Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma

Lv, Duoduo; Chen, Liyu; Du, Lingyao; Zhou, Lingyun; Tang, Hong

doi:10.3389/fcell.2021.691410

Cited by 16 publications

(15 citation statements)

References 152 publications

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“…The biological mechanism of hepatocarcinogenesis and its progression are complex. Accumulating evidence indicates the significance of liver cancer stem cells (LCSCs), which are small-population liver cancer cells with the potential for self-renewal and tumorigenicity, in tumorigenesis, recurrence, and metastasis [4,5]. Despite numerous studies having revealed the molecular basis for LCSCs, which includes genetic mutations, epigenetic disruption, signaling pathway dysregulation, and/or microenvironment remodeling [5], none of them have brought about an effective solution for eradicating LCSCs.…”

Section: Introductionmentioning

confidence: 99%

“…For example, glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has drastically inhibited the tumorigenicity and sorafenib resistance of LCSCs [16]. However, the plasticity of its metabolic phenotype is the main obstacle in targeting LCSCs [4,5]. Therefore, the energy sources for LSCSs, other than the metabolic phenotypes, need to be better understood.…”

Section: Introductionmentioning

confidence: 99%

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KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism

Fan

Tian

Yang

et al. 2022

IJMS

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The presence of liver cancer stem cells (LCSCs) is one of the reasons for the treatment failure of hepatocellular carcinoma (HCC). For LCSCs, one of their prominent features is metabolism plasticity, which depends on transporters and ion channels to exchange metabolites and ions. The K+ channel protein KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) has been reported to promote cell metabolism and malignant progression of HCCs, but its influence on LCSC stemness has remained unclear. Here, we demonstrated that KCNN4 was highly expressed in L-CSCs by RT-PCR and Western blot. Then, we illustrated that KCNN4 promoted the stemness of HC-C cells by CD133+CD44+ LCSC subpopulation ratio analysis, in vitro stemness transcription factor detection, and sphere formation assay, as well as in vivo orthotopic liver tumor formation and limiting dilution tumorigenesis assays. We also showed that KCNN4 enhanced the glucose metabolism in LCSCs by metabolic enzyme detections and seahorse analysis, and the KCNN4-promoted increase in LCSC ratios was abolished by glycolysis inhibitor 2-DG or OXPHOS inhibitor oligomycin. Collectively, our results suggested that KCNN4 promoted LCSC stemness via enhancing glucose metabolism, and that KCNN4 would be a potential molecular target for eliminating LCSCs in HCC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism

Fan

Tian

Yang

et al. 2022

IJMS

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“…Moreover, several stemness-associated signaling pathways, such as Wnt/β-catenin signaling, Notch signaling, and JAK/STAT signaling, also greatly contribute to stemness properties in HCC [39]. In HCC, stemness properties are closely associated with drug resistance, tumor metastasis, and recurrence [39]. Stemness properties are closely associated with the EMT phenotype, which was previously reported to contribute to sorafenib resistance in HCC [40,41].…”

Section: Discussionmentioning

confidence: 96%

“…The maintenance of stemness properties relies on the activation of stemness-associated genes, such as Sox2, OCT4, and Nanog [38]. Moreover, several stemness-associated signaling pathways, such as Wnt/β-catenin signaling, Notch signaling, and JAK/STAT signaling, also greatly contribute to stemness properties in HCC [39]. In HCC, stemness properties are closely associated with drug resistance, tumor metastasis, and recurrence [39].…”

Section: Discussionmentioning

confidence: 99%

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

et al. 2022

Pharmaceutics

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Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial–mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC.

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“…The poor prognosis and response to therapy of HCC is in part due to the presence of cancer stem cells (CSCs), an immune-privileged cell population that can evade immune surveillance more effectively than non-CSCs (6,7). Liver cancer stem cells (LCSCs) are a subset of hepatocarcinoma cells with pluripotent and self-renew properties which are related to the major malignant phenotypes of HCC (8)(9)(10). The expression of CSC-related genes such as NANOG, SOX2 and OCT4 can be promoted by oncogenes and/or Original Article Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells overexpression of oncoproteins such as the HBV envelope protein PreS1, thereby driving the malignant biological behaviors of LCSCs (11).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells

Li¹,

Gu²,

Liu³

et al. 2022

Transl Cancer Res TCR

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Background: Lysyl oxidase-like 2 (LOXL2) plays a role in tumor microenvironment formation and metastasis of hepatocellular carcinoma (HCC), which has a high mortality burden. Liver cancer stem cells (LCSCs) are related with the major malignant phenotypes of HCC. The function of LOXL2 in regulation of LCSCs remains unknown. Methods: CD133 + HepG2 and CD133 + Hep3B cells were sorted by fluorescence-activated cell sorting (FACS) from two human hepatoblastoma cell lines. Spheroid formation, apoptosis, cell cycle, as well as transwell assays were performed upon LOXL2 knockdown in CD133 + HepG2 and CD133 + Hep3B cells. Protein and mRNA levels were quantified by Western blotting, immunofluorescence and reverse transcription-PCR (RT-PCR). Results: Knockdown of LOXL2 decreased spheroid formation, migration and invasion (P<0.05), also induced apoptosis (P<0.05) and cell cycle arrest (P<0.05) in CD133 + HepG2 and CD133 + Hep3B cells. Knockdown of LOXL2 effectively inhibited expression of the anti-apoptosis proteins baculoviral inhibitor of apoptosis protein (IAP) repeat-containing 3 (BIRC3) and murine double minute 2 (MDM2) (P<0.01), as well as autophagy marker microtubule-associated protein 1 light chain 3 B (LC3B) and autophagy gene ATG5 in CD133 + HepG2 and CD133 + Hep3B cells (P<0.01). Conclusions:The results revealed that LOXL2 inhibition could reduce the proliferation and expansion of LCSCs, making LOXL2 inhibitors an attractive and novel therapeutic strategy of HCC.

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Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma

Cited by 16 publications

References 152 publications

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism

KCNN4 Promotes the Stemness Potentials of Liver Cancer Stem Cells by Enhancing Glucose Metabolism

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells

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