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Cited by 239MicroRNA in disease regulationProteoglycans and glycosaminoglycans researchHead and Neck Cancer Studies

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Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells

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Bourguignon, L Y W, Earle, C, Wong, G, Spevak, C C, Krueger, K·2012·Oncogene
DOI 10.1038/onc.2011.222PMC PMC3179812
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Abstract

MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC.

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Crossref · 10.1038/onc.2011.222

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  • STAT3 directly activates MIR21 and MIR181b-1.

    “It is reported that the STAT3 directly activates MIR21 and MIR181b-1, respectively, suppressing the targets phosphatase and tensin homolog (PTEN) and CYLD (CYLD lysine 63 deubiquitinase) tumor suppressors [83,84].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [84]

    The Results section reports that Nanog-associated STAT3 binds the miR-21 promoter in HSC-3 cells following HA–CD44 interaction, supporting the miR-21 part of the claim. Our copy does not establish STAT3 activation of MIR181b-1 or suppression of CYLD or PTEN; it identifies PDCD4 as the miR-21 target instead. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MIR21 suppresses PTEN and MIR181b-1 suppresses CYLD.

    “It is reported that the STAT3 directly activates MIR21 and MIR181b-1, respectively, suppressing the targets phosphatase and tensin homolog (PTEN) and CYLD (CYLD lysine 63 deubiquitinase) tumor suppressors [83,84].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [84]

    The Introduction and Results identify PDCD4 as a tumor suppressor inhibited by miR-21, and the Abstract reports that inhibiting miR-21 increases PDCD4 expression. Searches for PTEN and for miR-181b-1/CYLD found no passage in our copy addressing either claimed pairing. The PDCD4 finding does not rule out those pairings, but it does not verify them. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Citations

Cites

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    Background

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Metadata

Authors
Bourguignon, L. Y. W., Earle, C., Wong, G., Spevak, C. C., & Krueger, K.
Affiliations
San Francisco VA Medical Center (US)
Corresponding author
Bourguignon, L Y W
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2011-06-20
Volume
31
Issue
2
Pages
149-160
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2011.222
PMC
PMC3179812
OpenAlex
W1985908128
Cited by
239
References
1
Citations by year
2025: 9 · 2024: 9 · 2023: 14 · 2022: 10 · 2021: 15 · 2020: 19 · 2019: 15 · 2018: 17 · 2017: 17 · 2016: 28 · 2015: 19 · 2014: 33 · 2013: 21 · 2012: 11
FWCI
7.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • University of Michigan
  • National Cancer Institute (R01CA066163, R01CA078633, R01 CA 78633, R01 CA 66163)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P01 AR39448, R01AR050023, P01AR039448)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
Keywords
head and neck squamous cell carcinoma, hyaluronic acid, CD44, Nanog, STAT3 signaling, miR-21, chemoresistance, PDCD4, inhibitor of apoptosis proteins, cancer stem cells, anti-miR-21, HSC-3 cells
MeSH terms
Nanog Homeobox Protein, Carcinoma, Squamous Cell, Cell Nucleus, Head and Neck Neoplasms, Humans, Hyaluronic Acid, Promoter Regions, Genetic, Signal Transduction, Homeodomain Proteins, Hyaluronan Receptors, Drug Resistance, Neoplasm, MicroRNAs, Cell Line, Tumor, STAT3 Transcription Factor

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