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Cited by 128Hepatocellular Carcinoma Treatment and PrognosisCytokine Signaling Pathways and InteractionsEpigenetics and DNA Methylation

DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation

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Lai, Ssu-Chuan, Su, Yu-Ting, Chi, Ching-Chi, Kuo, Yung-Che, Lee, Kam-Fai, Wu, Yu-Chih, Lan, Pei-Chi, Yang, Muh-Hwa +2 more·2019·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-019-1442-2PMC PMC6878666
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Abstract

Background: The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. Methods: HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. Results: We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. Conclusions: The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b–mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

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  • Increased serum IL-6 level and activated IL-6/STAT3 signaling are highly associated with early tumor recurrence and poor prognosis of HCC patients.

    “In the event of hepatocarcinogenesis and progression, increased serum IL-6 level and activated IL-6/STAT3 signaling is highly associated with early tumor recurrence and poor prognosis of HCC patients [61].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [61]

    The Results section reports that, among 144 HCC patients, higher serum IL-6 was associated with poorer overall survival and more early tumor recurrence. The paper also links IL-6/STAT3 activation to OCT4 expression, but the cited passages do not establish a direct association between measured STAT3 activation in patients and those clinical outcomes. (LLM, conf=0.84)

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Authors
Lai, S.-C., Su, Y.-T., Chi, C.-C., Kuo, Y.-C., Lee, K.-F., Wu, Y.-C., Lan, P.-C., Yang, M.-H., Chang, T.-S., & Huang, Y.-H.
Affiliations
  • Taipei Medical University (TW)
  • Chang Gung University (TW)
  • Chang Gung Memorial Hospital (TW)
  • Taipei Veterans General Hospital (TW)
  • Taipei Medical University Hospital (TW)
Corresponding author
  • Chang, Te-Sheng
  • Huang, Yen-Hua
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2019-11-26
Volume
38
Issue
1
Pages
10-10
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-019-1442-2
PMC
PMC6878666
OpenAlex
W2991450463
Cited by
128
References
1
Citations by year
2026: 6 · 2025: 13 · 2024: 21 · 2023: 34 · 2022: 27 · 2021: 14 · 2020: 13
FWCI
8.59
Type
journal article
Language
en
Update notices
correction (2020-01-13)
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Science and Technology (MOST 105-2628-B-038-008-MY3, MOST 106-3114-B-038-001, MOST 107-2321-B-038-002, MOST 107-2314-B-038-057, MOST108-2321-B-038-003)
  • Ministry of Education (DP2-107-21121-01-T-02, DP2-108-21121-01-T-02-02)
  • Chiayi Chang Gung Memorial Hospital (CORPG6F0053, CMRPG6F0163)
  • Taipei Medical University (TMU-T104-06, TMU-T105-06, 105TMU-CIT-01-3, TMU-T106-03)
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
hepatocellular carcinoma, DNMT3B, Oct4, sorafenib resistance, interleukin-6, STAT3, DNA methylation, DNMT1, nanaomycin A, ALDH activity, tumor recurrence, prognosis, combination therapy, epigenetic regulation, drug resistance, stem cells, Hep3B cells, xenograft models, cytokine signaling
MeSH terms
Sorafenib, DNA Methyltransferase 3B, Animals, Antineoplastic Agents, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferases, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Prognosis, Interleukin-6, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Cell Line, Tumor, STAT3 Transcription Factor, Octamer Transcription Factor-3, Mice, Hep G2 Cells, Heterografts

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