#OVERGROWTH FREE 209 VERIFICATION#
Therefore, identification and verification of new biomarkers and therapeutic targets for HNSCC are paramount and urgent to improve treatment outcome. Although intensive efforts have been made to unravel the genetic and environmental factors driving HNSCC tumorigenesis, however, mechanistic understanding about HNSCC tumorigenesis still remains far from complete.
Locoregional relapse, cervical lymph node metastasis and therapeutic resistance are recognized as the prevalent factors affecting patient prognosis. Despite tremendous advancement in multimodal therapies against HNSCC over the past decades, however, the long-term survival rate for these devastating diseases, especially for patients with advanced diseases, has not been markedly improved.
The major etiological risks for this malignancy include smoking abuse, alcohol consumption, betel quid chew and human papillomavirus (HPV) infection. Head neck squamous cell carcinoma (HNSCC) is the sixth most common cancers and one of the leading cancer-related death worldwide. Our findings indicate that pharmacological inhibition of Bmi1 is a novel therapeutic strategy for HNSCC patients, especially with those with aberrant Bmi1 overexpression. Importantly, in vivo PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model probably by Bmi1 inhibition and impaired cell proliferation. Moreover, PTC-209 exposure reduced colony formation, tumorsphere formation and the percentage of ALDH1 + subpopulation in both Cal27 and FaDu cells. PTC-209 treatment resulted in impaired cell proliferation, G1-phase cell cycle arrest, compromised migration and invasiveness, and increased cell apoptosis and chemosensitivity to 5-FU and cisplatin in vitro. Our data revealed that PTC-209 robustly reduced the expression of Bmi1 in Cal27 and FaDu cells presumably by post-transcriptional repression and ubiquitin-proteasomal degradation. Through comprehensive data mining and interrogation, we found that Bmi1 mRNA was frequently overexpressed in a subset of HNSCC samples. Moreover, the therapeutic effects of PTC-209 for HNSCC were determined in a xenograft animal model.
The phenotypical changes of HNSCC cells were observed upon PTC-209 treatment in vitro. The PTC-209, a selective and potent Bmi1 inhibitor, was exploited and its effect on Bmi1 expression was measured in two HNSCC cell lines Cal27 and FaDu. The mutation pattern, mRNA level of Bmi1 in HNSCC and its associations with clinicopathological parameters were determined through comprehensive data mining and interrogation using publicly available databases GENT, cBioPortal, Oncomine and TCGA. Here we sought to determine the therapeutic efficiency of PTC-209, a potent and selective Bmi1 inhibitor, in head neck squamous cell carcinoma (HNSCC) cells and a HNSCC xenograft model. Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) contributes to human tumorigenesis via epigenetic transcriptional silencing and represents a novel therapeutic target with great potentials.
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