Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies

Wang, Nuozhou; Wang, Shanshan; Li, Mingyue; Hu, Baoguang; Liu, Liping; Yang, Shengli; Yang, Shengsheng; Gong, Zhongqin; Lai, Paul; Chen, George G.

doi:10.1177/1758835918816287

Cited by 90 publications

(78 citation statements)

References 213 publications

(274 reference statements)

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“…We also showed that PDK1-dependent IR-resistance is associated with the enhanced metastatic and CSCs-like phenotypes of HCC cells (Figure 4 and Supplementary Figure S3). This is consistent with contemporary knowledge that CSCs-like cells exhibit increased resistance to chemo-and radiotherapy compared to their non-CSCs counterparts in same tumor niche [32], even as cells undergoing EMT have been shown to exhibit resistance to genotoxic stress mediated by conventional radio-and chemotherapy [33,34], thus, linking resistance with CSCs-like and EMT-phenotypes. In fact, it was recently suggested that the acquisition of EMT and CSCs phenotypes is linked with the activation of PI3K/AKT/mTOR signaling in IR-resistant prostate cancer cells [11].…”

Section: Discussionsupporting

confidence: 90%

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

Bamodu

Chang

Ong

et al. 2020

Cells

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Resistance to radiotherapy (IR), with consequent disease recurrence, continues to limit the efficacy of contemporary anticancer treatment for patients with hepatocellular carcinoma (HCC), especially in late stage. Despite accruing evidence implicating the PI3K/AKT signaling pathway in cancer-promoting hypoxia, cancerous cell proliferation and radiotherapy-resistance, it remains unclear which molecular constituent of the pathway facilitates adaptation of aggressive HCC cells to tumoral stress signals and drives their evasion of repeated IR-toxicity. This present study investigated the role of PDK1 signaling in IR-resistance, enhanced DNA damage repair and post-IR relapse, characteristic of aggressive HCC cells, while exploring potential PDK1-targetability to improve radiosensitivity. The study employed bioinformatics analyses of gene expression profile and functional protein-protein interaction, generation of IR-resistant clones, flow cytometry-based ALDH activity and side-population (SP) characterization, siRNA-mediated loss-of-PDK1function, western-blotting, immunohistochemistry and functional assays including cell viability, migration, invasion, clonogenicity and tumorsphere formation assays. We showed that the aberrantly expressed PDK1 characterizes poorly differentiated HCC CVCL_7955, Mahlavu, SK-HEP1 and Hep3B cells, compared to the well-differentiated Huh7 or normal adult liver epithelial THLE-2 cells, and independently activates the PI3K/AKT/mTOR signaling. Molecular ablation of PDK1 function enhanced susceptibility of HCC cells to IR and was associated with deactivated PI3K/AKT/mTOR Cells 2020, 9, 746 2 of 19 signaling. Additionally, PDK1-driven IR-resistance positively correlated with activated PI3K signaling, enhanced HCC cell motility and invasiveness, augmented EMT, upregulated stemness markers ALDH1A1, PROM1, SOX2, KLF4 and POU5F1, increased tumorsphere-formation efficiency and suppressed biomarkers of DNA damage-RAD50, MSH3, MLH3 and ERCC2. Furthermore, the acquired IR-resistant phenotype of Huh7 cells was strongly associated with significantly increased ALDH activity, SP-enrichment, and direct ALDH1-PDK1 interaction. Moreover, BX795-mediated pharmacological inhibition of PDK1 synergistically enhances the radiosensitivity of erstwhile resistant cells, increased Bax/Bcl-2 apoptotic ratio, while suppressing oncogenicity and clonogenicity. We provide preclinical evidence implicating PDK1 as an active driver of IR-resistance by activation of the PI3K/AKT/mTOR signaling, up-modulation of cancer stemness signaling and suppression of DNA damage, thus, projecting PDK1-targeting as a putative enhancer of radiosensitivity and a potential new therapeutic approach for patients with IR-resistant HCC.

