounding hepatocytes and cholangiocytes, as evidenced by the abnormal zonation, the loss of cellular identity and the aberrant remodelling of the biliary tree, all of which are difficult to associate with a healthy regenerative process. Interestingly, expression of SOX4 , KLF6 and KRT23 has been associated not only with liver steatosis 58 , 59 and biliary remodelling 60 , 61 , but also with hepatocellular carcinoma 62 , 63 . Finally, our data indicate a role for the PI3K–AKT–mTOR pathway in regulating cholangiocyte-to-hepatocyte transdifferentiation.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of epithelial plasticity in human chronic liver disease

Gribben,

Galanakis,

Calderwood

et al. 2024

Nature

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For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1–4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K–AKT–mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.

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“…Metabolic disorders such as tyrosine and aspartate have been found in HCC patients and contribute to malignant progression 32 , 33 . FoxOs are master regulators that determine tumor growth, metastasis, and other characteristics and play important roles in the proliferation, invasion, and metastasis of HCC cells 34 , 35 . FoxO-Smad complexes can block G1/S transition by regulating the activity of cyclin D and CDK axis 36 .…”

Section: Discussionmentioning

confidence: 99%

CD69 serves as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma

Tang

et al. 2023

Sci Rep

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The prevalence and mortality of hepatocellular carcinoma (HCC) are still increasing. This study aimed to identify potential therapeutic targets related to patient prognosis. Data were downloaded from TCGA, GSE25097, GSE36376, and GSE76427 datasets. Differential analysis and enrichment analysis were performed in HCC. Cell deaths were evaluated, and least absolute shrinkage and selection operator regression (LASSO) regression was analyzed to screen candidate genes. Additionally, immune cell infiltration in HCC was assessed. We identified 4088 common DEGs with the same direction of differential expression in all four datasets, they were mainly enriched in immunoinflammation and cell cycle pathways. Apoptosis was significantly suppressed in HCC in GSEA and GSVA. After LASSO regression analysis, we screened CD69, CDC25B, MGMT, TOP2A, and TXNIP as candidate genes. Among them, CD69 significantly influenced the overall survival of HCC patients in both TCGA and GSE76427. CD69 may be a protective factor for outcome of HCC patients. In addition, CD69 was positive correlation with T cells and CD3E. CD69, CDC25B, MGMT, TOP2A, and TXNIP were potential diagnostic and prognostic target for HCC, especially CD69.

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Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy

Cited by 9 publications

References 177 publications

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Acquisition of epithelial plasticity in human chronic liver disease

CD69 serves as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma

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