Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

Méndez-Blanco, Carolina; Fondevila, Flavia; Fernández-Palanca, Paula; García‐Palomo, Andrés; Pelt, Jos van; Verslype, Chris; González‐Gallego, Javier; Mauriz, José L.

doi:10.3390/cancers11121984

Cited by 28 publications

(27 citation statements)

References 65 publications

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“…27 Research has reported that anti-CDK1 treatment can enhance sorafenib antitumor responses in a patientderived tumor xenograft model by targeting CSCs, revealing the direct effects of CSCs on sorafenib resistance. 28 Studies have shown that hypoxia can induce sorafenib resistance, 29 and it was found that hypoxia may increase the HCC CSC population by altering androgen receptor/miR-520f-3p/SOX9 signaling. 30 Combined sorafenib with silibinin significantly decreased the growth and induced the apoptosis of HCC cells with enhanced inhibition of the STAT3/ERK/ATK pathways by targeting CSCs.…”

Section: Discussionmentioning

confidence: 99%

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Liu¹,

Chen²,

Han³

et al. 2020

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Background: Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive. Methods: In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, β-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC. Results: The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial-mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib. Conclusion: LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.

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Section: Discussionmentioning

confidence: 99%

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Liu¹,

Chen²,

Han³

et al. 2020

OTT

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“…These effects potentiated tumor cell apoptosis (with increases on Bax expression and PARP hydrolysis) and were also associated with the reduction of tumor cell proliferation [ 18 ]. Conversely, under hypoxia conditions, which is a known phenotype associated with chemotherapy failure [ 74 ], mitophagy acted as a cytoprotective mechanism in HCC tumor cells. Thus, in Hep3B cells under hypoxia, it has been demonstrated that co-administration of 2 mM melatonin blocks the cytoprotective mitophagy induced by the hypoxic microenvironment after 5 mM sorafenib treatment; this blockage seems to be associated with the downregulation of the hypoxia inducible factor-1α (HIF-1α) through the inhibition of the mTOR complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway [ 4 ].…”

Section: Resultsmentioning

confidence: 99%

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

et al. 2021

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Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.

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“…HCC cells (SNU-182 and HUH7) were obtained from the American Type Culture Collection (Manassas, VA, USA) and routinely cultured in Roswell Park Memorial Institute 1640 (for SNU-182 cells) or Dulbecco's Modified Eagle's Medium (for HUH7 cells) supplemented with 10% fetal bovine serum, 100 U/mL of penicillin, and 100 mg/mL of streptomycin (Hyclone Laboratories, Inc., South Logan, UT, USA) under an atmosphere of 5% CO 2 at 37 • C. As a model for hypoxia, SNU-182 and HUH7 cells were cultured under an atmosphere of 1% O 2 /5% CO 2 /94% N 2 for 24 h. we also treated cells with CoCl 2 , a hypoxia mimetic agent (14), to simulated hypoxia. The CoCl 2 treatment performed under normoxic condition.…”

Section: Cell Culture and Hypoxic Conditionsmentioning

confidence: 99%

Hypoxia-Induced lncRNA-NEAT1 Sustains the Growth of Hepatocellular Carcinoma via Regulation of miR-199a-3p/UCK2

et al. 2020

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The long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has emerged as a novel player in hepatocellular carcinoma (HCC). Hypoxia is a common characteristic of the microenvironment of HCC. This study aimed to investigate whether lncRNA-NEAT1 is induced by hypoxia in HCC, and the mechanism that underlies LncRNA-NEAT1 function. Methods: The expression changes of lncRNA-NEAT1 in HCC cell lines under hypoxic conditions were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The regulatory effect of HIF-1α on lncRNA-NEAT1 was confirmed with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The function of lncRNA-NEAT1 on HCC cell growth under hypoxic conditions was determined by CCK-8 assay and flow cytometry. lncRNA-NEAT1 was predicted to serve as a competing endogenous RNA (ceRNA) within microRNA (miRNA)/mRNA axes based on microarray data, public HCC-related datasets and integrative bioinformatics analysis, and the miR-199a-3p/UCK2 axis was selected and validated by qRT-PCR, western blotting, RNA immunoprecipitation, and luciferase reporter analyses. The role of miR-199a-3p/UCK2 in HCC and its functional association with lncRNA-NEAT1 were assessed both in vitro and in vivo. Results: LncRNA-NEAT1 expression was significantly induced by hypoxia in SNU-182 and HUH7 cells. HIF-1α was shown to regulate lncRNA-NEAT1 transcription. Under hypoxic conditions, lncRNA-NEAT1 maintained the growth of HCC cells and inhibited apoptosis and cell cycle arrest. LncRNA-NEAT1 was predicted to regulate a panel of HCC-associated miRNA-mRNA pairs consisting of 8 miRNAs and 13 mRNAs. LncRNA-NEAT1 was shown to function as a ceRNA of miR-199a-3p/UCK2 both in HCC cells under hypoxic conditions and in an animal model. Conclusion: LncRNA-NEAT1 is a hypoxia-responsive lncRNA in HCC cell lines Insilico evidence suggested that LncRNA-NEAT1 may sustainthe growth of HCC cells by Zhang et al. LncRNA-NEAT1 in HCC Under Hypoxia regulating HCC-associated mRNAs that interact with tumor-suppressive miRNAs. The lncRNA-NEAT1/miR-199a-3p/UCK2 pathway may contribute to the progression of HCC cell lines in a hypoxic microenvironment and therefore may represent a novel therapeutic target for HCC.

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Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

Cited by 28 publications

References 65 publications

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

<p>IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells</p>

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Hypoxia-Induced lncRNA-NEAT1 Sustains the Growth of Hepatocellular Carcinoma via Regulation of miR-199a-3p/UCK2

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