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Section: Discussionsupporting

confidence: 90%

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

Bamodu

Chang

Ong

et al. 2020

Cells

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“…It is currently believed that the drug resistance pattern of OXA in HCC is mainly related to apoptosis escape, autophagy activation, drug excretion, and enhanced epigenetic transformation to HCC stem cells [25][26][27][28][29]. The EMT process is involved in most models [22,[30][31][32].…”

Section: Rbm8a (Y 14)mentioning

confidence: 99%

Mechanism and molecular network of RBM8A-mediated regulation of oxaliplatin resistance in hepatocellular carcinoma via EMT

Lin

Liang

Zhang

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) has been shown to be closely associated with Oxaliplatin (OXA) resistance. Previous study found that RBM8A is highly expressed in HCC and induce EMT, suggesting that it may be involved in the regulation of OXA resistance in HCC. However, the accurate mechanism has not been concluded. In our study, ectopic expression and silencing of RBM8A were performed to explore its function. The OXA resistance potential of RBM8A and its downstream pathway was investigated using in vitro and in vivo models. The results showed that RBM8A overexpression induced EMT in OXA-resistant HCC cells, thereby affecting cell proliferation, apoptosis, migration, and invasion and promoting OXA resistance in vivo and in vitro. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in drug-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. Histone deacetylase 9 (HDAC9) is an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathway represent potential markers of OXA resistance and therapeutic targets in HCC. BackgroundHepatocellular carcinoma (HCC) is a highly lethal cancer; although it has the sixth highest incidence of malignant tumors globally, its mortality rate ranks second among all cancers [1]. The advent of the molecularly targeted drug sorafenib has opened the door to advanced HCC drug therapies, but the objective response rate (ORR) and progression-free survival (PFS) for first-line therapies are limited and expensive to administer[2]. HCC is extremely complicated and refractory, and the difficulty in successfully treating it also highlights the necessity and importance of multiple methods and multidisciplinary comprehensive treatments, including systemic chemotherapy.The EACH trial and subsequent basic experiments and clinical trials have confirmed that OXA-based systemic chemotherapy for Asian patients with advanced HCC can improve the objective efficiency and has good tolerance and safety, a high cost-effectiveness ratio and easy clinical promotion; therefore, OXA is recognized as the most effective chemotherapy for HCC [3,4]. Even so, the effectiveness of OXA against HCC is still less than 20%, which is unsatisfactory. OXA resistance has 4 become a tremendous obstacle in the treatment of HCC. Identifying key targets affecting oxaliplatin resistance and its related signaling pathways and understanding their mechanism of action have become key issues to be solved urgently.Epithelial-mesenchymal transition (EMT) refers to the biological process by which epithelial cells gradually lose cell-cell adhesions and undergo a specific transformation to obtain characteristics of a strong mesenchymal phenotype, such as movement and migration; this process is closely related to the occurrence and development of a variety of tumors [5]. Ma et al.[6] reported that OXA-resistant HCC cells sh...

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“…Cancer stem cells are tumour cells with the ability to self-replicate and differentiate into solid tumours, including HCC 3 , and express known stem cell markers, such as CD133 in glioma, CD44 and CD24 in breast cancer and OV-6 in HCC [5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Correlation between cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis

Lin

Kuo

et al. 2020

Preprint

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Aims: Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process characterised by chronic inflammation and hepatocyte damage but the correlation between HCC, inflammation and cancer stem cell remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. Methods and results:We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining, and also immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between each other. DEN progressively induced inflammation at 7 week 7 (40%, 2/5), week 27 (75%, 6/8), week 33 (62.5%, 5/8) and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5), week 27 (87.5%, 7/8), week 33 (100%, 8/8) and week 50 (100%, 12/12). Data obtained showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5), week 27 (37.5%, 3/8), week 33 (50%, 4/8) and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver as shown above and applying Spearman's correlation to the data showed that expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001) Conclusions:There was a significant correlation between number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster. 4

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Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies

Cited by 90 publications

References 213 publications

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

Mechanism and molecular network of RBM8A-mediated regulation of oxaliplatin resistance in hepatocellular carcinoma via EMT

Correlation between cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis

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