miR‐9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC

Citron, Francesca; Segatto, Ilenia; Musco, Lorena; Pellarin, Ilenia; Vinciguerra, Gian Luca Rampioni; Franchin, Giovanni; Fanetti, Giuseppe; Miccichè, Francesco; Giacomarra, Vittorio; Lupato, Valentina; Favero, Andrea; Concina, Isabella; Srinivasan, Sanjana; Avanzo, Michele; Castiglioni, Isabella; Barzan, Luigi; Sulfaro, Sandro; Petrone, Gianluigi; Viale, Andrea; Draetta, Giulio; Vecchione, Andrea; Belletti, Barbara; Baldassarre, Gustavo

doi:10.15252/emmm.202012872

Cited by 20 publications

(15 citation statements)

References 51 publications

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“…Interestingly, a higher expression of miR-9-3p has been shown to correlate with the presence of vascular and perineural invasion, whereas the overexpression of miR-9-5p has been associated with longer survival in sinonasal SCC patients [ 189 ]. A recent study has also proposed that miR-9 may represent a valuable predictive biomarker of the response to radio-chemotherapy, since high miR-9 expression appeared to be associated with poor prognosis in HNSCC patients treated with RT+CTX (radiotherapy combined with the anti-EGFR monoclonal antibody cetuximab) [ 198 ].…”

Section: The Role Of the Most Common Mirnas In Hncmentioning

confidence: 99%

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

Thomaidou

Batsaki

Adamaki

et al. 2022

IJMS

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Head and neck cancers (HNCs) comprise a heterogeneous group of tumors that extend from the oral cavity to the upper gastrointestinal tract. The principal etiologic factors for oral tumors include tobacco smoking and alcohol consumption, while human papillomavirus (HPV) infections have been accused of a high incidence of pharyngeal tumors. Accordingly, HPV detection has been extensively used to categorize carcinomas of the head and neck. The diverse nature of HNC highlights the necessity for novel, sensitive, and precise biomarkers for the prompt diagnosis of the disease, its successful monitoring, and the timely prognosis of patient clinical outcomes. In this context, the identification of certain microRNAs (miRNAs) and/or the detection of alterations in their expression patterns, in a variety of somatic fluids and tissues, could serve as valuable biomarkers for precision oncology. In the present review, we summarize some of the most frequently studied miRNAs (including miR-21, -375, -99, -34a, -200, -31, -125a/b, -196a/b, -9, -181a, -155, -146a, -23a, -16, -29, and let-7), their role as biomarkers, and their implication in HNC pathogenesis. Moreover, we designate the potential of given miRNAs and miRNA signatures as novel diagnostic and prognostic tools for successful patient stratification. Finally, we discuss the currently ongoing clinical trials that aim to identify the diagnostic, prognostic, or therapeutic utility of miRNAs in HNC.

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Section: The Role Of the Most Common Mirnas In Hncmentioning

confidence: 99%

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

Thomaidou

Batsaki

Adamaki

et al. 2022

IJMS

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“…1C and S 1A, B ). EGFR is known to activate downstream targets through phosphorylation of ERK1/2 (p-ERK1/2) in HNSCC [ 31 ]. Therefore, the levels of p-ERK1/2 was determined by Western blot, EGFR-overexpressing cells showed less ERK1/2 activation at a lower concentration of EGF compared to the controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, miR-9-5p inhibits NOX4 and suppresses TGF-β1-induced phenotypic transformation of fibroblasts in vitro and potentially leading to a better therapeutic response in HPV-positive HNSCC patients [ 30 ]. There is also evidence of miR-9-5p having an oncogenic activity; EGFR activation has been suggested to upregulate miR-9-5p in HPV-negative HNSCC and high miR-9-5p expression is associated with poor patient prognosis [ 31 ]. Regulation of BRD4 by the microRNA has been previously demonstrated in neonatal rat ventricular myocytes [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

EGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma

et al. 2022

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EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome.

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“…The use of microRNA levels as biomarkers for disease progression or in the prediction for therapy response is emerging [13,14]. In the present study, we compared the expression levels of selected miRNAs with BCVA and central area thickness (CAT) at baseline and after 3 and 6 months of anti-VEGF therapy.…”

Section: Discussionmentioning

confidence: 99%

“…The use of microRNA levels in circulation to predict therapy efficacy has previously been established in rheumatoid arthritis patients treated with anti-TNFα [13], and in the prediction of the response to radiotherapy in head and neck squamous cell carcinoma patients [14]. In the current study, we investigated whether miRNA levels in the circulation at baseline could serve as a biomarker for the responsiveness to anti-VEGF therapy in patients with diabetic macular edema.…”

Section: Introductionmentioning

confidence: 98%

miRNA Levels as a Biomarker for Anti-VEGF Response in Patients with Diabetic Macular Edema

Vader

Habani

Schlingemann

et al. 2021

JPM

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Background: The aim of this study was to investigate whether miRNA levels in the circulation could serve as a predictive biomarker for responsiveness to anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema. Methods: Whole blood samples were collected at baseline from 135 patients who were included in the BRDME study, a randomized controlled comparative trial of monthly bevacizumab or ranibizumab treatment for 6 months in patients with diabetic macular edema (Trialregister.nl, NTR3247). Best corrected visual acuity letter score (BCVA) and retinal central area thickness (CAT) were measured monthly during the 6-month follow-up. Levels of selected miRNAs were quantified. Results: Following linear regression analysis, the levels of four miRNAs were negatively associated with baseline CAT. Multivariable regression analysis confirmed this association for miR-181a. No associations with changes in CAT after 3 or 6 months of anti-VEGF treatment were found. In addition, no associations with miRNA levels with baseline BCVA or change in BCVA after 3 or 6 months of anti-VEGF treatment were found. Conclusions: Circulating miR-181a levels were negatively associated with CAT at baseline. However, no associations between miRNA levels and the response to anti-VEGF therapy were found.

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miR‐9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC

Cited by 20 publications

References 51 publications

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

EGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma

miRNA Levels as a Biomarker for Anti-VEGF Response in Patients with Diabetic Macular Edema

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