Prognostic and clinicopathological significance of transcription factor c-Jun in hypopharyngeal squamous cell carcinoma: a 3-year follow-up retrospective study

Huang, Qiang; Ye, Min; Li, Feiran; Lin, Lan; Hu, Chunyan

doi:10.1186/s12885-022-10113-5

Cited by 4 publications

(6 citation statements)

References 18 publications

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“…This may indicate direct inhibition of transcription factor binding is a more efficient target in the c-Jun pathway. Indeed c-Jun is a notable oncogenic driver of multiple cancers [14][15][16], and more recently identified as a prognostic marker in head and neck cancer [17]. Our own interrogation of TCGA found JUN DNA amplification in patients with recurrent and metastatic disease was higher than patients with nonmetastatic, non-recurrent primary tumors.…”

Section: Discussionmentioning

confidence: 74%

“…Activation of c-Jun increases the transcription of target genes that play a role in apoptosis, differentiation, cellular division, proliferation, and cell survival [11,12]. Clinically c-Jun over expression has been noted in non-small cell lung cancers (NSCLCs) [13], vulvar squamous cell carcinoma [14], colorectal cancer [15], Hodgkin lymphoma [16], and recently in HNSCC [17]. Further, c-Jun has been reported to promote metastases and invasion in several tumors including breast, skin, liver, fibrosarcoma and HNSCC [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

Arnold,

Gomez,

Barry

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival. Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient. Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival. Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

Arnold,

Gomez,

Barry

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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“…DNA extracted from FFPE tissue was used to analyze mutations in the DICER1 gene. The specific protocol and reagents used can be referred to in our previous paper 8 …”

Section: Methodsmentioning

confidence: 99%

Pathogenic Somatic Mutation of DICER1 and Clinicopathological Features in Nasal Chondromesenchymal Hamartomas

Hu,

Liu,

Lin

et al. 2024

American Journal of Surgical Pathology

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Nasal chondromesenchymal hamartoma (NCMH) is a rare benign polypoid mesenchymal tumor arising in the nasal cavity and/or paranasal sinuses. Recognizing these sporadic, rare lesions is crucial, as surgical complete removal of the mass is the common treatment approach. This retrospective study analyzed the demographics, symptoms, and imaging data of 9 patients diagnosed with NCMH between January 2017 and June 2023, possibly representing the largest single-center adult case cohort to date. Diagnostic techniques included nasal endoscopy, CT/MRI scan, immunohistological studies, and morphologic comparisons. Pathologic specimens were subjected to Sanger sequencing of exons 24 and 25 of DICER1. The average age of 9 cases was 24.4 years, and the oldest was 55 years. Four of the patients were children, ranging from 1 year old to 11 years old, with an average of 4.5 years. Nasal congestion is the most common registered symptom. Endoscopic findings showed that most patients had smooth pink neoplasms or polypoid masses in the nasal meatus. Radiologic scanning revealed soft-tissue density masses that occupied the nasal cavity. Histologically, the characteristic structure of NCMHs is immature cellular cartilage nodules and mature cartilage nodules distributed in a loose mucoid matrix. Five of the 9 patients had somatic DICER1 missense mutations. Four of the patients with DICER1-mutated NCMH exhibited a p.E1813 missense hotspot mutation. We also report a case of a rare p.P1836H missense mutation. The detected DICER1 somatic mutations provide compelling evidence of an association with the DICER1 tumor family. We emphasize the importance of pathologic consultation and the need for pathologists to accumulate experience in NCMH diagnosis to avoid misdiagnosis.

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“…In HNSCC, increased nuclear pSTAT3 was shown to correlate with a dismal prognosis [30], and constitutive STAT3 activation is described as an early event in HNSCC development [31]. Moreover, high expression levels of c-JUN and p-c-JUN correlate with poor overall survival in hypopharyngeal squamous cell carcinoma [32]. Although these observations associate the expression of these factors with malignancy in HNSCCs, they do not prove their direct implication in cell self-renewal or any other malignant functions, as aggressive tumor stem-like cells may produce substantial amounts of differentiated bulk progeny.…”

Section: Hnscc Cells Recapitulate Controlled Stem Cell Differentiationmentioning

confidence: 99%

Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy

Oppel,

Gendreizig,

Martinez-Ruiz

et al. 2023

Preprint

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Head and neck squamous cell carcinomas harbor areas of differentiated tissue known as keratin pearls. Using defined cell culture conditions, we modeled this terminal differentiation by cornification in a primary tumor spheroid model leading to increased cell adhesion, proliferation stop, and diminished tumor-initiating potential. RNA-seq, ATAC-seq, and proteome analysis revealed chromatin closure and a wound healing-associated signaling program via STAT3, SMAD2/3, C/EBPβ, c-JUN and other effectors associated with increased expression of KRT17 and cornification markers including SPRR3. Although KRT17 represents a basal stem-cell marker in normal mucosa, we confirm KRT17 as differentiation marker in human HNSCC tissue. Moreover, we describe a common tissue architecture in normal mucosa and HNSCC tissue with distinct cell differentiation states transitioning from a proliferating basal-like compartment to a wound healing-associated signaling zone to a cornifying core. Thus, our data indicate that the targeted differentiation of HNSCC cells may be a promising strategy for anti-HNSCC therapy.

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Prognostic and clinicopathological significance of transcription factor c-Jun in hypopharyngeal squamous cell carcinoma: a 3-year follow-up retrospective study

Cited by 4 publications

References 18 publications

Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

Pathogenic Somatic Mutation of DICER1 and Clinicopathological Features in Nasal Chondromesenchymal Hamartomas

Inducible mucosa-like differentiation of head and neck cancer cells drives the epigenetically determined loss of cell malignancy

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