Mechanism of cancer stemness maintenance in human liver cancer

Liang, Ning; Yang, Tao; Huang, Qian; Yu, Pengfei; Liu, Chaoxu; Chen, Liusheng; Wang, Qian; Wang, Gang; He, Xianli

doi:10.1038/s41419-022-04848-z

Cited by 27 publications

(19 citation statements)

References 106 publications

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“…Recent studies have confirmed the effect of tumor stemness on immune cells in tumor microenvironment, namely, tumor-associated macrophages (TAMs), myeloid-derived suppressor cell (MDSC), and CD8 + T cells. In turn, these immune cells also play an important role in maintaining tumor stemness, creating a malignant environment [ 8 ]. However, there are few studies on tumor stemness in HCC, especially the relationship between tumor stemness and immune microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Zhang

Xie

Huo

et al. 2022

BioMed Research International

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, which is associated with a variety of risk factors. Cancer stem cells are self-renewal cells, which can promote the occurrence and metastasis of tumors and enhance the drug resistance of tumor treatment. This study aimed to develop a stemness score model to assess the prognosis of hepatocellular carcinoma (HCC) patients for the optimization of treatment. The single-cell sequencing data GSE149614 was downloaded from the GEO database. Then, we compared the gene expression of hepatic stem cells and other hepatocytes in tumor samples to screen differentially expressed genes related to stemness. R package “clusterProfiler” was used to explore the potential function of stemness-related genes. We then constructed a prognostic model using LASSO regression analysis based on the TCGA and GSE14520 cohorts. The associations of stemness score with clinical features, drug sensitivity, gene mutation, and tumor immune microenvironment were further explored. R package “rms” was used to construct the nomogram model. A total of 18 stemness-related genes were enrolled to construct the prognosis model. Kaplan-Meier analysis proved the good performance of the stemness score model at predicting overall survival (OS) of HCC patients. The stemness score was closely associated with clinical features, drug sensitivity, and tumor immune microenvironment of HCC. The infiltration level of CD8+ T cells was lower, and tumor-associated macrophages were higher in patients with high-stemness score, indicating an immunosuppressive microenvironment. Our study established an 18 stemness-related gene model that reliably predicts OS in HCC. The findings may help clarify the biological characteristics and progression of HCC and help the future diagnosis and therapy of HCC.

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Section: Introductionmentioning

confidence: 99%

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Zhang

Xie

Huo

et al. 2022

BioMed Research International

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“…CSCs are considered to be responsible for cancer initiation and progression 4 . Thus, we explored the effect of RAB6A KD on the stem cell properties of CCA cells.…”

Section: Resultsmentioning

confidence: 99%

“…CSCs are considered to be responsible for cancer initiation and progression. 4 Thus, we explored the effect of RAB6A KD on the stem were observed in tumor cells in the shRAB6A group. Collectively, these data suggest that RAB6A KD inhibits tumor growth in vivo.…”

Section: Rab6a Kd Inhibits Stem Cell Properties and Epithelial−mesenc...mentioning

confidence: 99%

“…The identification of the CCA stem‐like subset is still largely unaddressed, and studies have been limited to classical antigenic approaches. Similar to normal stem cells, CSCs are believed to reside in a specialized microenvironment (the CSC niche) within the tumor environment that supports their self‐renewal and drug resistance 1,4 . The discovery of new molecular targets related to CSCs has become a research hot spot to overcome the difficulties in the treatment of CCA.…”

Section: Introductionmentioning

confidence: 99%

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RAB6A functions as a critical modulator of the stem‐like subsets in cholangiocarcinoma

Yang

Zhu

Zheng

et al. 2023

Molecular Carcinogenesis

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RAB6A is a member of RAB GTPase family and plays an important role in the targeted transport of neurotrophic receptors and inflammatory cytokines. RAB6A‐mediated secretory pathway is involved in many physiological and pathological processes. Defects in RAB6A‐mediated secretory pathway may lead to the development of many diseases, including cancer. However, its role in cholangiocarcinoma (CCA) has not yet been revealed. We explored the regulatory role of RAB6A in the stem‐like subsets of CCA. We showed that RAB6A knockdown (KD) impedes cancer stem cells (CSCs) properties and epithelial−mesenchymal transition in vitro and that suppression of RAB6A inhibits tumor growth in vivo. We screened target cargos of RAB6A in CCA cells and identified a extracellular matrix component as the target cargo. RAB6A binds directly to OPN, and RAB6A KD suppressed OPN secretion and inhibited the interaction between OPN and αV integrin receptor. Moreover, RAB6A KD inhibited the AKT signaling pathway, which is a downstream effector of the integrin receptor signaling. In addition, shRNA targeting OPN blocked endogenous expression of OPN and consequently weakened CSCs properties in RAB6A‐formed spheres. Similarly, inhibitor of AKT signaling, MK2206 also impedes oncogenic function of RAB6A in the stem‐like subsets of CCA cells. In conclusion, our findings showed that RAB6A sustains CSCs phenotype maintenance by modulating the secretion of OPN and consequentially activating the downstream AKT signaling pathway. Targeting the RAB6A/OPN axis may be an effective strategy for CCA therapy.

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“…Original Article Identification of immune-related genes and patient selection for hepatocellular carcinoma immunotherapy However, alternative treatment methods for patients with unresectable middle and advanced HCC are limited, and new treatment strategies are urgently needed (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Identification of immune-related genes and patient selection for hepatocellular carcinoma immunotherapy

Chen¹,

Luo²,

Ye³

et al. 2023

Transl Cancer Res

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Background: Hepatocellular carcinoma (HCC) is a malignant disease with a poor prognosis. Among the treatment strategies for HCC, tumor immunotherapy (TIT) is a promising research hotspot, in which identifying novel immune-related biomarkers and selecting suitable patient population are urgent issues to be solved.Methods: In this study, an abnormal expression map of HCC cell genes was constructed using public high-throughput data from 7,384 samples (3,941 HCC vs. 3,. Through singlecell RNA sequencing (scRNA-seq) cell trajectory analysis, the genes defined as potential drivers of HCC cell differentiation and development were selected. By screening for both immune-related genes and those associated with high differentiation potential in HCC cell development, a series of target genes were identified. Coexpression analysis was performed using Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) to find the specific candidate genes involved in similar biological processes.Subsequently, nonnegative matrix factorization (NMF) was conducted to select patients suitable for HCC immunotherapy based on the coexpression network of candidate genes.Results: HSP90AA1, CDK4, HSPA8, HSPH1, and HSPA5 were identified as promising biomarkers for prognosis prediction and immunotherapy of HCC. Through the use of our molecular classification system, which was based on a function module containing 5 candidate genes, patients with specific characteristics were found to be suitable candidates for TIT.Conclusions: These findings provide new insights into the selection of candidate biomarkers and patient populations for future HCC immunotherapy.

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Mechanism of cancer stemness maintenance in human liver cancer

Cited by 27 publications

References 106 publications

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

RAB6A functions as a critical modulator of the stem‐like subsets in cholangiocarcinoma

Identification of immune-related genes and patient selection for hepatocellular carcinoma immunotherapy

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