Extracellular interleukin‐17F has a protective effect in oral tongue squamous cell carcinoma

Almahmoudi, Rabeia; Salem, Abdelhakim; Sieviläinen, Meri; Sundquist, Elias; Almangush, Alhadi; Toppila‐Salmi, Sanna; Paavonen, Timo; Salo, Tuula; Al‐Samadi, Ahmed

doi:10.1002/hed.25207

Cited by 11 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MCs are multifunctional immune cells that play crucial roles in tumor development and progression [39]. We recently reported that the MC-derived mediator, IL-17F, might be harnessed as a reliable prognostic factor in early-stage OTSCC patients [40]. Furthermore, we showed that MCs and their major granular constituent, histamine, are increased in OPMDs and could probably be involved in oral carcinogenesis [18].…”

Section: Discussionmentioning

confidence: 99%

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Salem

Almahmoudi

Hagström

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown. We, therefore, investigated the role of hBD2–histamine crosstalk signaling in promoting OLP pathology. Biopsies from OLP and oral tongue squamous cell carcinoma (OTSCC) patients, and healthy controls were used. Two OTSCC cell lines and normal human oral keratinocytes (HOKs) were used. HBD-2 and other targets were mapped by immunostaining and analyzed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinically derived and in vitro samples, respectively. H4R was challenged with the specific agonist HST-10 and inverse agonist ST-1007. HBD-2 was highly induced in OLP lesions. In contrast, hBD2 expression was attenuated in OTSCC tissues, while very low levels of hBD-2 messenger RNA (mRNA) were observed in OTSCC cells. Together with tumor necrosis factor-α (TNF-α), histamine upregulated hBD-2 mRNA expression in HOKs. Activation of H4R seems to modulate the expression of epithelial hBD-2. These findings suggest the involvement of hBD-2 in the pathogenesis of OLP and may, thus, be harnessed for therapeutic interventions in OLP.

show abstract

Section: Discussionmentioning

confidence: 99%

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Salem

Almahmoudi

Hagström

et al. 2019

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…We also showed that supernatants from activated human MCs were able to downregulate oral oncogenes [23]. Moreover, we found that MC-derived extracellular IL-17F was associated with better overall survival of OTSCC patients [19]. Here, we further demonstrate that IL-17F reduced highly aggressive oral tongue cancer (HSC-3) cell proliferation and random migration.…”

Section: Discussionmentioning

confidence: 51%

“…However, to the best of our knowledge, there is no data concerning IL-17F concentrations in tissue. We assume that it is higher than in serum since it is produced by stromal cells, such as MCs [13,19]. Based on this assumption, we tested the effect of low-level (1 ng/mL) IL-17A and IL-17F on HUVEC cell angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…These cytokines are secreted by several cell types, such as CD4+ T lymphocytes, mast cells (MCs), and natural killer cells [13,14]. IL-17F, the newest member of the IL-17 family that shares the greatest homology with IL-17A, was reported to provide protective effects against several types of cancer, such as oral, colon, and hepatocellular carcinoma [15,16,17,18,19]. It is believed that this anti-tumor effect is mediated via different and complex mechanisms, including influencing cell cycle arrest and inhibition of angiogenesis [15,17,20].…”

Section: Introductionmentioning

confidence: 99%

“…It is believed that this anti-tumor effect is mediated via different and complex mechanisms, including influencing cell cycle arrest and inhibition of angiogenesis [15,17,20]. Furthermore, we showed in our recent multicenter study that MC-derived extracellular (rather than intracellular) IL-17F at the cancer invasion front correlates with better disease-specific survival in OTSCC patients [19]. However, the mechanisms through which IL-17F imparts such favorable effects in OTSCC remain unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interleukin-17F Has Anti-Tumor Effects in Oral Tongue Cancer

Almahmoudi

Salem

Murshid

et al. 2019

Cancers

Self Cite

View full text Add to dashboard Cite

We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.

show abstract

Evaluation Challenges in the Validation of B7-H3 as Oral Tongue Cancer Prognosticator

Sieviläinen

Wirsing

Hyytiäinen

et al. 2020

Head and Neck Pathol

Self Cite

View full text Add to dashboard Cite

B7-H3 was the only molecule identified with prognostic potential from a recent systematic review of the prognostic value of immune checkpoints in oral cancer. We aimed to validate this finding in a multicenter international cohort. We retrospectively retrieved 323 oral tongue squamous cell carcinoma (OTSCC) samples from three different countries (Brazil, Finland, and Norway) for immunostaining and scoring for B7-H3. We evaluated tumor immunogenicity by analyzing the amount of tumor-infiltrating lymphocytes and divided the tumors into immune hot and cold. To increase the reliability of the results, both digital and manual visual scoring were used. Survival curves were constructed based on the Kaplan-Meier method, and the Cox proportional hazard model was utilized for univariate and multivariate survival analysis. B7-H3 expression was not significantly associated with overall or disease-specific survival in the whole OTSCC cohort. When divided into immune hot and cold tumors, high B7-H3 expression was significantly associated with poor disease-specific and overall survival in the immune hot group, depending on the scoring method and the country of the cohort. This was achieved only in the univariate analysis. In conclusion, B7-H3 was a negative prognosticator for OTSCC patient survival in the subgroup of immune hot tumors, and was not validated as a prognosticator in the full cohort. Our findings suggest that the immune activity of the tumor should be considered when testing immune checkpoints as biomarkers.

show abstract

Extracellular interleukin‐17F has a protective effect in oral tongue squamous cell carcinoma

Cited by 11 publications

References 30 publications

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

Interleukin-17F Has Anti-Tumor Effects in Oral Tongue Cancer

Evaluation Challenges in the Validation of B7-H3 as Oral Tongue Cancer Prognosticator

Contact Info

Product

Resources

About